Insulin Action and Its Disturbances in Disease - part 8 pdf

418 GENETICS OF THE METABOLIC SYNDROME
proposed as a cause of T2DM
42
possibly through an ectopic overload of fatty
acids and lipotoxicity of non-adipose tissues.
167
A role for resistin could there-
fore be envisioned in the prediabetic syndrome of insulin resistance by virtue
of its ability to block adipocyte differentiation.
At the genic level, SNPS in non-coding regions of the human resistin gene
were either not significantly associated with insulin resistance (G1326C in 3

UTR; −167C → T, 157C → T, 299G → A in introns)
168, 169
or associated with
an insulin sensitivity index in the case of a promoter SNP (−394C → G)
170
(Table 13.3). A genetic variant in intron 2, IVS2 + 181G → A, was signifi-
cantly involved in a possible interaction between obesity and the association
between T2DM and the SNP.
171
A study that combined population data from
the Quebec Family Study and the Saguenay-Lac-St-Jean region of Quebec found
two promoter SNPs (−537A → C and −420C → G) to be associated with
increased risk for BMI, but this result was not replicated in a population from
Scandinavia.
172
A trinucleotide (ATG) repeat at the 3

UTR of the gene was,
on the other hand, associated with a decreased risk of insulin resistance.

173
It is
too early at this point to draw any definitive conclusions regarding the role of
resistin in the aetiology of the metabolic syndrome but its proposed physiological
role and early genetic studies suggest a link between resistin and the metabolic
syndrome. However, its effects may be mediated by intermediate factors such
as oxidative stress or population-specific environmental factors.
PC-1
Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyro-
sine kinase activity and subsequent cellular signalling, possibly by inhibiting
the IR by directly interacting with a specific region in the IR α-subunit.
174
IR kinase activity is impaired in muscle, fibroblasts and other tissues of many
patients with T2DM but abnormalities in the insulin receptor gene are not the
cause of this decreased kinase activity. Skin fibroblasts, however, from cer-
tain insulin-resistant patients show increased enzymatic activity by PC-1, while
overexpression of PC-1 in transfected cultured cells reduces insulin-stimulated
tyrosine kinase activity.
175
Using an assay to determine concentrations of cir-
culating PC-1, it was shown that plasma PC-1 of 19 ng/ml or less identified a
cluster of insulin-resistance-related alterations with 75 per cent accuracy, indi-
cating that circulating PC-1 is related to insulin sensitivity.
176, 177
In addition,
women with gestational diabetes mellitus and T2DM have an increased PC-1
content, which could contribute to lower phosphorylation levels of IRS-1. These
post-receptor defects in the insulin signalling pathway are greater in these two
groups of women than in women with normal pregnancy.
178

At the genic level, an SNP (transversion A → C in codon 121) that resulted
in an amino-acid substitution, Lys121Gln, was strongly associated with insulin
resistance
179
(Table 13.3). The same SNP was associated with higher fasting
CANDIDATE GENES 419
Table 13.4 Genome scans and linkages for metabolic syndrome phenotypes
Locus or gene Phenotype(s) LOD score or p-value Reference
2p21 (D2S1788) Leptin levels, fat mass LOD = 4.95 312
3q27 Several indicators LOD = 2.4–3.5 314
17p12 Several indicators LOD = 5.0 314
APO E Weight/fat factor in IR
∗
p-value = 0.01 315
CEPT Lipid factor in IR
∗
p-value = 0.002 315
16p13–pter CHD LOD = 3.06 316
3q27 CHD LOD = 2.13 316
8q23 T2DM, HBP LOD = 2.55 316
6q22–q23 Insulin resistance, obesity LOD = 3.5 183
∗
Insulin resistance.
plasma glucose, higher systolic blood pressure and higher fasting insulin levels
in diabetic patients as well as normal individuals and, therefore, it may not be
enough to increase susceptibility to T2DM.
180
The same SNP (Lys121Gly), how-
ever, was not associated with T2DM among Danish Caucasians.
181

A haplotype
of three SNPs in the 3

UTR of PC-1 (G2897A, G2906C and C2948T) was asso-
ciated with increased PC-1 protein content and insulin resistance in Caucasians
from Sicily
182
(Table 13.3). Furthermore, PC-1 maps to a region on chromosome
6q22–q23 that has been strongly linked to several insulin-resistance-related
phenotypes in Mexican Americans
183
(Table 13.4), which further suggests a
potential role for PC-1 in the aetiology of the metabolic syndrome, possibly in
interaction with genes that contribute to the aetiology of obesity and/or hyper-
tension, using a rather direct pathway of action to inhibit insulin signalling.
PPARγ
Recently, several pedigrees have been described with severe insulin resistance,
diabetes, and peripheral fat wasting. The manifestation of this inherited partial
lipodystrophy syndrome is quite similar to the metabolic syndrome-X, with the
exception that these patients do not respond to the anti-diabetic thiazolidine-
diones (TZDs). These families were found to have mutations in the PPAR-γ
nuclear transcription factor gene at the ligand binding pocket.
184
This results
in impaired activation of gene transcription by the TZDs. PPAR-γ is a ligand-
activated nuclear receptor that regulates adipocyte differentiation and possibly
lipid metabolism and insulin sensitivity.
185
Predominantly expressed in the intes-
tine and adipose tissue, it triggers adipocyte differentiation and promotes lipid

storage.
186
It could therefore play a significant role in the development of the
metabolic syndrome through its ability to stimulate adipocyte differentiation and
prevent lipid spillage to the liver and the muscle (i.e. prevent ectopic lipotoxic-
ity). PPAR-γ and its agonists are subjects of intense investigation as therapeutic
agents for insulin resistance and the metabolic syndrome.
187
Using a gain-of-
function approach, Wang et al. showed that constitutive activation of PPAR-γ
420 GENETICS OF THE METABOLIC SYNDROME
was sufficient to prevent endothelial cells (ECs) from converting into a pro-
inflammatory phenotype, suggesting that genetic modification of the PPAR-γ
activity in ECs may be a potential method for therapeutic intervention in inflam-
matory disorders including the metabolic syndrome.
188
A common polymorphism, Pro12Ala, was associated with adiposity and
insulin resistance
189
and decreased risk of the insulin resistance syndrome
190
(Table 13.3). Newer PPAR-γ ligands with a different structural backbone have
been shown to bypass CGL mutations in vitro.
191
Agarwal and Garg describe
a C to T heterozygous mutation at nucleotide 1273 in exon 6 of the PPAR-γ
gene with a phenotype of lipodystrophy.
192
Although rare, these mutations are
instructive in the sense that the metabolic sequelae are almost identical to the

‘garden-variety’ obesity and illustrate the utility of PPAR-γ agonists in the treat-
ment of the metabolic syndrome. PPAR-γ is therefore a strong candidate gene
for the metabolic syndrome with effects on adipocyte differentiation, as well
as the development of obesity, dyslipidaemia and insulin resistance. Its mode
of action may be indirect by means of regulating the transcriptional activation
of several adipose tissue-specific genes, thus altering adipose tissue mass and
leading to insulin resistance.
β3-adrenoreceptor
Five adrenoreceptors are involved in the adrenergic regulation of fat cell func-
tions: beta1- (β1-), β2-, β3-, alpha1- (α1-) and α2-adrenergic receptors (ADRs).
cAMP production and cAMP-related cellular responses are mediated through
the control of adenyl cyclase activity that is stimulated by β1-, β2-, and β3-
adrenoreceptors while activation of α1-adrenoreceptors stimulates phosphoinosi-
tidase C activity so that a balance among adrenoreceptor subtypes determines
the final effects of physiological amines in adipocytes.
193
The cloning of the human β3-adrenoreceptor (β3-ADR) produced new excite-
ment in the field of obesity because of its thermogenic, anti-obesity and antidi-
abetic activities in animal models.
194
Structurally, the human β3-adrenoreceptor
consists of two coding exons, and the pharmacological properties of the full
length cDNA differ somewhat from those of the truncated receptor.
195
The
human β3-ADR gene is expressed predominantly in infant peripheral brown
adipose tissue (which also expresses the thermogenic mitochondrial uncoupling
protein UCP1), and in adults it is expressed at low levels in deep fat, such as
perirenal and omental, but at much lower levels in subcutaneous fat.
196

It is also
highly expressed in the gallbladder but to a lower extent in the colon, suggesting
a potential role in the control of lipid metabolism and triglyceride storage and
mobilization in adipose tissues.
196, 197
However, doubts about its therapeutic
effects were raised when it was found that β3-ADR is also expressed in human
heart, where agonists for this receptor induce a negative inotropic effect, while
in blood vessels stimulation of β3-ADR produces a vasodilation.
198
CANDIDATE GENES 421
Transcriptionally, β3-ADR is regulated by C/EBP-α through a binding site in
an enhancer cis-acting element at position −3306.
199
Mutational analysis of the
human β3-ADR identified a missense polymorphism that resulted in an amino-
acid substitution, Trp64Arg, that was associated with early onset of T2DM in
the Pima Indians
200
(Table 13.3). The Trp64Arg SNP was also found to con-
tribute significantly to the accumulation of multiple risk factors in male subjects
with hyperuricaemia,
201
modulate the effects of β-blockers on triglyceride and
HDL cholesterol concentrations in an Indo-Mauritian population,
202
predict a
greater tendency to develop abdominal adiposity and high blood pressure,
203
be associated with visceral obesity but lower serum triglyceride

204
and confer
increased sensitivity to the pressor effect of noradrenaline.
205
On the other hand,
the Trp64Arg SNP was not associated with obesity phenotypes in the Quebec
Family Study and Swedish Obese Subjects cohorts,
206
T2DM and features of
the insulin resistance syndrome in a Finnish population
207
or components of the
metabolic syndrome in Chinese subjects.
208
Taken together, the data show inconsistent associations of this SNP with the
metabolic syndrome. The end result may depend on population-specific char-
acteristics such as ethnic origin, diet, exercise and environmental factors, i.e.
gene–gene or gene–environment interactions, that require further investigation.
11β-HSD
The 11beta-hydroxysteroid dehydrogenase (11β-HSD) enzymes convert cortisol
into inactive cortisone and vice versa. There are two isoforms of 11β-HSD:
11β-HSD-1 (mainly localized in the liver), which acts bidirectionally potentially
restoring cortisone into active cortisol, and 11β-HSD-2 (mainly localized in the
kidney), which inactivates cortisol unidirectionally.
209
The renal 11β-HSD-2
inactivates 11-hydroxysteroids in the kidney, thus protecting the non-selective
mineralocorticoid receptor from occupation by glucocorticoids.
210
Hepatic transcription of 11β-HSD-1 is regulated by members of the C/EBP

family of transcription factors providing a mechanism of cross-talk between
C/EBP and the glucocorticoid signalling pathway.
211
11β-HSD is highly expres-
sed in all sodium-transporting epithelia, and mutations in the gene cause a rare
monogenic juvenile hypertensive syndrome called apparent mineralocorticoid
excess (AME).
210
Recent studies have shown a prolonged half-life of cortisol and
an increased ratio of urinary cortisol to cortisone metabolites in some patients
with essential hypertension, similar to the effects of a CA-repeat polymorphism
in the first intron, although there was no correlation between this marker and
blood pressure.
210
The same CA-repeat, however, was associated with a mean
arterial pressure difference between the sodium-loaded and the sodium-depleted
states
212, 213
(Table 13.3). In another study, a proband with AME was homozy-
gous for a mutation (Ala328Val) resulting in a protein devoid of activity,
214
while
a different individual with AME was homozygous for a Pro227Leu mutation
215
422 GENETICS OF THE METABOLIC SYNDROME
(Table 13.3). In other cases, the polymorphism Arg213Cys was strongly associ-
ated with AME,
216
while two other mutations (Lys179Arg, Arg208His) resulted
again in protein devoid of activity.

217
Other polymorphisms in 11β-HSD-2 have also been associated with essen-
tial hypertension.
218 – 220
From these data, we conclude that 11β-HSD-2 plays a
significant role in essential hypertension and is therefore an important candi-
date gene that may contribute to the development of the metabolic syndrome.
Its mode of action may be independent of abnormal adipose tissue biology
or the insulin signalling pathways, but it may exert its effects directly on the
development of hypertension.
TNF-α
TNF-α is a cytokine that is produced by macrophages, monocytes, endothelial
cells, neutrophils, smooth muscle cells, activated lymphocytes, astrocytes and
adipocytes.
221
TNF-α is a transmembrane glycoprotein and a cytotoxin with
a variety of functions, such as mediating expression of genes for growth fac-
tors, cytokines, transcription factors and receptors. TNF-α suppresses adipocyte-
specific genes and activates expression of preadipocyte genes in 3T3-L1 cells,
with NF-κB being an obligatory mediator.
222
TNF-α has been termed an adipo-
stat because its adipose tissue expression is, like leptin, more or less proportional
to the degree of adiposity.
TNF-α is synthesized as a 26 kDa transmembrane protein found on the sur-
face or processed to release the 17 kDa soluble form.
223
The ways in which
TNF-α may be involved in the aetiology of obesity include its inhibitory effect
on lipoprotein lipase (LPL) activity, its effects on glucose homeostasis and

its effects on leptin. There are significant positive relationships between TNF-
α expression, BMI and leptin, and a negative significant correlation between
TNF-α and LPL activity, suggesting that TNF-α may be a homeostatic mech-
anism that may prevent further fat deposition by regulating LPL activity and
leptin production.
224
Higher plasma levels of TNF-α are also associated with
insulin resistance, higher BMI, higher fasting glucose levels and higher LDL-C
levels.
225
Using confirmatory factor analysis and structural equation modelling,
it was shown that obesity, dyslipidaemia and cytokines such as TNF-α were
the principal explanatory variables for the various components of the metabolic
syndrome.
226
Human obesity and T2DM are associated with alterations in the
sterol regulatory element binding protein (SREBP)-1 transcription factor that
is downregulated at the transcriptional level by TNF-α.
227
TNF-α has also
been proposed to link obesity with insulin resistance, with serine phospho-
rylation of the insulin receptor substrate-1 being a prominent mechanism for
TNF-α-induced insulin resistance.
228
Physiologically, TNF-α could affect sev-
eral metabolic functions (probably involving the adipose tissue) but its mode of
action could be indirect, possibly requiring the development of insulin resistance
for its effects to become evident (Figure 13.1).
CANDIDATE GENES 423
In terms of genetic variants in TNF-α, there have been numerous publica-

tions, centred mostly on two promoter variants: −308G → A and −238G → A.
There are data that do not support an involvement of these two SNPs in the
development of the metabolic syndrome
229 – 235
but also a body of data that sup-
ports an involvement of the two promoter variants in the aetiology of insulin
resistance, obesity or T2DM
236 – 242
(Table 13.3). A linkage between obesity and
a marker (dinucleotide repeat) near the TNF-α locus in the Pima Indians has
also been reported.
243
Another promoter SNP (−857C → T) was present at
higher frequencies in obese patients with diabetes (T/T homozygotes) than in
lean subjects
244, 245
(Table 13.3). Taking together the physiological functions of
TNF-α and the genetic variants, TNF-α may play a role in the development of
the metabolic syndrome but the association studies are somewhat inconclusive.
Glucocorticoid receptor
The glucocorticoid receptor (GR) is the essential receptor by which glucocor-
ticoids exert their regulatory effects on gene expression. GR is a member of
the steroid family of nuclear receptors, and in the absence of its cognate lig-
and it is transcriptionally inactive.
246
There are two isoforms of GR (GR-α and
GR-β), which are products of alternative splicing, but only GR-α has functional
properties.
246
Inside the DNA-binding domain of the receptor molecule, there

are two zinc-finger structures, each containing four cysteines that are stabilized
by bonds of Zn
2+
ions.
247
These zinc fingers enable GR homodimers to bind to
palindromic DNA sequences and GR response elements found in the promot-
ers of GR-regulated genes.
248
The receptor then communicates with the basal
transcriptional machinery to either enhance or repress transcription.
246
Mutations in GR have often been associated with the metabolic syndrome in
association with hyperactivity or abnormal regulation of the HPA axis.
249, 250
A
restriction fragment length polymorphism (RFLP), Bcl I, has been studied exten-
sively by several groups and appears to be associated with several subphenotypes
of the metabolic syndrome. Specifically, in a study regarding the effects of GR in
response to overfeeding, 2.3/2.3 kb homozygotes for the GR Bcl I RFLP expe-
rience greater increases in body weight, blood pressure, cholesterol levels and
visceral fat than 4.5/2.3 kb subjects
251
(Table 13.3). In another study involving
the Quebec Family Study, the 4.5 kb allele of the GR Bcl I RFLP was associ-
ated with a higher amount of abdominal visceral fat (AVF) depot independent
of the levels of total body fat.
252
The 4.5 kb allele of the GR Bcl I RFLP was
also associated with elevated BMI, WHR, abdominal sagittal diameter, leptin

and associated borderline with elevated systolic blood pressure.
253
In a separate
study, the 4.5 kb allele was again associated with higher AVF independently of
total body fat, suggesting that the GR Bcl I RFLP or a locus in linkage disequi-
librium with it may contribute to the accumulation of AVF.
254
The Bcl I RFLP
in GR has also been associated with indices of glucose metabolism in obesity,
424 GENETICS OF THE METABOLIC SYNDROME
where 4.5 kb homozygotes had elevated both fasting insulin and an index of
insulin resistance.
255
Another RFLP in the 5

flanking region of the GR gene (3.8/3.4 kb) was
associated (the 3.8 kb homozygotes) with elevated total and evening cortisol
levels in a cohort of randomly selected middle-aged men.
256
Heterozygotes for
another SNP resulting in an amino-acid substitution, Asn363Ser, had higher
BMI but normal blood pressure,
257
but two other studies did not find an asso-
ciation between the Asn363Ser SNP and altered sensitivity to glucocorticoids
or obesity
258, 259
(Table 13.3). Yet a recent study reports an association of the
Asn363Ser SNP with increased WHR in males for the 363Ser allele but no
association with blood pressure, BMI, serum cholesterol, triglycerides, LDL

or glucose tolerance status.
260
Other mutations in patients with primary cortisol
resistance have been reported for GR due to complete lack or reduction of trans-
activation capacity (Arg477His and Gly679Ser, respectively)
261
(Table 13.3).
Additional evidence for involvement of GR in the metabolic syndrome comes
from a study for a haplogroup of the Glu22Arg/Glu23Lys SNPs where carriers
of the less frequent alleles had lower fasting insulin, HOMA-IR index and total
LDL cholesterol concentrations.
262
Other mutations in the promoter (−22C →
A) and 3

UTR exon 9β (A → G in a AUUUA motif) have been reported
263, 264
in GR, but they were not associated with phenotypes of the metabolic syndrome.
Taking together the functional properties of the GR and the various SNPs and
RFLPs that have been associated with the metabolic syndrome, we conclude that
DNA sequence variations in the GR gene play a significant role in the aetiology
of the syndrome.
Hypothalamic genes
The role of the hypothalamus in the metabolic syndrome has been discussed
before in terms of cortisol and the glucocorticoid receptors,
265, 266
as well
as in terms of hypothalamic arousal and its effects on the development of
endocrine abnormalities, insulin resistance, central obesity, dyslipidaemia and
hypertension.

266
The melanocortin receptor 4 (MC4R) is involved in satiation
and is antagonized by the agouti protein in the paraventricular nucleus as well
as in other tissues.
267, 268
Null mutations in MC4R in mice result in hyperpha-
gia, obesity and longitudinal growth while MC3R knockout mice exhibit 50–60
per cent increase in adipose mass and 50 per cent reduction in locomotory
activity.
269
A missense variant of the porcine MC4R gene was associated with
backfat, growth rate and food intake,
270
while frameshift mutations in humans
were associated with dominantly inherited obesity
271 – 275
(Table 13.3). There are
in addition four other neuropeptides that have been shown to play significant
roles in the regulation of food intake and energy balance: agouti-related protein
(AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript
(CART) and pro-opiomelanocortin (POMC).
CANDIDATE GENES 425
AgRP binds competitively to the melanocortin receptors and is a potent appetite
effector
276
and therefore represents a strong case as a candidate gene for obesity
and consequently the metabolic syndrome. The murine and human AgRP orthologs
stimulate hyperphagia when administered intracerebroventricularly
277 – 279
or when

overexpressed in transgenic mice.
280
The minimal promoter of the gene has been
characterized and a functional polymorphism in the promoter (−38C → T) was
associated with decreased obesity in Blacks
281
(Table 13.3). AgRP plasma levels
were elevated in obese individuals
282
or increased by 75 per cent after a two-hour
fast.
283
Further studies in another cohort showed that the T alleleof the −38C → T
SNP in the promoter of AgRP was linked with reduced visceral adiposity, percent-
age body fat and T2DM.
281, 284
A structural polymorphism (Ala67Thr) has been
strongly associated with resistance to late-onset obesity
285
(Table 13.3). The same
SNP was also reported to be associated with anorexia nervosa.
286
This SNP rep-
resents a rare example for a common polymorphism that was found in Caucasians
only and was associated with resistance to obesity in the parental population but not
in the offspring.
285
This parallels the syndromic characteristics of the metabolic
syndrome, which is also a late onset disease, with components of its complex
phenotype expressing gradually in the range of 35–55 years of age.

NPY is also a strong orexigenic gene
287, 288
regulated by leptin and other
peripheral signals.
289
There have been numerous studies linking NPY with feed-
ing behaviour in several mammalian systems. NPY knockout mice have an
attenuated obese phenotype,
289
while its receptors have important physiological
functions.
290 – 292
A polymorphism in the signal peptide (Leu7Pro) resulted in
altered intracellular processing and release of NPY
293
(Table 13.3). The same
SNP has been associated with phenotypes of the metabolic syndrome including
nephropathy in T2DM,
294
enhanced carotid atherosclerosis in elderly patients
with T2DM,
294
carotid atherosclerosis, blood pressure, serum lipids in Finnish
men
295
and serum lipids in patients with coronary heart disease,
296
as well as
alcohol consumption and alcohol dependence.
297, 298

CART is a hypothalamic anorectic peptide that is upregulated by leptin
299, 300
and is also a candidate gene for the metabolic syndrome by virtue of its ability
to regulate food intake. CART blocks the feeding response induced by NPY
and its C-terminus is the active part of the protein.
301
It has been shown to
modulate the voltage-gated Ca
2+
signalling in the hippocampal neurons,
302
and
expression studies in the brain further suggest a role for CART in the regula-
tion of energy homeostasis.
303, 304
CART is a drug target for obesity therapy,
and polymorphisms in its promoter region have been associated with obesity in
humans.
305, 306
Specifically, SNP −156A → G in the promoter of the gene was
associated with high BMI and was found at higher frequencies in obese individ-
uals, while a neighbouring SNP (−929G → C) was in linkage disequilibrium
with the −156A → GSNP
306
(Table 13.3). A mutation in the 3

UTR of the
gene, A1475G, was significantly associated with WHR in heterozygous males,
426 GENETICS OF THE METABOLIC SYNDROME
thus suggesting a role by CART in fat distribution and variables related to the

metabolic syndrome
307
(Table 13.3).
POMC is the precursor of α-MSH, a strong anorectic peptide activated by
leptin
308
and therefore a candidate gene for the metabolic syndrome. Post-
translational processing of POMC results in five distinct proteins with different
physiological functions: adrenocorticotropin, β-lipotropin, α-MSH, β-MSH and
β-endorphin. Mice lacking POMC have obesity and defective adrenal devel-
opment and, when treated with α-MSH agonists, they lose weight.
309, 310
A
missense mutation disrupting a dibasic prohormone processing site in hPOMC
was associated with early onset obesity
311
(Table 13.3).
A role for several hypothalamic neuropeptides can therefore be envisioned
in the development of the metabolic syndrome either as a result of elevated or
diminished arousal of the hypothalamus or due to genetic alterations that may
affect the expression levels or the activities of the protein products of these
genes. It must be noted that these neuropeptides are also expressed in peripheral
tissues and, therefore, their mode of action is quite complex. Hence, there are
several routes by which these genes could influence the development of the
metabolic syndrome (Figure 13.1).
13.6 Genomic scans
There is abundant literature on linkage analyses and genome scans for the main
subphenotypes of the metabolic syndrome (Figure 13.1) considered individu-
ally. In contrast, very few scans have been performed using a single integrated
metabolic syndrome phenotype. This is probably due to the complexity of the

syndrome and the lack of comprehensive physiological and clinical data in fam-
ily cohorts that would allow an adequate definition of the syndrome phenotype.
Yet there are reports providing suggestive linkages that may apply to the meta-
bolic syndrome as a whole. Comuzzie and colleagues have reported a significant
LOD score on 2p21 (LOD = 4.95) for microsatellite D2S1788 that may deter-
mine serum leptin levels and fat mass in Mexican-Americans
312
(Table 13.4).
Indeed, this locus accounted for 47 per cent of the variation in serum leptin levels
and contains several potential candidate genes including the glucokinase regula-
tory protein and POMC. However, it was not significantly linked to hypertension
in African-Americans.
313
In a study that directly scanned the genome for QTLs for the metabolic
syndrome, Kissebah and colleagues reported two QTLs with significant LOD
scores.
314
Specifically, using a 10 cM map in 2209 individuals distributed over
507 nuclear Caucasian families, a QTL on 3q27 was strongly linked with six
traits characteristic of the metabolic syndrome, and this QTL was in possible
epistatic interaction with a second QTL on 17p12
314
(Table 13.4).
Another study used sib-pair linkage analysis with women twins in an effort
to identify lipoprotein candidate genes for multivariate factors of the insulin
REFERENCES 427
resistance syndrome. Specifically, quantitative sib-pair analysis based on factor
scores with markers for nine candidate genes was carried out using 126 dizygotic
women twins.
315

There was suggestive evidence for linkage for the weight/fat
factor and the APO E gene (0.01) and stronger evidence for linkage with the
lipid factor and the cholesterol ester transfer protein (p − value = 0.002)
315
(Table 13.4). A genome-wide scan in Indo-Mauritians for coronary heart dis-
ease (CHD) identified a susceptibility locus on chromosome 16p13–pter and was
able to replicate the previously reported linkage
314
with the metabolic syndrome
on 3q27
316
(Table 13.4). A suggestive linkage was also identified for T2DM
and high blood pressure on 8q23 (LOD = 2.55).
316
A significant LOD score
(LOD = 3.5) was identified on chromosome 6q22–q23 (D6S403, D6S264) for
fasting glucose, specific insulin values and other insulin resistance-related phe-
notypes with strong pleiotropic effects with obesity-related phenotypes in non-
diabetic Mexican-Americans
183
(Table 13.4). It would therefore appear that there
are suggestive linkages and candidate QTLs for the metabolic syndrome, but no
single locus stands out as of yet. Additional linkage studies are required to deter-
mine whether there are any compelling QTLs for the metabolic syndrome. In this
regard, it may be useful to revisit previous genomic scan studies and re-analyse
data from cohorts in which linkages with single phenotypes were reported, with
the aim of testing more comprehensive metabolic syndrome phenotypes.
13.7 Conclusions
The metabolic syndrome in humans is a multi-component disease whose car-
dinal features include obesity, abnormal adipose tissue metabolism, ectopic fat

deposition, insulin resistance, hyperinsulinaemia, dyslipidaemia and hyperten-
sion. The genetic causes for each of the components of the syndrome are under
intense investigation. A number of genes have emerged as possible regulators
but no genetic master switch has been identified yet for the syndrome as a
whole. At this point the genetic data are not particularly robust, and intense
work lies ahead in order to define the genetic aetiology of the disease. The
present review of epidemiological, Mendelian and syndromic data; candidate
genes and polymorphisms; and linkage studies highlights several features and
genetic hypotheses that deserve further research. The field would benefit greatly
from concertation among informative cohorts already assembled and from new
collections of longitudinal data on large populations over an extended period of
time. Innovative genomic scan studies are also needed to identify key loci and
QTLs for the syndrome defined as a single integrated phenotype. Until then, the
candidate gene approach appears to be the best way to identify functional SNPs
that may contribute to the development of the metabolic syndrome.
References
1. Jahnke, K., Daweke, H., Liebermeister, H., Thamer, G., Preiss, H. and Gries, F. A.
(1969) Hormonal and metabolic aspects of obesity in humans. In: Milner, R. D. G., ed.
428 GENETICS OF THE METABOLIC SYNDROME
Proceedings of the Sixth Congress of the International Diabetes Federation.Amsterdam:
Excerpta Medica Foundation, 533–539.
2. Williams, R. R., Hunt, S. C., Hopkins, P. N., Stults, B. M., Wu, L. L., Hasstedt, S. J.,
Barlow, G. K., Stephenson, S. H., Lalouel, J. M. and Kuida, H. (1988) Familial
dyslipidemic hypertension. Evidence from 58 Utah families for a syndrome present
in approximately 12% of patients with essential hypertension. JAMA 259, 3579–3586.
3. Reaven, G. M. (1988) Banting Lecture 1988. Role of insulin resistance in human
disease. Diabetes 37, 1595–1607.
4. Bjorntorp, P. (1992) Abdominal obesity and the metabolic syndrome. Ann Med 24,
465–468.
5. DeFronzo, R. A. and Ferrannini, E. (1991) Insulin resistance. A multifaceted syndrome

responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic
cardiovascular disease. Diabetes Care 14, 173–194.
6. Kaplan, N. M. (1989) The deadly quartet. Upper-body obesity, glucose intolerance,
hypertriglyceridemia, and hypertension. Arch Intern Med 149, 1514–1520.
7. Crepaldi, G., Tiengo, A. and Manzato, E. (1993) Diabetes, Obesity and Hyperlipi-
demias: V: the Plurimetabolic Syndrome. Amsterdam: Excerpta Medica.
8. Flegal, K. M., Carroll, M. D., Ogden, C. L. and Johnson, C. L. (2002) Prevalence and
trends in obesity among US adults, 1999–2000. JAMA 288, 1723–1727.
9. Ford, E. S., Giles, W. H. and Dietz, W. H. (2002) Prevalence of the metabolic
syndrome among US adults: findings from the third National Health and Nutrition
Examination Survey. JAMA 287, 356–359.
10. Bouchard, C. (1995) Genetics and the metabolic syndrome. Int J Obes Relat Metab
Disord 19 (Suppl. 1), S52–59.
11. Han, T. S., Williams, K., Sattar, N., Hunt, K. J., Lean, M. E. and Haffner, S. M.
(2002) Analysis of obesity and hyperinsulinemia in the development of metabolic
syndrome: San Antonio Heart Study. Obes Res 10, 923–931.
12. Smith, S. R. (1999) Regional fat distribution. In: Ryan, D. H., ed. Nutrition Genetic
and Obesity. Baton Rouge, LA: LSU Press, 433–458.
13. Kissebah, A. H. and Peiris, A. N. (1989) Biology of regional body fat distribution:
relationship to non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 5, 83–109.
14. Despres, J. P., Lemieux, S., Lamarche, B., Prud’homme, D., Moorjani, S., Brun, L. D.,
Gagne, C. and Lupien, P. J. (1995) The insulin resistance–dyslipidemic syndrome:
contribution of visceral obesity and therapeutic implications. Int J Obes Relat Metab
Disord 19 (Suppl. 1), S76–86.
15. Banerji, M. A., Chaiken, R. L., Gordon, D., Kral, J. G. and Lebovitz, H. E. (1995)
Does intra-abdominal adipose tissue in black men determine whether NIDDM is insulin-
resistant or insulin-sensitive? Diabetes 44, 141–146.
16. Albu, J. B., Murphy, L., Frager, D. H., Johnson, J. A. and Pi-Sunyer, F. X. (1997)
Visceral fat and race-dependent health risks in obese nondiabetic premenopausal
women. Diabetes 46, 456–462.

17. Albu, J. B., Kovera, A. J. and Johnson, J. A. (2000) Fat distribution and health in
obesity. AnnNYAcadSci904, 491–501.
18. Randle, P. J., Garland, P. B., Hales, C. N. and Newsholme, E. A. (1963) The glucose
fatty acid cycle: its role in insulin sensitivity and metabolic disturbances of diabetes
mellitus. Lancet i, 7285–7289.
19. Kelley, D. E. and Mandarino, L. J. (2000) Fuel selection in human skeletal muscle in
insulin resistance: a reexamination. Diabetes 49, 677–683.
20. Bergman, R. N. and Ader, M. (2000) Free fatty acids and pathogenesis of type 2
diabetes mellitus. Trends Endocrinol Metab 11, 351–356.
REFERENCES 429
21. Bjorntorp, P. (1990) ‘Portal’ adipose tissue as a generator of risk factors for
cardiovascular disease and diabetes. Arteriosclerosis 10, 493–496.
22. Frayn, K. N., Samra, J. S. and Summers, L. K. (1997) Visceral fat in relation to health:
is it a major culprit or simply an innocent bystander? [letter]. Int J Obes Relat Metab
Disord 21, 1191–1192.
23. Kelley, D. E., Thaete, F. L., Troost, F., Huwe, T. and Goodpaster, B. H. (2000)
Subdivisions of subcutaneous abdominal adipose tissue and insulin resistance. Am J
Physiol 278, E941.
24. Smith, S. R., Lovejoy, J. C., Greenway, F., Ryan, D., deJonge, L., de la Bretonne, J.,
Volafova, J. and Bray, G. A. (2001) Contributions of total body fat, abdominal
subcutaneous adipose tissue compartments, and visceral adipose tissue to the metabolic
complications of obesity. Metabolism 50, 425–435.
25. Lundgren, C. H., Brown, S. L., Nordt, T. K., Sobel, B. E. and Fujii, S. (1996)
Elaboration of type-1 plasminogen activator inhibitor from adipocytes. A potential
pathogenetic link between obesity and cardiovascular disease. Circulation 93, 106–110.
26. Bruun, J. M., Pedersen, S. B. and Richelsen, B. (2000) Interleukin-8 production
in human adipose tissue. inhibitory effects of anti-diabetic compounds, the
thiazolidinedione ciglitazone and the biguanide metformin. Horm Metab Res 32,
537–541.
27. Straczkowski, M., Dzienis-Straczkowska, S., Stepien, A., Kowalska, I., Szelachowska,

M. and Kinalska, I. (2002) Plasma interleukin-8 concentrations are increased in obese
subjects and related to fat mass and tumor necrosis factor-alpha system. J Clin
Endocrinol Metab 87, 4602–4606.
28. Engeli, S., Negrel, R. and Sharma, A. M. (2000) Physiology and pathophysiology of
the adipose tissue renin–angiotensin system. Hypertension 35, 1270–1277.
29. Steppan, C. M., Bailey, S. T., Bhat, S., Brown, E. J., Banerjee, R. R., Wright, C. M.,
Patel, H. R., Ahima, R. S. and Lazar, M. A. (2001) The hormone resistin links obesity
to diabetes. Nature 409, 307–312.
30. Harris, R. B. (1998) Acute and chronic effects of leptin on glucose utilization in lean
mice. Biochem Biophys Res Commun 245, 502–509.
31. Muoio, D. M., Dohm, G. L., Fiedorek, F. T., Jr., Tapscott, E. B., Coleman, R. A. and
Dohn, G. L. (1997) Leptin directly alters lipid partitioning in skeletal muscle [published
erratum appears in Diabetes 1997 46 (10), 1663]. Diabetes 46, 1360–1363.
32. Muoio, D. M., Dohm, G. L., Tapscott, E. B. and Coleman, R. A. (1999) Leptin
opposes insulin’s effects on fatty acid partitioning in muscles isolated from obese ob/ob
mice. Am J Physiol 276, E913–921.
33. Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y.,
Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., Ezaki, O., Akanuma, Y., Gavrilova,
O., Vinson, C., Reitman, M. L., Kagechika, H., Shudo, K., Yoda, M., Nakano, Y.,
Tobe, K., Nagai, R., Kimura, S., Tomita, M., Froguel, P. and Kadowaki, T. (2001)
The fat-derived hormone adiponectin reverses insulin resistance associated with both
lipoatrophy and obesity. Nat Med 7, 941–946.
34. Ouchi, N., Kihara, S., Arita, Y., Maeda, K., Kuriyama, H., Okamoto, Y., Hotta, K.,
Nishida, M., Takahashi, M., Nakamura, T., Yamashita, S., Funahashi, T. and Mat-
suzawa, Y. (1999) Novel modulator for endothelial adhesion molecules: adipocyte-
derived plasma protein adiponectin. Circulation 100, 2473–2476.
35. Goldfine, I. D., Maddux, B. A., Youngren, J. F., Frittitta, L., Trischitta, V. and
Dohm, G. L. (1998) Membrane glycoprotein PC-1 and insulin resistance. Mol Cell
Biochem 182, 177–184.
36. Shao, J., Catalano, P. M., Yamashita, H., Ruyter, I., Smith, S., Youngren, J. and

Friedman, J. E. (2000) Decreased insulin receptor tyrosine kinase activity and plasma
430 GENETICS OF THE METABOLIC SYNDROME
cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women
with gestational diabetes mellitus (GDM): evidence for increased serine/threonine
phosphorylation in pregnancy and GDM. Diabetes 49, 603–610.
37. Kahn, C. R., Bruning, J. C., Michael, M. D. and Kulkarni, R. N. (2000) Knockout
mice challenge our concepts of glucose homeostasis and the pathogenesis of diabetes
mellitus. J Pediatr Endocrinol Metab 13 (Suppl. 6), 1377–1384.
38. Mauvais-Jarvis, F., Kulkarni, R. N. and Kahn, C. R. (2002) Knockout models are
useful tools to dissect the pathophysiology and genetics of insulin resistance. Clin
Endocrinol (Oxf) 57, 1–9.
39. Bogardus, C., Lillioja, S., Stone, K. and Mott, D. (1984) Correlation between muscle
glycogen synthase activity and in vivo insulin action in man. J Clin Invest 73,
1185–1190.
40. McGarry, J. D. (1992) What if Minkowski had been ageusic? An alternative angle on
diabetes. Science 258, 766–770.
41. Sinha, R., Dufour, S., Petersen, K. F., LeBon, V., Enoksson, S., Ma, Y. Z., Savoye,
M., Rothman, D. L., Shulman, G. I. and Caprio, S. (2002) Assessment of skeletal
muscle triglyceride content by (1)H nuclear magnetic resonance spectroscopy in lean
and obese adolescents: relationships to insulin sensitivity, total body fat, and central
adiposity. Diabetes 51, 1022–1027.
42. Danforth, E., Jr. (2000) Failure of adipocyte differentiation causes type II diabetes
mellitus? Nat Genet 26, 13.
43. Smith, S. R. and Ravussin, E. (2002) Increased fat intake, impaired fat oxidation, and
failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type
2 diabetes mellitus. AnnNYAcadSci967, 363–378.
44. Colberg, S. R., Simoneau, J. A., Thaete, F. L. and Kelley, D. E. (1995) Skeletal muscle
utilization of free fatty acids in women with visceral obesity. J Clin Invest 95,
1846–1853.
45. Dobbins, R. L., Szczepaniak, L. S., Bentley, B., Esser, V., Myhill, J. and McGarry,

J. D. (2001) Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes
intramyocellular lipid accumulation and insulin resistance in rats. Diabetes 50, 123–130.
46. Kim, Y. B., Shulman, G. I. and Kahn, B. B. (2002) Fatty acid infusion selectively
impairs insulin action on Akt1 and PKC lambda/zeta but not on glycogen synthase
kinase-3. JBiolChem277, 32 915–32 922.
47. Pasquali, R., Cantobelli, S., Casimirri, F., Capelli, M., Bortoluzzi, L., Flamia, R.,
Labate, A. M. and Barbara, L. (1993) The hypothalamic–pituitary–adrenal axis in
obese women with different patterns of body fat distribution. J Clin Endocrinol Metab
77, 341–346.
48. Marin, P., Darin, N., Amemiya, T., Andersson, B., Jern, S. and Bjorntorp, P. (1992)
Cortisol secretion in relation to body fat distribution in obese premenopausal women.
Metabolism 41, 882–886.
49. Rosmond, R., Holm, G. and Bjorntorp, P. (2000) Food-induced cortisol secretion in
relation to anthropometric, metabolic and haemodynamic variables in men. Int J Obes
Relat Metab Disord 24, 416–422.
50. Bujalska, I. J., Kumar, S. and Stewart, P. M. (1997) Does central obesity reflect
‘Cushing’s disease of the omentum’? Lancet 349, 1210–1213.
51. Masuzaki, H., Paterson, J., Shinyama, H., Morton, N. M., Mullins, J. J., Seckl, J. R.
and Flier, J. S. (2001) A transgenic model of visceral obesity and the metabolic
syndrome. Science 294, 2166–2170.
52. Tataranni, P. A., Young, J. B., Bogardus, C. and Ravussin, E. (1997) A low
sympathoadrenal activity is associated with body weight gain and development of
central adiposity in Pima Indian men. Obes Res 5, 341–347.
REFERENCES 431
53. Bray, G. A. (1991) Obesity, a disorder of nutrient partitioning: the MONA LISA
hypothesis. JNutr121, 1146–1162.
54. Astrup, A., Buemann, B., Christensen, N. J., Toubro, S., Thorbek, G., Victor, O. J. and
Quaade, F. (1992) The effect of ephedrine/caffeine mixture on energy expenditure and
body composition in obese women. Metabolism 41, 686–688.
55. Toubro, S., Astrup, A. V., Breum, L. and Quaade, F. (1993) Safety and efficacy of

long-term treatment with ephedrine, caffeine and an ephedrine/caffeine mixture. Int J
Obes Relat Metab Disord 17 (Suppl. 1), S69–72.
56. Weyer, C., Tataranni, P., Snitker, S., Danforth, E. and Ravussin, E. (1998) Increase in
insulin action and fat oxidation after treatment with CL 316,243, a highly selective
beta3-adrenoceptor agonist in humans. Diabetes 47, 1555–1561.
57. Berthoud, H. R. (2002) Multiple neural systems controlling food intake and body
weight. Neurosci Biobehav Rev 26, 393–428.
58. Miles, P. D. G., Li, S., Hart, M., Romeo, O., Cheng, J., Cohen, A., Raafat, K.,
Moossa, A. R. and Olefsky, J. M. (1998) Mechanisms of insulin resistance in
experimental hyperinsulinemic dogs. J Clin Invest 101, 202–211.
59. Hamilton-Wessler, M., Ader, M., Dea, M. K., Moore, D., Loftager, M., Markussen, J.
and Bergman, R. N. (2002) Mode of transcapillary transport of insulin and insulin
analog NN304 in dog hindlimb: evidence for passive diffusion. Diabetes 51, 574–582.
60. Pinkney, J. H., Stehouwer, C. D., Coppack, S. W. and Yudkin, J. S. (1997) Endothelial
dysfunction: cause of the insulin resistance syndrome. Diabetes 46 (Suppl. 2), S9–13.
61. Minokoshi, Y., Kim, Y. B., Peroni, O. D., Fryer, L. G., Muller, C., Carling, D. and
Kahn, B. B. (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated
protein kinase. Nature 415, 339–343.
62. Fryer, L. G., Parbu-Patel, A. and Carling, D. (2002) The anti-diabetic drugs
rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct
signaling pathways. JBiolChem277, 25 226–25 232.
63. Aschenbach, W. G., Hirshman, M. F., Fujii, N., Sakamoto, K., Howlett, K. F. and
Goodyear, L. J. (2002) Effect of AICAR treatment on glycogen metabolism in skeletal
muscle. Diabetes 51, 567–573.
64. Hardie, D. G. and Carling, D. (1997) The AMP-activated protein kinase – fuel gauge
of the mammalian cell? Eur J Biochem 246, 259–273.
65. Muoio, D. M., Seefeld, K., Witters, L. A. and Coleman, R. A. (1999) AMP-activated
kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver
and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target.
Biochem J 338, 783–791.

66. Hutber, C. A., Hardie, D. G. and Winder, W. W. (1997) Electrical stimulation
inactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinase.
Am J Physiol 272, E262–266.
67. Du, X. L., Edelstein, D., Rossetti, L., Fantus, I. G., Goldberg, H., Ziyadeh, F.,
Wu, J. and Brownlee, M. (2000) Hyperglycemia-induced mitochondrial superoxide
overproduction activates the hexosamine pathway and induces plasminogen activator
inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 97,
12 222–12 226.
68. Hawkins, M., Barzilai, N., Liu, R., Hu, M., Chen, W. and Rossetti, L. (1997) Role of
the glucosamine pathway in fat-induced insulin resistance. J Clin Invest 99, 2173–2182.
69. Prentki, M., Tornheim, K. and Corkey, B. E. (1997) Signal transduction mechanisms
in nutrient-induced insulin secretion. Diabetologia 40 (Suppl. 2), S32–41.
70. Bouchard, C. and Perusse, L. (1994) Genetics of causes and manifestations of the
metabolic syndrome. In: Crepaldi, G., ed. 6th European Symposium on Metabolism:
the Plurimetabolic Syndrome. Amsterdam: Elsevier, 67–74.
432 GENETICS OF THE METABOLIC SYNDROME
71. Nelson, T. L., Vogler, G. P., Pedersen, N. L., Hong, Y. and Miles, T. P. (2000) Genetic
and environmental influences on body fat distribution, fasting insulin levels and CVD:
are the influences shared? Twin Res 3, 43–50.
72. Burke, G. L., Savage, P. J., Sprafka, J. M., Selby, J. V., Jacobs, D. R., Jr., Perkins,
L. L., Roseman, J. M., Hughes, G. H. and Fabsitz, R. R. (1991) Relation of risk
factor levels in young adulthood to parental history of disease. The CARDIA study.
Circulation 84, 1176–1187.
73. Manson, J. E., Colditz, G. A., Stampfer, M. J., Willett, W. C., Krolewski, A. S.,
Rosner, B., Arky, R. A., Speizer, F. E. and Hennekens, C. H. (1991) A prospective
study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke
in women. Arch Intern Med 151, 1141–1147.
74. Sarlund, H., Pyorala, K., Penttila, I. and Laakso, M. (1992) Early abnormalities in
coronary heart disease risk factors in relatives of subjects with non-insulin-dependent
diabetes. Arterioscler Thromb 12, 657–663.

75. Ukkola, O. and Bouchard, C. (2001) Clustering of metabolic abnormalities in obese
individuals: the role of genetic factors. Ann Med 33, 79–90.
76. Carmelli, D., Cardon, L. R. and Fabsitz, R. (1994) Clustering of hypertension, diabetes,
and obesity in adult male twins: same genes or same environments? Am J Hum Genet
55, 566–573.
77. Liese, A. D., Mayer-Davis, E. J., Tyroler, H. A., Davis, C. E., Keil, U., Schmidt, M. I.,
Brancati, F. L. and Heiss, G. (1997) Familial components of the multiple metabolic
syndrome: the ARIC study. Diabetologia 40, 963–970.
78. Selby, J. V., Newman, B., Quiroga, J., Christian, J. C., Austin, M. A. and Fab-
sitz, R. R. (1991) Concordance for dyslipidemic hypertension in male twins. JAMA
265, 2079–2084.
79. Mitchell, B. D., Kammerer, C. M., Mahaney, M. C., Blangero, J., Comuzzie, A. G.,
Atwood, L. D., Haffner, S. M., Stern, M. P. and MacCluer, J. W. (1996) Genetic
analysis of the IRS. Pleiotropic effects of genes influencing insulin levels on lipoprotein
and obesity measures. Arterioscler Thromb Vasc Biol 16, 281–288.
80. Hong, Y., Pedersen, N. L., Brismar, K. and de Faire, U. (1997) Genetic and
environmental architecture of the features of the insulin-resistance syndrome. Am J
Hum Genet 60, 143–152.
81. Katzmarzyk, P. T., Perusse, L., Rice, T., Gagnon, J., Skinner, J. S., Wilmore, J. H.,
Leon, A. S., Rao, D. C. and Bouchard, C. (2000) Familial resemblance for coronary
heart disease risk: the HERITAGE Family Study. Ethn Dis 10, 138–147.
82. Katzmarzyk, P. T., Perusse, L., Malina, R. M., Bergeron, J., Despres, J. P. and
Bouchard, C. (2001) Stability of indicators of the metabolic syndrome from childhood
and adolescence to young adulthood: the Quebec Family Study. J Clin Epidemiol 54,
190–195.
83. Ohlson, L. O., Larsson, B., Bjorntorp, P., Eriksson, H., Svardsudd, K., Welin, L.,
Tibblin, G. and Wilhelmsen, L. (1988) Risk factors for type 2 (non-insulin-dependent)
diabetes mellitus. Thirteen and one-half years of follow-up of the participants in a study
of Swedish men born in 1913. Diabetologia 31, 798–805.
84. Martin, B. C., Warram, J. H., Krolewski, A. S., Bergman, R. N., Soeldner, J. S. and

Kahn, C. R. (1992) Role of glucose and insulin resistance in development of type
2 diabetes mellitus: results of a 25-year follow-up study. Lancet 340, 925–929.
85. Haffner, S. M., Stern, M. P., Hazuda, H. P., Mitchell, B. D. and Patterson, J. K. (1988)
Increased insulin concentrations in nondiabetic offspring of diabetic parents. N Engl J
Med 319, 1297–1301.
REFERENCES 433
86. Eriksson, H., Welin, L., Wilhelmsen, L., Larsson, B., Ohlson, L. O., Svardsudd, K. and
Tibblin, G. (1992) Metabolic disturbances in hypertension: results from the population
study ‘men born in 1913’. J Intern Med 232, 389–395.
87. Williams, R. R., Hunt, S. C., Hasstedt, S. J., Hopkins, P. N., Wu, L. L., Berry, T. D.,
Stults, B. M., Barlow, G. K., Schumacher, M. C. and Lifton, R. P. et al. (1991) Are
there interactions and relations between genetic and environmental factors predisposing
to high blood pressure? Hypertension 18, I29–37.
88. Stamler, J., Vaccaro, O., Neaton, J. D. and Wentworth, D. (1993) Diabetes, other risk
factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor
Intervention Trial. Diabetes Care 16, 434–444.
89. Schumacher, M. C., Maxwell, T. M., Wu, L. L., Hunt, S. C., Williams, R. R. and
Elbein, S. C. (1992) Dyslipidemias among normoglycemic members of familial
NIDDM pedigrees. Diabetes Care 15, 1285–1289.
90. Laws, A., Stefanick, M. L. and Reaven, G. M. (1989) Insulin resistance and
hypertriglyceridemia in nondiabetic relatives of patients with noninsulin-dependent
diabetes mellitus. J Clin Endocrinol Metab 69, 343–347.
91. Selby, J. V., Austin, M. A., Newman, B., Zhang, D., Quesenberry, C. P., Jr., Mayer,
E. J. and Krauss, R. M. (1993) LDL subclass phenotypes and the insulin resistance
syndrome in women. Circulation 88, 381–387.
92. Haffner, S. M., Stern, M. P., Hazuda, H. P., Mitchell, B. D., Patterson, J. K. and
Ferrannini, E. (1989) Parental history of diabetes is associated with increased
cardiovascular risk factors. Arteriosclerosis 9, 928–933.
93. Rice, T., Province, M., Perusse, L., Bouchard, C. and Rao, D. C. (1994) Cross-trait
familial resemblance for body fat and blood pressure: familial correlations in the Quebec

Family Study. Am J Hum Genet 55, 1019–1029.
94. Rice, T., Nadeau, A., Perusse, L., Bouchard, C. and Rao, D. C. (1996) Familial
correlations in the Quebec Family Study: cross-trait familial resemblance for body
fat with plasma glucose and insulin. Diabetologia 39, 1357–1364.
95. Perusse, L., Rice, T., Despres, J. P., Rao, D. C. and Bouchard, C. (1997) Cross-trait
familial resemblance for body fat and blood lipids: familial correlations in the Quebec
Family Study. Arterioscler Thromb Vasc Biol 17, 3270–3277.
96. Hong, Y., Rice, T., Gagnon, J., Despres, J. P., Nadeau, A., Perusse, L., Bouchard, C.,
Leon, A. S., Skinner, J. S., Wilmore, J. H. and Rao, D. C. (1998) Familial clustering
of insulin and abdominal visceral fat: the HERITAGE Family Study. J Clin Endocrinol
Metab 83, 4239–4245.
97. An, P., Rice, T., Gagnon, J., Leon, A. S., Skinner, J. S., Wilmore, J. H., Bouchard, C.
and Rao, D. C. (2000) Cross-trait familial resemblance for resting blood pressure and
body composition and fat distribution: the HERITAGE family study. Am J Human Biol
12, 32–41.
98. Mayer, E. J., Newman, B., Austin, M. A., Zhang, D., Quesenberry, C. P., Jr., Edwards,
K. and Selby, J. V. (1996) Genetic and environmental influences on insulin levels and
the insulin resistance syndrome: an analysis of women twins. Am J Epidemiol 143,
323–332.
99. Knutsen, S. F. and Knutsen, R. (1990) Wives of coronary high-risk men – are they also
at higher risk? The Tromso Heart Study. J Intern Med 228, 333–337.
100. Hamosh, A., Scott, A. F., Amberger, J., Valle, D. and McKusick, V. A. (2000) Online
Mendelian Inheritance in Man (OMIM). Hum Mutat 15, 57–61.
101. Bray, G. (1998) Contemporary Diagnosis and Management of Obesity. 1st edn.
Newtown, PA: Handbooks in Healthcare, 289.
434 GENETICS OF THE METABOLIC SYNDROME
102. Hoybye, C., Hilding, A., Jacobsson, H. and Thoren, M. (2002) Metabolic profile and
body composition in adults with Prader–Willi syndrome and severe obesity. J Clin
Endocrinol Metab 87, 3590–3597.
103. Nicholls, R. D. and Knepper, J. L. (2001) Genome organization, function, and

imprinting in Prader–Willi and Angelman syndromes. Annu Rev Genomics Hum Genet
2, 153–175.
104. Gallagher, R. C., Pils, B., Albalwi, M. and Francke, U. (2002) Evidence for the role
of PWCR1/HBII-85 C/D box small nucleolar RNAs in Prader–Willi syndrome. Am J
Hum Genet 71, 669–678.
105. Cummings, D. E., Clement, K., Purnell, J. Q., Vaisse, C., Foster, K. E., Frayo, R. S.,
Schwartz, M. W., Basdevant, A. and Weigle, D. S. (2002) Elevated plasma ghrelin
levels in Prader Willi syndrome. Nat Med 8, 643–644.
106. Wren, A. M., Seal, L. J., Cohen, M. A., Brynes, A. E., Frost, G. S., Murphy, K. G.,
Dhillo, W. S., Ghatei, M. A. and Bloom, S. R. (2001) Ghrelin enhances appetite and
increases food intake in humans. J Clin Endocrinol Metab 86, 5992.
107. Garg, A. (2000) Lipodystrophies. Am J Med 108, 143–152.
108. Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. and Lodish, H. F. (1995) A
novel serum protein similar to C1q, produced exclusively in adipocytes. JBiolChem
270, 26 746–26 749.
109. Fruebis, J., Tsao, T. S., Javorschi, S., Ebbets-Reed, D., Erickson, M. R., Yen, F. T.,
Bihain, B. E. and Lodish, H. F. (2001) Proteolytic cleavage product of 30-kDa
adipocyte complement-related protein increases fatty acid oxidation in muscle and
causes weight loss in mice. Proc Natl Acad Sci USA 98, 2005–2010.
110. Berg, A. H., Combs, T. P., Du, X., Brownlee, M. and Scherer, P. E. (2001) The
adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7,
947–953.
111. Berg, A. H., Combs, T. P. and Scherer, P. E. (2002) ACRP30/adiponectin: an
adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 13, 84–89.
112. Maeda, N., Shimomura, I., Kishida, K., Nishizawa, H., Matsuda, M., Nagaretani, H.,
Furuyama, N., Kondo, H., Takahashi, M., Arita, Y., Komuro, R., Ouchi, N., Kihara, S.,
Tochino, Y., Okutomi, K., Horie, M., Takeda, S., Aoyama, T., Funahashi, T. and Mat-
suzawa, Y. (2002) Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.
Nat Med 8, 731–737.
113. Kondo, H., Shimomura, I., Matsukawa, Y., Kumada, M., Takahashi, M., Matsuda, M.,

Ouchi, N., Kihara, S., Kawamoto, T., Sumitsuji, S., Funahashi, T. and Matsuzawa, Y.
(2002) Association of adiponectin mutation with type 2 diabetes: a candidate gene for
the insulin resistance syndrome. Diabetes 51, 2325–2328.
114. Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S.,
Noda, M., Kita, S., Ueki, K., Eto, K., Akanuma, Y., Froguel, P., Foufelle, F., Ferre, P.,
Carling, D., Kimura, S., Nagai, R., Kahn, B. B. and Kadowaki, T. (2002) Adiponectin
stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated
protein kinase. Nat Med 8, 1288–1295.
115. Arita, Y., Kihara, S., Ouchi, N., Takahashi, M., Maeda, K., Miyagawa, J., Hotta, K.,
Shimomura, I., Nakamura, T., Miyaoka, K., Kuriyama, H., Nishida, M., Yamashita, S.,
Okubo, K., Matsubara, K., Muraguchi, M., Ohmoto, Y., Funahashi, T. and Mat-
suzawa, Y. (1999) Paradoxical decrease of an adipose-specific protein, adiponectin,
in obesity. Biochem Biophys Res Commun 257, 79–83.
116. Matsubara, M., Maruoka, S. and Katayose, S. (2002) Decreased plasma adiponectin
concentrations in women with dyslipidemia. J Clin Endocrinol Metab 87, 2764–2769.
117. Stefan, N., Vozarova, B., Funahashi, T., Matsuzawa, Y., Weyer, C., Lindsay, R. S.,
Youngren, J. F., Havel, P. J., Pratley, R. E., Bogardus, C. and Tataranni, P. A. (2002)
REFERENCES 435
Plasma adiponectin concentration is associated with skeletal muscle insulin receptor
tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-
body insulin sensitivity in humans. Diabetes 51, 1884–1888.
118. Ouchi, N., Kihara, S., Arita, Y., Nishida, M., Matsuyama, A., Okamoto, Y., Ishigami,
M., Kuriyama, H., Kishida, K., Nishizawa, H., Hotta, K., Muraguchi, M., Ohmoto,
Y., Yamashita, S., Funahashi, T. and Matsuzawa, Y. (2001) Adipocyte-derived
plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger
receptor expression in human monocyte-derived macrophages. Circulation 103,
1057–1063.
119. Weyer, C., Funahashi, T., Tanaka, S., Hotta, K., Matsuzawa, Y., Pratley, R. E. and
Tataranni, P. A. (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close
association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86,

1930–1935.
120. Takahashi, M., Arita, Y., Yamagata, K., Matsukawa, Y., Okutomi, K., Horie, M.,
Shimomura, I., Hotta, K., Kuriyama, H., Kihara, S., Nakamura, T., Yamashita, S.,
Funahashi, T. and Matsuzawa, Y. (2000) Genomic structure and mutations in adipose-
specific gene, adiponectin. Int J Obes Relat Metab Disord 24, 861–868.
121. Menzaghi, C., Ercolino, T., Di Paola, R., Berg, A. H., Warram, J. H., Scherer, P. E.,
Trischitta, V. and Doria, A. (2002) A haplotype at the adiponectin locus is associated
with obesity and other features of the insulin resistance syndrome. Diabetes 51,
2306–2312.
122. Stumvoll, M., Tschritter, O., Fritsche, A., Staiger, H., Renn, W., Weisser, M.,
Machicao, F. and Haring, H. (2002) Association of the T-G polymorphism in
adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history
of type 2 diabetes. Diabetes 51, 37–41.
123. Hara, K., Boutin, P., Mori, Y., Tobe, K., Dina, C., Yasuda, K., Yamauchi, T.,
Otabe, S., Okada, T., Eto, K., Kadowaki, H., Hagura, R., Akanuma, Y., Yazaki, Y.,
Nagai, R., Taniyama, M., Matsubara, K., Yoda, M., Nakano, Y., Tomita, M., Kimura,
S., Ito, C., Froguel, P. and Kadowaki, T. (2002) Genetic variation in the gene encoding
adiponectin is associated with an increased risk of type 2 diabetes in the Japanese
population. Diabetes 51, 536–540.
124. Vasseur, F., Helbecque, N., Dina, C., Lobbens, S., Delannoy, V., Gaget, S., Boutin, P.,
Vaxillaire, M., Lepretre, F., Dupont, S., Hara, K., Clement, K., Bihain, B., Kad-
owaki, T. and Froguel, P. (2002) Single-nucleotide polymorphism haplotypes in the
both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted
adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in
French Caucasians. Hum Mol Genet 11, 2607–2614.
125. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. and Friedman, J. M.
(1994) Positional cloning of the mouse obese gene and its human homologue [published
erratum appears in Nature 1995 374 (6521), 479] [see comments]. Nature 372,
425–432.
126. Green, E. D., Maffei, M., Braden, V. V., Proenca, R., DeSilva, U., Zhang, Y.,

Chua, S. C., Jr., Leibel, R. L., Weissenbach, J. and Friedman, J. M. (1995) The human
obese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic,
and genetic maps of chromosome 7. Genome Res 5, 5–12.
127. Karvonen, M. K., Pesonen, U., Heinonen, P., Laakso, M., Rissanen, A., Naukkari-
nen, H., Valve, R., Uusitupa, M. I. and Koulu, M. (1998) Identification of new sequence
variants in the leptin gene. J Clin Endocrinol Metab 83, 3239–3242.
128. Akerman, F., Lei, Z. M. and Rao, C. V. (2002) Human umbilical cord and fetal
membranes co-express leptin and its receptor genes. Gynecol Endocrinol 16, 299–306.
436 GENETICS OF THE METABOLIC SYNDROME
129. Leroy, P., Dessolin, S., Villageois, P., Moon, B. C., Friedman, J. M., Ailhaud, G. and
Dani, C. (1996) Expression of ob gene in adipose cells. Regulation by insulin. JBiol
Chem 271, 2365–2368.
130. Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D.,
Lallone, R. L., Burley, S. K. and Friedman, J. M. (1995) Weight-reducing effects of
the plasma protein encoded by the obese gene [see comments]. Science 269, 543–546.
131. Vaisse, C., Halaas, J. L., Horvath, C. M., Darnell, J. E., Jr., Stoffel, M. and Fried-
man, J. M. (1996) Leptin activation of Stat3 in the hypothalamus of wild-type and
ob/ob mice but not db/db mice. Nat Genet 14, 95–97.
132. Shimon, I., Yan, X., Magoffin, D. A., Friedman, T. C. and Melmed, S. (1998) Intact
leptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas
and signals human fetal pituitary growth hormone secretion. J Clin Endocrinol Metab
83, 4059–4064.
133. Spicer, L. J. (2001) Leptin: a possible metabolic signal affecting reproduction. Domest
Anim Endocrinol 21, 251–270.
134. Brann, D. W., Wade, M. F., Dhandapani, K. M., Mahesh, V. B. and Buchanan, C. D.
(2002) Leptin and reproduction. Steroids 67, 95–104.
135. Ravussin, E., Pratley, R. E., Maffei, M., Wang, H., Friedman, J. M., Bennett, P. H. and
Bogardus, C. (1997) Relatively low plasma leptin concentrations precede weight gain
in Pima Indians. Nat Med 3, 238–240.
136. Hinney, A., Bornscheuer, A., Depenbusch, M., Mierke, B., Tolle, A., Middeke, K.,

Ziegler, A., Roth, H., Gerber, G., Zamzow, K., Ballauff, A., Hamann, A., Mayer, H.,
Siegfried, W., Lehmkuhl, G., Poustka, F., Schmidt, M. H., Hermann, H., Herpertz-
Dahlmann, B. M., Fichter, M., Remschmidt, H. and Hebebrand, J. (1998) No evidence
for involvement of the leptin gene in anorexia nervosa, bulimia nervosa, underweight
or early onset extreme obesity: identification of two novel mutations in the coding
sequence and a novel polymorphism in the leptin gene linked upstream region. Mol
Psychiatry 3, 539–543.
137. Hager, J., Clement, K., Francke, S., Dina, C., Raison, J., Lahlou, N., Rich, N.,
Pelloux, V., Basdevant, A., Guy-Grand, B., North, M. and Froguel, P. (1998) A
polymorphism in the 5

untranslated region of the human ob gene is associated with
low leptin levels. Int J Obes Relat Metab Disord 22, 200–205.
138. Ohshiro, Y., Ueda, K., Nishi, M., Ishigame, M., Wakasaki, H., Kawashima, H.,
Furuta, H., Sasaki, H., Sanke, T., Takasu, N. and Nanjo, K. (2000) A polymorphic
marker in the leptin gene associated with Japanese morbid obesity. JMolMed78,
516–520.
139. Mammes, O., Betoulle, D., Aubert, R., Herbeth, B., Siest, G. and Fumeron, F. (2000)
Association of the G-2548A polymorphism in the 5

region of the LEP gene with
overweight. Ann Hum Genet 64, 391–394.
140. Hoffstedt, J., Eriksson, P., Mottagui-Tabar, S. and Arner, P. (2002) A polymorphism in
the leptin promoter region (−2548 g/a) influences gene expression and adipose tissue
secretion of leptin. Horm Metab Res 34, 355–359.
141. Shintani, M., Ikegami, H., Fujisawa, T., Kawaguchi, Y., Ohishi, M., Katsuya, T.,
Higaki, J., Shimamoto, K. and Ogihara, T. (2002) Leptin gene polymorphism is
associated with hypertension independent of obesity. J Clin Endocrinol Metab 87,
2909–2912.
142. Montague, C. T., Farooqi, I. S., Whitehead, J. P., Soos, M. A., Rau, H., Ware-

ham, N. J., Sewter, C. P., Digby, J. E., Mohammed, S. N., Hurst, J. A., Cheetham,
C. H., Earley, A. R., Barnett, A. H., Prins, J. B. and O’Rahilly, S. (1997) Congenital
leptin deficiency is associated with severe early-onset obesity in humans. Nature 387,
903–908.
REFERENCES 437
143. Farooqi, I. S., Keogh, J. M., Kamath, S., Jones, S., Gibson, W. T., Trussell, R.,
Jebb, S. A., Lip, G. Y. and O’Rahilly, S. (2001) Partial leptin deficiency and human
adiposity. Nature 414, 34–35.
144. Thompson, D. B., Ravussin, E., Bennett, P. H. and Bogardus, C. (1997) Structure and
sequence variation at the human leptin receptor gene in lean and obese Pima Indians.
Hum Mol Genet 6, 675–679.
145. Clement, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., Gourme-
len, M., Dina, C., Chambaz, J., Lacorte, J. M., Basdevant, A., Bougneres, P., Lebouc,
Y., Froguel, P. and Guy-Grand, B. (1998) A mutation in the human leptin receptor
gene causes obesity and pituitary dysfunction. Nature 392, 398–401.
146. Chagnon, Y. C., Chung, W. K., Perusse, L., Chagnon, M., Leibel, R. L. and Bouchard,
C. (1999) Linkages and associations between the leptin receptor (LEPR) gene and
human body composition in the Quebec Family Study. Int J Obes Relat Metab Disord
23, 278–286.
147. Lakka, H. M., Oksanen, L., Tuomainen, T. P., Kontula, K. and Salonen, J. T. (2000)
The common pentanucleotide polymorphism of the 3

-untranslated region of the leptin
receptor gene is associated with serum insulin levels and the risk of type 2 diabetes in
non-diabetic men: a prospective case–control study. J Intern Med 248, 77–83.
148. Chagnon, Y. C., Wilmore, J. H., Borecki, I. B., Gagnon, J., Perusse, L., Chagnon, M.,
Collier, G. R., Leon, A. S., Skinner, J. S., Rao, D. C. and Bouchard, C. (2000)
Associations between the leptin receptor gene and adiposity in middle-aged Caucasian
males from the HERITAGE family study. J Clin Endocrinol Metab 85, 29–34.
149. de Silva, A. M., Walder, K. R., Aitman, T. J., Gotoda, T., Goldstone, A. P., Hodge,

A. M., de Courten, M. P., Zimmet, P. Z. and Collier, G. R. (1999) Combination of
polymorphisms in OB-R and the OB gene associated with insulin resistance in Nauruan
males. Int J Obes Relat Metab Disord 23, 816–822.
150. Quinton, N. D., Lee, A. J., Ross, R. J., Eastell, R. and Blakemore, A. I. (2001) A
single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat
mass and leptin levels in postmenopausal Caucasian women. Hum Genet 108, 233–236.
151. Wauters, M., Mertens, I., Chagnon, M., Rankinen, T., Considine, R. V., Chagnon,
Y. C., Van Gaal, L. F. and Bouchard, C. (2001) Polymorphisms in the leptin receptor
gene, body composition and fat distribution in overweight and obese women. Int J Obes
Relat Metab Disord 25, 714–720.
152. Wauters, M., Mertens, I., Rankinen, T., Chagnon, M., Bouchard, C. and Van Gaal, L.
(2001) Leptin receptor gene polymorphisms are associated with insulin in obese women
with impaired glucose tolerance. J Clin Endocrinol Metab 86, 3227–3232.
153. Mammes, O., Aubert, R., Betoulle, D., Pean, F., Herbeth, B., Visvikis, S., Siest, G. and
Fumeron, F. (2001) LEPR gene polymorphisms: associations with overweight, fat mass
and response to diet in women. Eur J Clin Invest 31, 398–404.
154. Gotoda, T., Manning, B. S., Goldstone, A. P., Imrie, H., Evans, A. L., Strosberg,
A. D., McKeigue, P. M., Scott, J. and Aitman, T. J. (1997) Leptin receptor gene
variation and obesity: lack of association in a white British male population. Hum
Mol Genet 6, 869–876.
155. Silver, K., Walston, J., Chung, W. K., Yao, F., Parikh, V. V., Andersen, R., Che-
skin, L. J., Elahi, D., Muller, D., Leibel, R. L. and Shuldiner, A. R. (1997) The
Gln223Arg and Lys656Asn polymorphisms in the human leptin receptor do not associate
with traits related to obesity. Diabetes 46, 1898–1900.
156. Rand, L., Winchester, E. C., Millwood, I. Y., Penny, M. A. and Kessling, A. M.
(2001) Maternal leptin receptor gene variant Gln223Arg is not associated with variation
in birth weight or maternal body mass index in UK and South Asian populations. Int J
Obes Relat Metab Disord 25, 753–755.
438 GENETICS OF THE METABOLIC SYNDROME
157. Heo, M., Leibel, R. L., Fontaine, K. R., Boyer, B. B., Chung, W. K., Koulu, M., Kar-

vonen, M. K., Pesonen, U., Rissanen, A., Laakso, M., Uusitupa, M. I., Chagnon, Y.,
Bouchard, C., Donohoue, P. A., Burns, T. L., Shuldiner, A. R., Silver, K., Ander-
sen, R. E., Pedersen, O., Echwald, S., Sorensen, T. I., Behn, P., Permutt, M. A.,
Jacobs, K. B., Elston, R. C., Hoffman, D. J., Gropp, E. and Allison, D. B. (2002) A
meta-analytic investigation of linkage and association of common leptin receptor
(LEPR) polymorphisms with body mass index and waist circumference. Int J Obes
Relat Metab Disord 26, 640–646.
158. Holcomb, I. N., Kabakoff, R. C., Chan, B., Baker, T. W., Gurney, A., Henzel, W.,
Nelson, C., Lowman, H. B., Wright, B. D., Skelton, N. J., Frantz, G. D., Tumas, D. B.,
Peale, F. V., Jr., Shelton, D. L. and Hebert, C. C. (2000) FIZZ1, a novel cysteine-rich
secreted protein associated with pulmonary inflammation, defines a new gene family.
EMBO J 19, 4046–4055.
159. Way, J. M., Gorgun, C. Z., Tong, Q., Uysal, K. T., Brown, K. K., Harrington, W. W.,
Oliver, W. R., Jr., Willson, T. M., Kliewer, S. A. and Hotamisligil, G. S. (2001)
Adipose tissue resistin expression is severely suppressed in obesity and stimulated
by peroxisome proliferator-activated receptor gamma agonists. JBiolChem276,
25 651–25 653.
160. Savage, D. B., Sewter, C. P., Klenk, E. S., Segal, D. G., Vidal-Puig, A., Consi-
dine, R. V. and O’Rahilly, S. (2001) Resistin/Fizz3 expression in relation to obesity
and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes 50,
2199–2202.
161. Nagaev, I. and Smith, U. (2001) Insulin resistance and type 2 diabetes are not related to
resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun
285, 561–564.
162. Lay, S. L., Boucher, J., Rey, A., Castan-Laurell, I., Krief, S., Ferre, P., Valet, P. and
Dugail, I. (2001) Decreased resistin expression in mice with different sensitivities to a
high-fat diet. Biochem Biophys Res Commun 289, 564–567.
163. Janke, J., Engeli, S., Gorzelniak, K., Luft, F. C. and Sharma, A. M. (2002) Resistin
gene expression in human adipocytes is not related to insulin resistance. Obes Res 10,
1–5.

164. Rajala, M. W., Lin, Y., Ranalletta, M., Yang, X. M., Qian, H., Gingerich, R.,
Barzilai, N. and Scherer, P. E. (2002) Cell type-specific expression and coregulation
of murine resistin and resistin-like molecule-alpha in adipose tissue. Mol Endocrinol
16, 1920–1930.
165. McTernan, C. L., McTernan, P. G., Harte, A. L., Levick, P. L., Barnett, A. H. and
Kumar, S. (2002) Resistin, central obesity, and type 2 diabetes. Lancet 359, 46–47.
166. Kim, K. H., Lee, K., Moon, Y. S. and Sul, H. S. (2001) A cysteine-rich adipose
tissue-specific secretory factor inhibits adipocyte differentiation. JBiolChem276,
11 252–11 256.
167. Unger, R. H. and Orci, L. (2000) Lipotoxic diseases of nonadipose tissues in obesity.
Int J Obes Relat Metab Disord 24 (Suppl. 4), S28–32.
168. Sentinelli, F., Romeo, S., Arca, M., Filippi, E., Leonetti, F., Banchieri, M., Di
Mario, U. and Baroni, M. G. (2002) Human resistin gene, obesity, and type 2 diabetes:
mutation analysis and population study. Diabetes 51, 860–862.
169. Osawa, H., Onuma, H., Murakami, A., Ochi, M., Nishimiya, T., Kato, K., Shimizu, I.,
Fujii, Y., Ohashi, J. and Makino, H. (2002) Systematic search for single nucleotide
polymorphisms in the resistin gene: the absence of evidence for the association of three
identified single nucleotide polymorphisms with Japanese type 2 diabetes. Diabetes 51,
863–866.
REFERENCES 439
170. Wang, H., Chu, W. S., Hemphill, C. and Elbein, S. C. (2002) Human resistin gene:
molecular scanning and evaluation of association with insulin sensitivity and type 2
diabetes in Caucasians. J Clin Endocrinol Metab 87, 2520–2524.
171. Ma, X., Warram, J. H., Trischitta, V. and Doria, A. (2002) Genetic variants at the
resistin locus and risk of type 2 diabetes in Caucasians. J Clin Endocrinol Metab 87,
4407–4410.
172. Engert, J. C., Vohl, M. C., Williams, S. M., Lepage, P., Loredo-Osti, J. C., Faith, J.,
Dore, C., Renaud, Y., Burtt, N. P., Villeneuve, A., Hirschhorn, J. N., Altshuler, D.,
Groop, L. C., Despres, J. P., Gaudet, D. and Hudson, T. J. (2002) 5


flanking variants
of resistin are associated with obesity. Diabetes 51, 1629–1634.
173. Pizzuti, A., Argiolas, A., Di Paola, R., Baratta, R., Rauseo, A., Bozzali, M.,
Vigneri, R., Dallapiccola, B., Trischitta, V. and Frittitta, L. (2002) An ATG repeat in
the 3

-untranslated region of the human resistin gene is associated with a decreased risk
of insulin resistance. J Clin Endocrinol Metab 87, 4403–4406.
174. Maddux, B. A. and Goldfine, I. D. (2000) Membrane glycoprotein PC-1 inhibition of
insulin receptor function occurs via direct interaction with the receptor alpha-subunit.
Diabetes 49, 13–19.
175. Maddux, B. A., Sbraccia, P., Kumakura, S., Sasson, S., Youngren, J., Fisher, A.,
Spencer, S., Grupe, A., Henzel, W. and Stewart, T. A. et al. (1995) Membrane
glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus
[see comments]. Nature 373, 448–451.
176. Frittitta, L., Spampinato, D., Solini, A., Nosadini, R., Goldfine, I. D., Vigneri, R. and
Trischitta, V. (1998) Elevated PC-1 content in cultured skin fibroblasts correlates with
decreased in vivo and in vitro insulin action in nondiabetic subjects: evidence that
PC-1 may be an intrinsic factor in impaired insulin receptor signaling. Diabetes 47,
1095–1100.
177. Frittitta, L., Camastra, S., Baratta, R., Costanzo, B. V., D’Adamo, M., Graci, S.,
Spampinato, D., Maddux, B. A., Vigneri, R., Ferrannini, E. and Trischitta, V. (1999)
A soluble PC-1 circulates in human plasma: relationship with insulin resistance and
associated abnormalities. J Clin Endocrinol Metab 84, 3620–3625.
178. Tomazic, M., Janez, A., Sketelj, A., Kocijancic, A., Eckel, J. and Sharma, P. M. (2002)
Comparison of alterations in insulin signalling pathway in adipocytes from Type II
diabetic pregnant women and women with gestational diabetes mellitus. Diabetologia
45, 502–508.
179. Pizzuti, A., Frittitta, L., Argiolas, A., Baratta, R., Goldfine, I. D., Bozzali, M.,
Ercolino, T., Scarlato, G., Iacoviello, L., Vigneri, R., Tassi, V. and Trischitta, V. (1999)

A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is
strongly associated with insulin resistance. Diabetes 48, 1881–1884.
180. Gu, H. F., Almgren, P., Lindholm, E., Frittitta, L., Pizzuti, A., Trischitta, V. and
Groop, L. C. (2000) Association between the human glycoprotein PC-1 gene and
elevated glucose and insulin levels in a paired-sibling analysis. Diabetes 49, 1601–1603.
181. Rasmussen, S. K., Urhammer, S. A., Pizzuti, A., Echwald, S. M., Ekstrom, C. T.,
Hansen, L., Hansen, T., Borch-Johnsen, K., Frittitta, L., Trischitta, V. and Pedersen, O.
(2000) The K121Q variant of the human PC-1 gene is not associated with insulin
resistance or type 2 diabetes among Danish Caucasians. Diabetes 49, 1608–1611.
182. Frittitta, L., Ercolino, T., Bozzali, M., Argiolas, A., Graci, S., Santagati, M. G.,
Spampinato, D., Di Paola, R., Cisternino, C., Tassi, V., Vigneri, R., Pizzuti, A. and
Trischitta, V. (2001) A cluster of three single nucleotide polymorphisms in the
3

-untranslated region of human glycoprotein PC-1 gene stabilizes PC-1 mRNA
and is associated with increased PC-1 protein content and insulin resistance-related
abnormalities. Diabetes 50, 1952–1955.
440 GENETICS OF THE METABOLIC SYNDROME
183. Duggirala, R., Blangero, J., Almasy, L., Arya, R., Dyer, T. D., Williams, K. L.,
Leach, R. J., O’Connell, P. and Stern, M. P. (2001) A major locus for fasting insulin
concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects
on obesity-related phenotypes in nondiabetic Mexican Americans. Am J Hum Genet 68,
1149–1164.
184. Barroso, I., Gurnell, M., Crowley, V. E., Agostini, M., Schwabe, J. W., Soos, M. A.,
Maslen, G. L., Williams, T. D., Lewis, H., Schafer, A. J., Chatterjee, V. K. and
O’Rahilly, S. (1999) Dominant negative mutations in human PPARgamma asso-
ciated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402,
880–883.
185. Yen, C. J., Beamer, B. A., Negri, C., Silver, K., Brown, K. A., Yarnall, D. P.,
Burns, D. K., Roth, J. and Shuldiner, A. R. (1997) Molecular scanning of the human

peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic
Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem
Biophys Res Commun 241, 270–274.
186. Bocher, V., Chinetti, G., Fruchart, J. C. and Staels, B. (2002) Role of the peroxisome
proliferator-activated receptors (PPARS) in the regulation of lipids and inflammation
control. J Soc Biol 196, 47–52.
187. Olefsky, J. M. and Saltiel, A. R. (2000) PPAR gamma and the treatment of insulin
resistance. Trends Endocrinol Metab 11, 362–368.
188. Wang, N., Verna, L., Chen, N. G., Chen, J., Li, H., Forman, B. M. and Stemer-
man, M. B. (2002) Constitutive activation of peroxisome proliferator-activated receptor-
gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial
cells. JBiolChem277, 34176–34181.
189. Gonzalez Sanchez, J. L., Serrano Rios, M., Fernandez Perez, C., Laakso, M. and
Martinez Larrad, M. T. Effect of the Pro12Ala polymorphism of the peroxisome
proliferator-activated receptor gamma-2 gene on adiposity, insulin sensitivity and lipid
profile in the Spanish population. Eur J Endocrinol 147, 495–501.
190. Frederiksen, L., Brodbaek, K., Fenger, M., Jorgensen, T., Borch-Johnsen, K., Mads-
bad, S. and Urhammer, S. A. (2002) Comment: studies of the Pro12Ala polymorphism
of the PPAR-gamma gene in the Danish MONICA cohort: homozygosity of the Ala
allele confers a decreased risk of the insulin resistance syndrome. J Clin Endocrinol
Metab 87, 3989–3992.
191. Fischer, P., Moller, P., Bindl, L., Melzner, I., Tornqvist, H., Debatin, K. M. and
Wabitsch, M. (2002) Induction of adipocyte differentiation by a thiazolidinedione in
cultured, subepidermal, fibroblast-like cells of an infant with congenital generalized
lipodystrophy. J Clin Endocrinol Metab 87, 2384–2390.
192. Agarwal, A. K. and Garg, A. (2002) A novel heterozygous mutation in peroxisome
proliferator-activated receptor-gamma gene in a patient with familial partial
lipodystrophy. J Clin Endocrinol Metab 87, 408–411.
193. Lafontan, M. and Berlan, M. (1993) Fat cell adrenergic receptors and the control of
white and brown fat cell function. J Lipid Res 34, 1057–1091.

194. Emorine, L. J., Marullo, S., Briend-Sutren, M. M., Patey, G., Tate, K., Delavier-
Klutchko, C. and Strosberg, A. D. (1989) Molecular characterization of the human beta
3-adrenergic receptor. Science 245, 1118–1121.
195. Granneman, J. G., Lahners, K. N. and Chaudhry, A. (1993) Characterization of the
human beta 3-adrenergic receptor gene. Mol Pharmacol 44, 264–270.
196. Krief, S., Lonnqvist, F., Raimbault, S., Baude, B., Van Spronsen, A., Arner, P.,
Strosberg, A. D., Ricquier, D. and Emorine, L. J. (1993) Tissue distribution of beta
3-adrenergic receptor mRNA in man. J Clin Invest 91, 344–349.
REFERENCES 441
197. Lafontan, M. (1994) Differential recruitment and differential regulation by physiological
amines of fat cell beta-1, beta-2 and beta-3 adrenergic receptors expressed in native fat
cells and in transfected cell lines. Cell Signal 6, 363–392.
198. Balligand, J. L. (2000) Beta 3 adrenergic receptor: physiologic role and potential
therapeutic applications. Bull Mem Acad R Med Belg 155, 311–317; discussion
317–319.
199. Dixon, T. M., Daniel, K. W., Farmer, S. R. and Collins, S. (2001) CCAAT/enhancer-
binding protein alpha is required for transcription of the beta 3-adrenergic receptor gene
during adipogenesis. JBiolChem276, 722–728.
200. Walston, J., Silver, K., Bogardus, C., Knowler, W. C., Celi, F. S., Austin, S., Man-
ning, B., Strosberg, A. D., Stern, M. P. and Raben, N. et al. (1995) Time of onset of
non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-
receptor gene. N Engl J Med 333, 343–347.
201. Hayashi, H., Nagasaka, S., Ishikawa, S., Kawakami, A., Rokkaku, K., Nakamura, T.,
Saito, T., Kusaka, I., Higashiyama, M., Kubota, K. and Murakami, T. (1998)
Contribution of a missense mutation (Trp64Arg) in beta3-adrenergic receptor gene to
multiple risk factors in Japanese men with hyperuricemia. Endocr J 45, 779–784.
202. Manraj, M., Francke, S., Hebe, A., Ramjuttun, U. S. and Froguel, P. (2001) Genetic
and environmental nature of the insulin resistance syndrome in Indo-Mauritian subjects
with premature coronary heart disease: contribution of beta3-adrenoreceptor gene
polymorphism and beta blockers on triglyceride and HDL concentrations. Diabetologia

44, 115–122.
203. Strazzullo, P., Iacone, R., Siani, A., Cappuccio, F. P., Russo, O., Barba, G., Bar-
bato, A., D’Elia, L., Trevisan, M. and Farinaro, E. (2001) Relationship of the Trp64Arg
polymorphism of the beta3-adrenoceptor gene to central adiposity and high blood pres-
sure: interaction with age. Cross-sectional and longitudinal findings of the Olivetti
Prospective Heart Study. J Hypertens 19, 399–406.
204. Kim-Motoyama, H., Yasuda, K., Yamaguchi, T., Yamada, N., Katakura, T., Shuldiner,
A. R., Akanuma, Y., Ohashi, Y., Yazaki, Y. and Kadowaki, T. (1997) A mutation of
the beta 3-adrenergic receptor is associated with visceral obesity but decreased serum
triglyceride. Diabetologia 40, 469–472.
205. Melis, M. G., Secchi, G., Brizzi, P., Severino, C., Maioli, M. and Tonolo, G. (2002)
The Trp64Arg beta3-adrenergic receptor amino acid variant confers increased sensitivity
to the pressor effects of noradrenaline in Sardinian subjects. Clin Sci (Lond) 103,
397–402.
206. Gagnon, J., Mauriege, P., Roy, S., Sjostrom, D., Chagnon, Y. C., Dionne, F. T.,
Oppert, J. M., Perusse, L., Sjostrom, L. and Bouchard, C. (1996) The Trp64Arg
mutation of the beta3 adrenergic receptor gene has no effect on obesity phenotypes
in the Quebec Family Study and Swedish Obese Subjects cohorts. J Clin Invest 98,
2086–2093.
207. Rissanen, J., Kuopusjarvi, J., Pihlajamaki, J., Sipilainen, R., Heikkinen, S., Van-
hala, M., Kekalainen, P., Kuusisto, J. and Laakso, M. (1997) The Trp64Arg polymor-
phism of the beta 3-adrenergic receptor gene. Lack of association with NIDDM and
features of insulin resistance syndrome. Diabetes Care 20, 1319–1323.
208. Thomas, G. N., Tomlinson, B., Chan, J. C., Young, R. P. and Critchley, J. A. (2000)
The Trp64Arg polymorphism of the beta3-adrenergic receptor gene and obesity in
Chinese subjects with components of the metabolic syndrome. Int J Obes Relat Metab
Disord 24, 545–551.
209. Vogeser, M., Zachoval, R., Felbinger, T. W. and Jacob, K. (2002) Increased ratio of
serum cortisol to cortisone in acute-phase response. Horm Res 58, 172–175.
442 GENETICS OF THE METABOLIC SYNDROME

210. Ferrari, P. and Krozowski, Z. (2000) Role of the 11beta-hydroxysteroid dehydrogenase
type 2 in blood pressure regulation. Kidney Int 57, 1374–1381.
211. Williams, L. J., Lyons, V., MacLeod, I., Rajan, V., Darlington, G. J., Poli, V.,
Seckl, J. R. and Chapman, K. E. (2000) C/EBP regulates hepatic transcription of
11beta-hydroxysteroid dehydrogenase type 1. A novel mechanism for cross-talk
between the C/EBP and glucocorticoid signaling pathways. JBiolChem275,
30 232–30 239.
212. White, P. C., Agarwal, A. K., Nunez, B. S., Giacchetti, G., Mantero, F. and Stew-
art, P. M. (2000) Genotype–phenotype correlations of mutations and polymorphisms
in HSD11B2, the gene encoding the kidney isozyme of 11beta-hydroxysteroid dehy-
drogenase. Endocr Res 26, 771–780.
213. Agarwal, A. K., Giacchetti, G., Lavery, G., Nikkila, H., Palermo, M., Ricketts, M.,
McTernan, C., Bianchi, G., Manunta, P., Strazzullo, P., Mantero, F., White, P. C. and
Stewart, P. M. (2000) CA-repeat polymorphism in intron 1 of HSD11B2: effects on
gene expression and salt sensitivity. Hypertension 36, 187–194.
214. Li, A., Li, K. X., Marui, S., Krozowski, Z. S., Batista, M. C., Whorwood, C. B.,
Arnhold, I. J., Shackleton, C. H., Mendonca, B. B. and Stewart, P. M. (1997) Apparent
mineralocorticoid excess in a Brazilian kindred: hypertension in the heterozygote state.
J Hypertens 15, 1397–1402.
215. Wilson, R. C., Dave-Sharma, S., Wei, J. Q., Obeyesekere, V. R., Li, K., Ferrari, P.,
Krozowski, Z. S., Shackleton, C. H., Bradlow, L., Wiens, T. and New, M. I. (1998)
A genetic defect resulting in mild low-renin hypertension. Proc Natl Acad Sci USA 95,
10 200–10 205.
216. Rogoff, D., Smolenicka, Z., Bergada, I., Vallejo, G., Barontini, M., Heinrich, J. J. and
Ferrari, P. (1998) The codon 213 of the 11beta-hydroxysteroid dehydrogenase type 2
gene is a hot spot for mutations in apparent mineralocorticoid excess. J Clin Endocrinol
Metab 83, 4391–4393.
217. Nunez, B. S., Rogerson, F. M., Mune, T., Igarashi, Y., Nakagawa, Y., Phillipov, G.,
Moudgil, A., Travis, L. B., Palermo, M., Shackleton, C. and White, P. C. (1999)
Mutants of 11beta-hydroxysteroid dehydrogenase (11-HSD2) with partial activity:

improved correlations between genotype and biochemical phenotype in apparent
mineralocorticoid excess. Hypertension 34, 638–642.
218. Odermatt, A., Dick, B., Arnold, P., Zaehner, T., Plueschke, V., Deregibus,
M. N., Repetto, H., Frey, B. M., Frey, F. J. and Ferrari, P. (2001) A mutation
in the cofactor-binding domain of 11beta-hydroxysteroid dehydrogenase type 2 asso-
ciated with mineralocorticoid hypertension. J Clin Endocrinol Metab 86, 1247–
1252.
219. Sugiyama, T., Kato, N., Ishinaga, Y., Yamori, Y. and Yazaki, Y. (2001) Evaluation of
selected polymorphisms of the Mendelian hypertensive disease genes in the Japanese
population. Hypertens Res 24, 515–521.
220. Poch, E., Gonzalez, D., Giner, V., Bragulat, E., Coca, A. and de La Sierra, A.
(2001) Molecular basis of salt sensitivity in human hypertension. Evaluation
of renin–angiotensin–aldosterone system gene polymorphisms. Hypertension 38,
1204–1209.
221. Smith, A. D., (2000) Oxford Dictionary of Biochemistry and Molecular Biology.
Revised edn. Oxford: Oxford University Press.
222. Ruan, H., Hacohen, N., Golub, T. R., Van Parijs, L. and Lodish, H. F. (2002) Tumor
necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of
preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-
alpha is obligatory. Diabetes 51, 1319–1336.