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. [...]... 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