INSIG2 SNPs Associated With Obesity and Glucose Homeostasis Traits in Hispanics: The IRAS Family Study

The genome‐wide association study by Herbert et al. identified the INSIG2 single‐nucleotide polymorphism (SNP) rs7566605 as contributing to increased BMI in ethnically distinct cohorts. The present study sought to further clarify the matter, by testing whether SNPs of INSIG2 influenced quantitative adiposity or glucose homeostasis traits in Hispanics of the Insulin Resistance Atherosclerosis Family Study (IRASFS). Using a tagging SNP approach, rs7566605 and 31 additional SNPs were genotyped in 1,425 IRASFS Hispanics. SNPs were tested for association with six adiposity measures: BMI, waist circumference (WAIST), waist‐to‐hip ratio (WHR), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and VAT to SAT ratio (VSR). SNPs were also tested for association with fasting glucose (GFAST), fasting insulin (FINS), and three measures obtained from the frequently sampled intravenous glucose tolerance test: insulin sensitivity (S_I), acute insulin response (AIR), and disposition index (DI). Most prominent association was observed with direct computed tomography (CT)‐measured adiposity phenotypes, including VAT, SAT, and VSR (P values range from 0.007 to 0.044 for rs17586756, rs17047718, rs17047731, rs9308762, rs12623648, and rs11673900). Multiple SNP associations were observed with all glucose homeostasis traits (P values range from 0.001 to 0.031 for rs17047718, rs17047731, rs2161829, rs10490625, rs889904, and rs12623648). Using BMI as a covariate in evaluation of glucose homeostasis traits slightly reduced their association. However, association with adiposity and glucose homeostasis phenotypes is not significant following multiple comparisons adjustment. Trending association after multiple comparisons adjustment remains suggestive of a role for genetic variation of INSIG2 in obesity, but these results require validation.     

Hepatocyte nuclear factor 4 alpha P2 promoter variants associate with insulin resistance

This study aimed to investigate the associations of hepatocyte nuclear factor 4 (HNF4) alpha single nucleotide polymorphisms (SNPs) and haplotype with insulin resistance and metabolic syndrome parameters. Nine SNPs spanning the HNF4 alpha P2 promoter (rs4810424, rs1884613 and rs1884614) and coding region (rs2144908, rs6031551, rs6031552, rs1885088, rs1028583 and rs3818247) were genotyped in 160 subjects without diabetes or metabolic syndrome. The HNF4 alpha P2 promoter SNPs rs4810424, rs1884613 and rs1884614 were associated with insulin resistance (p = 0.017; 0.037; 0.024) and body mass index (BMI) (p = 0.03; 0.035; 0.039). The intron 1D SNP rs2144908 was associated with high-density lipoprotein cholesterol (HDLc) (p = 0.020) and the intron 9 SNP rs3818247 showed association with systolic (p = 0.02) and diastolic (p = 0.034) blood pressure. HNF4 alpha common haplotype CCCGTC associated with higher insulin resistance (p = 0.022), fasting blood glucose (FBG) (p = 0.035) and lower HDLc (p = 0.001). In conclusion, subjects with HNF4 alpha P2 variants and haplotypes have been shown to have a higher insulin resistance and are therefore at a higher risk for developing type 2 diabetes mellitus.     

Association of RBP4 Gene Variants and Serum HDL Cholesterol Levels in the Newfoundland Population

Retinol‐binding protein 4 (RBP4) is a novel adipokine that likely contributes to systemic insulin resistance and dyslipidemia. The role of genetic variations in RBP4 on phenotypes of glucose and lipid metabolism is not clear in humans. The purpose of this study was to examine five single‐nucleotide polymorphisms (SNPs) in the RBP4 gene to determine their relationship with markers of insulin resistance and serum lipids in the CODING Study. The CODING Study consists of 1,836 subjects recruited from the genetically homogeneous population of Newfoundland and Labrador (NL), Canada. Serum glucose, insulin, homeostasis model assessment of insulin resistance (HOMA_IR), HOMA for β cell function (HOMA_β), total cholesterol (Chol), high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), and triglycerides were determined after a 12‐h fast. Five SNPs within RBP4 (rs3758539, G/A 5′ flanking region; rs61461737, A/G intron; rs10882280, C/A intron; rs11187545, A/G intron; and rs12265684, C/G intron) were genotyped using TaqMan validated or functionally tested SNP genotyping assays. After correcting for multiple testing, we observed a significant association between the minor allele of two noncoding SNPs (rs10882280 and rs11187545) and higher serum HDL‐C (P = 0.043 and 0.042, respectively). No significant associations were observed with any other parameter related to lipid metabolism. We also found no significant association between any variant sites and markers of insulin resistance. Our results suggest that genetic variations in RBP4 may play a role in the differences in serum HDL‐C levels in the NL population.     

Association Studies on Ghrelin and Ghrelin Receptor Gene Polymorphisms With Obesity

Ghrelin exerts a stimulatory effect on appetite and regulates energy homeostasis. Ghrelin gene variants have been shown to be associated with metabolic traits, although there is evidence suggesting linkage and association with obesity and the ghrelin receptor (GHSR). We hypothesized that these genes are good candidates for susceptibility to obesity. Direct sequencing identified 12 ghrelin single‐nucleotide polymorphisms (SNPs) and 8 GHSR SNPs. The 10 common SNPs were genotyped in 1,275 obese subjects and in 1,059 subjects from a general population cohort of European origin. In the obesity case‐control study, the GHSR SNP rs572169 was found to be associated with obesity (P = 0.007 in additive model, P = 0.001 in dominant model, odds ratio (OR) 1.73, 95% confidence interval (1.23–2.44)). The ghrelin variant, g.A265T (rs4684677), showed an association with obesity (P = 0.009, BMI adjusted for age and sex) in obese families. The ghrelin variant, g.A‐604G (rs27647), showed an association with insulin levels at 2‐h post‐oral glucose tolerance test (OGTT) (P = 0.009) in obese families. We found an association between the eating behavior “overeating” and the GHSR SNP rs2232169 (P = 0.02) in obese subjects. However, none of these associations remained significant when corrected for multiple comparisons. Replication of the nominal associations with obesity could not be confirmed in a German genome‐wide association (GWA) study for rs4684677 and rs572169 polymorphisms. Our data suggest that common polymorphisms in ghrelin and its receptor genes are not major contributors to the development of polygenic obesity, although common variants may alter body weight and eating behavior and contribute to insulin resistance, in particular in the context of early‐onset obesity.     

Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity

Objective : Allelic variation (rs738409C→G) in adiponutrin (patatin‐like phospholipase domain‐containing protein 3, PNPLA3) has been associated with hepatic steatosis and liver fibrosis. The physiologic impact of the PNPLA3 G allele may be exacerbated in patients with severe obesity. In this study, we investigated the interactions of PNPLA3 rs738409 with a broad panel of metabolic and histologic characteristics of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) in patients with medically complicated obesity. Design and Methods : Consecutive patients undergoing bariatric surgery were selected for a prospective study. They underwent extensive laboratory and histologic (liver biopsy) assessment, as well as evaluation of rs738409 polymorphism by TaqMan assay. Results : Only 12 (8.3%) of the 144 patients had normal liver histology, with 72 (50%) NASH, of whom 15 (10.4% of total patients) had fibrosis stage 2‐3. PNPLA3 GG genotype correlated positively (P < 0.05) with serum levels of alanine aminotransferase (ALT), asparate aminotransferase (AST), glucose, fibrinogen, and insulin‐dependent diabetes mellitus, homeostasis model assessment—insulin resistance, and presence of NASH. Multivariate analysis indicated that PNPLA3 rs738409 G versus C allele remained an (independent) risk factor for NASH, in addition to CK‐18 >145 IU/l, glucose >100 mg/dl, and C‐reactive protein (CRP) >0.8 mg/dl. The probability of NASH increased from 9% (no risk factor) to 82% if all four risk factors were present. Conclusions : In this cohort of patients with medically complicated obesity, PNPLA3 rs738409 G allelic expression is associated with hepatic (NASH) and nonhepatic complications of obesity, such as insulin resistance. These novel findings may be related to a greater impact of PNPLA3 variant in magnitude and scope in patients with severe obesity than in less obese populations. Further studies are needed to characterize the nature of these associations.     

Variants at the endocannabinoid receptor CB1 gene (CNR1) and insulin sensitivity, type 2 diabetes, and coronary heart disease

Inhibition of the endocannabinoid receptor CB1 improves insulin sensitivity, lowers glycemia, and slows atherosclerosis. We analyzed whether common variants in the gene encoding CB1, CNR1, are associated with insulin resistance, risk of type 2 diabetes (T2D) or coronary heart disease (CHD). We studied 2,411 participants of the Framingham Offspring Study (mean age 60 years, 52% women) for quantitative traits and CHD, and the Framingham SHARe database for T2D risk. We genotyped 19 single-nucleotide polymorphisms (SNPs) that tagged 85% (at r(2) = 0.8) of common (>5%) CNR1 SNPs. Fasting blood glucose and insulin at the 7th (1999-2001) exam were collected. We used age-, sex-, BMI-adjusted models to test additive associations of genotype with homeostasis model assessment of insulin resistance (HOMA(IR)) (linear mixed-effect models), T2D, or CHD. To account for multiple tests of SNPs, we generated empirical P values. The C allele at SNP rs806365 (frequency, 57.4%), ~4.1 kb 3' from CNR1, was associated with increased HOMA(IR) (n = 2,261, β = 0.05 per C, empirical P = 0.01), risk of T2D (674 cases, odds ratio = 1.19 per C, nominal P = 0.01) and CHD (237 cases, hazard ratio = 1.23 per C, nominal P = 0.04). The association of rs806365 with HOMA(IR) was replicated in a meta-analysis of two independent cohorts (National Health and Nutrition Examination Survey III genetic cohort (NHANES-III) plus Partners Case-Control Diabetes Study; 2,540 white individuals, β = 0.037, nominal P = 0.007), but not in the large Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Consortium (n = 29,248, nominal P = 0.74). The association of rs806365 was not replicated either with T2D in Diabetes Genetics Replication and Meta-analysis (DIAGRAM) (n = 10,128, nominal P = 0.31), or with CHD in PROCARDIS (n = 13,614, nominal P = 0.37). Although supported by initial results, we found no reproducible statistical association of common variation at CNR1 with insulin resistance, T2D, or CHD.     

The SH2B gene is associated with serum leptin and body fat in normal female twins

Src-homology-2 (SH2)-B, a Janus tyrosine kinase 2-interacting protein, has been identified recently as a key regulator of leptin and insulin sensitivity, glucose homeostasis, and body weight in mice. The aim of this study was to determine whether single-nucleotide polymorphisms (SNPs) in the human SH2B gene are associated with these variables. A tagging SNP (tSNP), Ala484Thr (rs7498665), was selected to represent five common SNPs (minor allele frequency > 0.05) in perfect linkage disequilibrium in a 16-kb region encompassing the SH2B gene. The tSNP was genotyped in 2455 white female twins (mean age, 47.4 +/- 12.6 years) from the St. Thomas' United Kingdom Adult Twin Registry (Twins United Kingdom). Ala484Thr (minor allele frequency, 0.38) was associated with serum leptin, total fat, waist circumference, and body weight (P = 0.02 to 0.04). The coding SNP has no predicted effect on protein structure or function and is likely to be in linkage disequilibrium with an as-yet unidentified functional variant in the SH2B gene. Our results support a role for SH2-B in modulating the regulation of body weight and fat by leptin in this female population. If SH2-B signaling is attenuated in diet-induced obesity, it could become a target for drug-induced leptin sensitization.     

Beneficial effect of CLOCK gene polymorphism rs1801260 in combination with low-fat diet on insulin metabolism in the patients with metabolic syndrome

Genetic variation at the Circadian Locomotor Output Cycles Kaput (CLOCK) locus has been associated with lifestyle-related conditions such as obesity, metabolic syndrome (MetS) and cardiovascular diseases. In fact, it has been suggested that the disruption of the circadian system may play a causal role in manifestations of MetS. The aim of this research was to find out whether habitual consumption of a low-fat diet, compared with a Mediterranean diet enriched with olive oil, modulates the associations between common CLOCK single nucleotide polymorphisms (SNPs) (rs1801260, rs3749474 and rs4580704) and lipid and glucose-related traits among MetS patients. Plasma lipid and insulin concentrations, indexes related with insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)) and CLOCK SNPs were determined in 475 MetS subjects participating in the CORDIOPREV clinical trial (NCT00924937). Gene–diet interactions were analyzed after a year of dietary intervention (Mediterranean diet (35% fat, 22% monounsaturated fatty acids (MUFA)) versus low-fat diet (28% fat, 12% MUFA)). We found significant gene–diet interactions between rs1801260 SNP and the dietary pattern for insulin concentrations (p?=?0.009), HOMA-IR (p?=?0.014) and QUICKI (p?=?0.028). Specifically, after 12 months of low-fat intervention, subjects who were homozygous for the major allele (TT) displayed lower plasma insulin concentrations (p?=?0.032), lower insulin resistance (HOMA-IR; p?=?0.027) and higher insulin sensitivity (QUICKI; p?=?0.024) compared with carriers of the minor allele C (TC?+?CC). In contrast, in the Mediterranean intervention group a different trend was observed although no significant differences were found between CLOCK genotypes after 12 months of treatment. Our data support the notion that a chronic consumption of a healthy diet may play a contributing role in triggering glucose metabolism by interacting with the rs1801260 SNP at CLOCK gene locus in MetS patients. Due to the complex nature of gene–environment interactions, dietary adjustment in subjects with the MetS may require a personalized approach.     

Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes

Recent studies have shown that SNPs in the FTO gene predispose to childhood and adult obesity. In this study, we examined the association between variants in FTO and KIAA1005, a gene that maps closely to FTO, and obesity, as well as obesity related traits among 450 well characterised severely obese children and 512 normal weight controls. FTO showed significant association with several obesity related traits while SNPs in KIAA1005 did not. When stratified by gender, the FTO variant rs9939609 showed association with obesity and BMI among girls (P = 0.006 and 0.004, respectively) but not among boys. Gender differences were also found in the associations of the FTO rs9939609 with obesity related traits such as insulin sensitivity and plasma glucose. This study suggests that FTO may have an important role for gender specific development of severe obesity and insulin resistance in children.     

Variants in the CD36 gene locus determine whole-body adiposity, but have no independent effect on insulin sensitivity

CD36 variants have been associated with type 2 diabetes, features of the metabolic syndrome, and alterations in lipid metabolism. In contrast, the effect of single-nucleotide polymorphisms (SNPs) in CD36 on insulin resistance is controversial in literature. Therefore, we investigated whether genetic variation within the CD36 gene locus affects insulin resistance in a well-phenotyped cohort of white European subjects at increased risk for type 2 diabetes. We genotyped 1,790 subjects (1,174 women, 616 men) for six SNPs tagging 100% of common variants (minor allele frequency ≥0.05) within the CD36 gene locus with an r2 ≥ 0.8. All subjects underwent an oral glucose tolerance test (OGTT) and a subset additionally a hyperinsulinemic-euglycemic clamp (n = 523). Ectopic hepatic lipids (n = 346) were assessed by magnetic resonance spectroscopy. After appropriate adjustment and Bonferroni correction for multiple comparisons, the four CD36 SNPs rs9784998, rs3211883, rs3211908, and rs3211956 significantly associated with BMI and rs3211883 and rs3211908 significantly associated with waist circumference (all P < 0.0042). In contrast, CD36 SNPs rs3211816 and rs3211960 were not associated with measures of adiposity (all P ≥ 0.11). No reliable association was detected between the six CD36 SNPs and insulin sensitivity or ectopic hepatic lipid accumulation after adjustment for age, gender, and BMI. In the long run, genetic variation within the CD36 locus may contribute to metabolic disease via its effect on body adiposity, but not via an independent effect on insulin sensitivity.     

Variation in IGF2BP2 Interacts With Adiposity to Alter Insulin Sensitivity in Mexican Americans

Genome‐wide association studies showed variation in insulin‐like growth factor‐2 binding protein 2 (IGF2BP2) to be associated with type 2 diabetes mellitus (T2DM). We examined a 20‐kb region of IGF2BP2 for association with T2DM‐related quantitative traits in Mexican American families of a proband with gestational diabetes mellitus (GDM) from the BetaGene study. We genotyped 14 single‐nucleotide polymorphisms (SNPs) in 717 individuals from 146 families phenotyped by oral glucose tolerance test (OGTT), intravenous glucose tolerance tests (IVGTTs) with minimal model analysis, and dual‐energy X‐ray absorptiometry scan for percent body fat. Three SNPs and one SNP combination that captured the majority of the variation in the region were tested for association with T2DM‐related quantitative traits using a variance components framework. After correction for multiple testing, rs11705701 showed association with percent body fat (P_ACT = 0.041) with body fat decreasing ～1.5–2% per copy of the A allele. We next tested whether the interaction between rs11705701 and body fat was associated with T2DM‐relative quantitative traits. rs11705701 was significantly associated with insulin sensitivity (Bonferroni P = 0.028) and marginally associated with OGTT 2‐h insulin (Bonferroni P = 0.066) and disposition index (DI) (Bonferroni P = 0.072). We conclude that rs11705701 in IGF2BP2 is associated with body fat and this effect on body fat influences insulin resistance which may contribute to T2DM risk.     

Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis

Leptin activates the long form of the leptin receptor (LRb) to control feeding and neuroendocrine function and thus regulate adiposity. While adiposity influences insulin sensitivity, leptin also regulates glucose homeostasis independently of energy balance. Disruption of the LRb/STAT3 signal in s/s mice results in hyperphagia, neuroendocrine dysfunction, and obesity similar to LRb null db/db mice. Insulin resistance and glucose intolerance are improved in s/s compared to db/db animals, however, suggesting that LRb/STAT3-independent signals may contribute to the regulation of glucose homeostasis by leptin. Indeed, caloric restriction normalized glycemic control in s/s animals, but db/db mice of similar weight and adiposity remained hyperglycemic. These differences in glucose homeostasis were not attributable to differences in insulin production between s/s and db/db animals but rather to decreased insulin resistance in s/s mice. Thus, in addition to LRb/STAT3-mediated adiposity signals, non-LRb/STAT3 leptin signals mediate an important adiposity-independent role in promoting glycemic control.     

Association of Common Genetic Variants in the MAP4K4 Locus with Prediabetic Traits in Humans

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is expressed in all diabetes-relevant tissues and mediates cytokine-induced insulin resistance. We investigated whether common single nucleotide polymorphisms (SNPs) in the MAP4K4 locus associate with glucose intolerance, insulin resistance, impaired insulin release, or elevated plasma cytokines. The best hit was tested for association with type 2 diabetes. Subjects (N = 1,769) were recruited from the Tübingen Family (TÜF) study for type 2 diabetes and genotyped for tagging SNPs. In a subgroup, cytokines were measured. Association with type 2 diabetes was tested in a prospective case-cohort study (N = 2,971) derived from the EPIC-Potsdam study. Three SNPs (rs6543087, rs17801985, rs1003376) revealed nominal and two SNPs (rs11674694, rs11678405) significant associations with 2-hour glucose levels. SNPs rs6543087 and rs11674694 were also nominally associated with decreased insulin sensitivity. Another two SNPs (rs2236936, rs2236935) showed associations with reduced insulin release, driven by effects in lean subjects only. Three SNPs (rs11674694, rs13003883, rs2236936) revealed nominal associations with IL-6 levels. SNP rs11674694 was significantly associated with type 2 diabetes. In conclusion, common variation in MAP4K4 is associated with insulin resistance and β-cell dysfunction, possibly via this gene’s role in inflammatory signalling. This variation’s impact on insulin sensitivity may be more important since its effect on insulin release vanishes with increasing BMI.     

Risk of obesity and metabolic syndrome associated with FTO gene variants discloses clinically relevant gender difference among Turks

Gene variations in the fat mass- and obesity-associated gene (FTO) have shown controversial associations with obesity and metabolic syndrome (MetS) in several populations. We explored the association of FTO gene with obesity, MetS, and insulin-related parameters separately in men and women. Two SNPs in the FTO, gene rs9939609 and rs1421085, were genotyped by the Taqman System in 1967 adults (mean age of the whole group 50.1 ± 12.0; 48.4 % male). A random sample of the Turkish Adult Risk Factor cohort was cross-sectionally analyzed. Both SNPs exhibited strong linkage disequilibrium (r² = 0.85) and minor alleles were associated with risk of obesity in women and of MetS in men. Carriers of the rs1421085 C-allele exhibited higher body mass index (BMI) in each gender. Adjusted fasting insulin and HOMA index were significantly higher in C-allele carriers in men alone. Logistic regression analysis demonstrated significantly increased likelihood for obesity in female C-risk allele carriers (OR 1.61; 95 % CI 1.19–2.18), after adjustment for age, smoking status, alcohol usage, physical activity grade and presence of diabetes mellitus. Male C-allele carriers were at increased risk for MetS (OR 1.44; 95 % CI 1.07–1.95), adjusted for age, smoking status, alcohol consumption, and physical activity. Further adjustment for BMI attenuated the MetS risk, indicating interaction between C-allele, gender and BMI. The FTO gene in Turkish adults contributes independently to obesity in women and—by interacting with BMI—to MetS and insulin resistance in men.     

Regulation of Insulin and Leptin Signaling by Muscle Suppressor of Cytokine Signaling 3 (SOCS3)

Skeletal muscle resistance to the key metabolic hormones, leptin and insulin, is an early defect in obesity. Suppressor of cytokine signaling 3 (SOCS3) is a major negative regulator of both leptin and insulin signaling, thereby implicating SOCS3 in the pathogenesis of obesity and associated metabolic abnormalities. Here, we demonstrate that SOCS3 mRNA expression is increased in murine skeletal muscle in the setting of diet-induced and genetic obesity, inflammation, and hyperlipidemia. To further evaluate the contribution of muscle SOCS3 to leptin and insulin resistance in obesity, we generated transgenic mice with muscle-specific overexpression of SOCS3 (MCK/SOCS3 mice). Despite similar body weight, MCK/SOCS3 mice develop impaired systemic and muscle-specific glucose homeostasis and insulin action based on glucose and insulin tolerance tests, hyperinsulinemic-euglycemic clamps, and insulin signaling studies. With regards to leptin action, MCK/SOCS3 mice exhibit suppressed basal and leptin-stimulated activity and phosphorylation of alpha2 AMP-activated protein kinase (α2AMPK) and its downstream target, acetyl-CoA carboxylase (ACC). Muscle SOCS3 overexpression also suppresses leptin-regulated genes involved in fatty acid oxidation and mitochondrial function. These studies demonstrate that SOC3 within skeletal muscle is a critical regulator of leptin and insulin action and that increased SOCS may mediate insulin and leptin resistance in obesity.     

Association of adiponectin promoter variants with traits and clusters of metabolic syndrome in Arabs: Family-based study

Plasma levels of adiponectin are decreased in type 2 diabetes, obesity and hypertension. Our aim was to use a family-based analysis to identify the genetic variants of the adiponectin (ADIPOQ) gene that are associated with obesity, insulin resistance, dyslipidemia and hypertension, among Arabs. We screened 328 Arabs in one large extended family for single nucleotide polymorphisms (SNPs) in the promoter region of the ADIPOQ gene. Two common SNPs were detected: rs17300539 and rs266729. Evidences of association between traits related to the metabolic syndrome and the SNPs were studied by implementing quantitative genetic association analysis. Results showed that SNP rs266729 was significantly associated with body weight (p-value = 0.001), waist circumference (p-value = 0.037), BMI (p-value = 0.015) and percentage of total body fat (p-value = 0.003). Up to 4.1% of heritability of obesity traits was explained by the rs266729 locus. Further cross-sectional analysis showed that carriers of the G allele had significantly higher values of waist circumference, BMI and percentage of total body fat (p-values 0.014, 0.004 and 0.032, respectively). No association was detected between SNP rs266729 and other clusters of metabolic syndrome or their traits except for HOMA-IR and fasting plasma insulin levels, p-values 0.035 and 0.004, respectively. In contrast, both measured genotype and cross-sectional analysis failed to detect an association between the SNP rs17300539 with traits and clusters of metabolic syndrome. In conclusion, we showed family-based evidence of association of SNP rs266729 at ADIPOQ gene with traits defining obesity in Arab population. This is important for future prediction and prevention of obesity in population where obesity is in an increasing trend.     

The FTO gene is associated with adulthood obesity in the Mexican population

Common polymorphisms in the fat mass and obesity-associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican-Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single-nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B-cell function (HOMA-B), and with higher homeostasis model assessment of insulin sensitivity (HOMA-S) only in nonobese individuals (P (dom) = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican-Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals.