Gender differences in the relationship of ENPP1/PC-1 variants to obesity in a Turkish population

The ectoenzyme ENPP1 (also termed membrane glycoprotein PC-1 or ENPP1/PC-1) is an inhibitor of insulin-induced activation of the insulin receptor. There is evidence from previous studies that coding variants of ENPP1/PC-1 (K121Q) are associated with type 2 diabetes (T2D) and obesity. Studies in the general Turkish population have demonstrated: unique plasma lipid characteristics, a high prevalence of cardiovascular risk factors, and an increased prevalence of obesity and T2D. We investigated, therefore, the association of ENPP1/PC-1 variants with obesity and T2D in Turkish individuals. The TaqMan allelic discrimination assay was used for genotyping the relationship of ENPP1/PC-1 variants to obesity and T2D in a genetic association study of 1,553 genotyped, randomly selected subjects from the Turkish Heart Study. The K121Q (rs1044498) variant and other previously reported variants (rs997509, rs1799774, rs1044548, rs11964389, rs7754561) were analyzed. In this cohort, the minor allele frequency (MAF) of the K121Q variant was associated with obesity in male, but not in female subjects (male, odds ratio 1.64, 95% confidence interval 1.004-2.698, P = 0.048; female, odds ratio 1.003, 95% confidence interval 0.684-1.471, P = ns). In addition, the previously reported ENPP1/PC-1 "risk haplotype" (Q (rs1044498), delT (rs1799774), and G (rs7754561) alleles) was found to be associated with obesity in male, but not in female, subjects (P = 0.035). In contrast, there was no association of either the K121Q variant or the ENPP1/PC-1 haplotype with T2D. We find evidence that variants of ENPP1/PC-1 are associated with obesity in the male Turkish population; thus, these variants may contribute to the development of the obesity in these individuals.     

Common variants in FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 show evidence of association with adult obesity in the Greek population

Twenty-four single-nucleotide polymorphisms (SNPs) have been reproducibly associated with obesity. We performed a follow-up study for obesity in the Greek adult population. A total of 510 obese and 469 lean adults were genotyped for 24 SNPs. We tested the association with obesity status using logistic regression and we evaluated the combined genetic risk of 24 SNPs by calculating the area under the receiver-operating characteristic (ROC) curves. We nominally replicated the association with obesity (BMI ≥30 kg/m(2)) of six SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci (1.28 ≤ odds ratio (OR) ≤ 1.35; 0.004 ≤ P ≤ 0.043). The discrimination ability for obesity was slightly stronger (P = 9.59 × 10(-6)) when the genetic information of the 24 SNPs was added to nongenetic risk factors (area under the curve (AUC) = 0.722) in comparison with nongenetic factors analyzed alone (AUC = 0.685). Our data suggest that SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci contribute to obesity risk in the Greek population.     

Investigation of a genome wide association signal for obesity: synthetic association and haplotype analyses at the melanocortin 4 receptor gene locus

Background

Independent genome-wide association studies (GWAS) showed an obesogenic effect of two single nucleotide polymorphisms (SNP; rs12970134 and rs17782313) more than 150 kb downstream of the melanocortin 4 receptor gene (MC4R). It is unclear if the SNPs directly influence MC4R function or expression, or if the SNPs are on a haplotype that predisposes to obesity or includes functionally relevant genetic variation (synthetic association). As both exist, functionally relevant mutations and polymorphisms in the MC4R coding region and a robust association downstream of the gene, MC4R is an ideal model to explore synthetic association.

Methodology/Principal Findings

We analyzed a genomic region (364.9 kb) encompassing the MC4R in GWAS data of 424 obesity trios (extremely obese child/adolescent and both parents). SNP rs12970134 showed the lowest p-value (p = 0.004; relative risk for the obesity effect allele: 1.37); conditional analyses on this SNP revealed that 7 of 78 analyzed SNPs provided independent signals (p≤0.05). These 8 SNPs were used to derive two-marker haplotypes. The three best (according to p-value) haplotype combinations were chosen for confirmation in 363 independent obesity trios. The confirmed obesity effect haplotype includes SNPs 3′ and 5′ of the MC4R. Including MC4R coding variants in a joint model had almost no impact on the effect size estimators expected under synthetic association.

Conclusions/Significance

A haplotype reaching from a region 5′ of the MC4R to a region at least 150 kb from the 3′ end of the gene showed a stronger association to obesity than single SNPs. Synthetic association analyses revealed that MC4R coding variants had almost no impact on the association signal. Carriers of the haplotype should be enriched for relevant mutations outside the MC4R coding region and could thus be used for re-sequencing approaches. Our data also underscore the problems underlying the identification of relevant mutations depicted by GWAS derived SNPs.     

The role of common and rare MC4R variants and FTO polymorphisms in extreme form of obesity

Melanocortin 4 receptor (MC4R) is an important regulator of food intake and number of studies report genetic variations influencing the risk of obesity. Here we explored the role of common genetic variation from MC4R locus comparing with SNPs from gene FTO locus, as well as the frequency and functionality of rare MC4R mutations in cohort of 380 severely obese individuals (BMI > 39 kg/m²) and 380 lean subjects from the Genome Database of Latvian Population (LGDB). We found correlation for two SNPs—rs11642015 and rs62048402 in the fat mass and obesity-associated protein (FTO) with obesity but no association was detected for rs17782313 located in the MC4R locus in these severely obese individuals. We sequenced the whole gene MC4R coding region in all study subjects and found five previously known heterozygous non-synonymous substitutions V103I, I121T, S127L, V166I and I251L. Expression in mammalian cells showed that the S127L, V166I and double V103I/S127L mutant receptors had significantly decreased quantity at the cell surface compared to the wild type MC4R. We carried out detailed functional analysis of V166I that demonstrated that, despite low abundance in plasma membrane, the V166I variant has lower EC₅₀ value upon αMSH activation than the wild type receptor, while the level of AGRP inhibition was decreased, implying that V166I cause hyperactive satiety signalling. Overall, this study suggest that S127L may be the most frequent functional MC4R mutation leading to the severe obesity in general population and provides new insight into the functionality of population based variants of the MC4R.     

Polymorphisms in the NPY2R gene show significant associations with BMI that are additive to FTO, MC4R, and NPFFR2 gene effects

Neuropeptide Y (NPY) is an appetite hormone that acts centrally to control feeding behavior. The 5' and exon 2 regions of NPY2R, one of five NPY receptor genes, have been weakly and inconsistently implicated with obesity. With the ATG start site of the gene at the beginning of exon 2, single-nucleotide polymorphisms (SNPs) across intron 1 may show stronger associations with obesity than expected. Two 5' SNPs, three intron 1 SNPs, and one synonymous exon 2 SNP were genotyped on 2,985 white Utah subjects. Previously associated FTO, NPY, NPY1R, MC4R, PPARGC1A, OR7D4, and four NPFFR2 SNPs were also genotyped and related to BMI. One NPY2R 5' SNP (rs12649641, P = 0.008), an exon 2 SNP (rs2880415, P = 0.009), and an intron 1 SNP (rs17376826, P = 7 × 10(-6)) were each significantly associated with BMI. All three SNPs, plus FTO (rs9939609, P = 1.5 × 10(-6)) and two NPFFR2 SNPs (rs4129733, P = 3.7 × 10(-13) and rs11940196, 4.2 × 10(-10)) remained significant in a multiple regression additive model. Diplotypes using the estimated haplotypes of NPY2R, NPFFR2, and MC4R were significantly associated with BMI (P = 1.0 × 10(-10), 3.2 × 10(-8), and 1.1 × 10(-4), respectively). Haplotypes of NPY2R, NPFFR2, and MC4R, plus the FTO SNP, explained 9.6% of the BMI variance. SNP effect sizes per allele for the four genes ranged from 0.8 to 3.5 kg/m(2). We conclude that haplotypes containing the rs17376826 SNP in intron 1 of NPY2R have strong associations with BMI, some NPFFR2 haplotypes are strongly protective against or increase risk of obesity, and both NPY2R and NPFFR2 play important roles in obesity predisposition independent of FTO and MC4R.     

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.     

The Q121 variant of ENPP1 may protect from childhood overweight/obesity in the Italian population

Ectonucleotide Pyrophosphatase Phosphodiesterase 1 (ENPP1) downregulates insulin signaling by inhibiting the insulin receptor's tyrosine-kinase. K121Q and other ENPP1 single-nucleotide polymorphisms (SNPs), IVS20delT-11 and A/G+1044TGA, have been previously associated with obesity in French children, and the risk haplotype QdelTG has also been associated with this condition in both French and German children. Our aim was to perform a case-control replication study in order to assess the possible association of childhood obesity and overweight with the above-mentioned ENPP1 SNPs, and with the QdelTG haplotype, in the Italian population. A total of 865 healthy Italian children were studied: 453 normal-weight, 243 overweight and 169 obese subjects. Genotyping was performed by Taq-Man or Light-Cycler Technology. The Q variant of K121Q showed a negative association with overweight-obesity under both additive (odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.57-0.97, P = 0.030) and recessive (OR = 0.32, 95% CI = 0.10-0.97, P = 0.035) modes of inheritance. The Z-score of BMI showed a significant decreasing trend from children K/K homozygous to K/Q heterozygous, and to Q/Q homozygous (0.45 vs. 0.28 vs. -0.19; P = 0.009), according to the additive model. The two other SNPs and the QdelTG haplotype did not exhibit any association with overweight/obesity. This is the first child-based study showing a protective role of the 121Q variant of ENPP1 against overweight/obesity.     

Association of Hepatocyte Nuclear Factor 4 Alpha Polymorphisms with Type 2 Diabetes With or Without Metabolic Syndrome in Malaysia

This study investigated the association of hepatocyte nuclear factor 4 (HNF4) alpha single nucleotide polymorphisms (SNPs) with type 2 diabetes with or without metabolic syndrome in Malaysia. Nine HNF4 alpha SNPs were genotyped in 390 type 2 diabetic subjects with metabolic syndrome, 135 type 2 diabetic subjects without metabolic syndrome, and 160 control subjects. The SNPs rs4810424, rs1884613, and rs2144908 were associated with protection against type 2 diabetes without metabolic syndrome (recessive P = 0.018, OR 0.32; P = 0.004, OR 0.25; P = 0.005, OR 0.24, respectively). The 6-SNP haplotype2 CCCGTC containing the risk genotype of these SNPs was associated with higher risk for type 2 diabetes with or without metabolic syndrome (P = 0.002, OR 2.2; P = 0.004, OR 3.1). These data suggest that HNF4 alpha SNPs and haplotypes contributed to increased type 2 diabetes risk in the Malaysian population.     

A common haplotype in NAPEPLD is associated with severe obesity in a Norwegian population-based cohort (the HUNT study)

Obesity has a strong genetic etiology involving numerous identified metabolic pathways and others not yet examined. We investigated the association between severe obesity and genetic variation in selected candidate genes, including three drug-related genes: cannabinoid receptor 1 (CNR1), N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD), and gastric lipase (LIPF); and three genes related to inflammation: nicotinamide phosphoribosyltransferase, six-transmembrane epithelial antigen of the prostate 4 (STEAP4) and interleukin 18 (IL-18). Subjects were 1,632 individuals with severe obesity (BMI ≥ 35 kg/m2) and 3,379 controls (BMI 20-24.9 kg/m2) that took part in a Norwegian population based cohort study. Tagging single-nucleotide polymorphisms (SNPs) of the coding region of these genes were analyzed. SNP-haplotypes for each gene were constructed in order to analyze allelic, genotypic, and haplotypic association to obesity. A single SNPs rs17605251 in NAPEPLD was nominally associated with BMI ≥ 35 kg/m2 (P = 0.035). A common haplotype in NAPEPLD was associated with BMI ≥ 35 kg/m2 after correction for multiple testing. The allele frequency was 56.8% in cases and 60.3% in controls, giving an odds ratio (OR) of 0.87 (95% confidence interval (CI) 0.79, 0.95; P = 0.0016). Homozygosity for this haplotype was protective against obesity (OR 0.79 (CI 0.70-0.91); P = 0.00059). The SNP rs7913071 in LIPF was associated with obesity, but the association lost statistical significance after correction for multiple testing. The CNR1, IL-18, STEAP4, and nicotinamide phosphoribosyltransferase genes were not associated with obesity. In conclusion a common haplotype in NAPEPLD, an enzyme involved in endocannabinoid synthesis, was protective against obesity.     

Association between type 2 diabetes mellitus-related SNP variants and obesity traits in a Saudi population

Obesity, commonly measured as body mass index (BMI), has been on a rapid rise around the world and is an underlying cause of several chronic non-communicable diseases, including type 2 diabetes mellitus (T2DM). In addition to the environmental factors, genetic factors may also contribute to the ongoing obesity epidemic in Saudi Arabia. This study investigated the association between variants of 36 previously established T2DM SNPs and obesity phenotypes in a population of Saudi subjects. Study subjects consisted of 975 obese (BMI: ≥30), 825 overweight (25–30) and 423 lean controls (18–25) and of these 927 had a history of T2DM. Subjects were genotyped for 36 SNPs, which have been previously proved to be T2DM linked, using the KASPar method and the means of BMI and waist circumference (WC) corresponding to each of the genotypes were compared by additive, recessive and dominant genetic models. Five and seven of 36 T2DM-related SNPs were significantly associated with the BMI and WC, respectively. Variants of SNPs rs7903146, rs1552224 and rs11642841 in the control group and rs7903146 in T2DM group showed significant association with both BMI and WC. Variant of SNP rs10440833 was significantly associated with BMI in T2DM group of both males [OR = 1.8 (1.0, 3.3); P = 0.04] and females [OR = 2.0 (1.0, 3.9); P = 0.04]. Genetic risk scores explained 19 and 14 % of WC and hip size variance in this population. Variants of a number of established T2DM related SNPs were associated with obesity phenotypes and may be significant hereditary factors in the pathogenesis of T2DM.     

Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP

Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs9939609, within the FTO locus and obesity as a consequence of a genome wide association (GWA) study of type 2 diabetes in adults. We examined the effects of two perfect surrogates for this SNP plus 11 other SNPs at this locus with respect to our childhood obesity cohort, consisting of both Caucasians and African Americans (AA). Utilizing data from our ongoing GWA study in our cohort of 418 Caucasian obese children (BMI>or=95th percentile), 2,270 Caucasian controls (BMI<95th percentile), 578 AA obese children and 1,424 AA controls, we investigated the association of the previously reported variation at the FTO locus with the childhood form of this disease in both ethnicities. The minor allele frequencies (MAF) of rs8050136 and rs3751812 (perfect surrogates for rs9939609 i.e. both r(2) = 1) in the Caucasian cases were 0.448 and 0.443 respectively while they were 0.391 and 0.386 in Caucasian controls respectively, yielding for both an odds ratio (OR) of 1.27 (95% CI 1.08-1.47; P = 0.0022). Furthermore, the MAFs of rs8050136 and rs3751812 in the AA cases were 0.449 and 0.115 respectively while they were 0.436 and 0.090 in AA controls respectively, yielding an OR of 1.05 (95% CI 0.91-1.21; P = 0.49) and of 1.31 (95% CI 1.050-1.643; P = 0.017) respectively. Investigating all 13 SNPs present on the Illumina HumanHap550 BeadChip in this region of linkage disequilibrium, rs3751812 was the only SNP conferring significant risk in AA. We have therefore replicated and refined the association in an AA cohort and distilled a tag-SNP, rs3751812, which captures the ancestral origin of the actual mutation. As such, variants in the FTO gene confer a similar magnitude of risk of obesity to children as to their adult counterparts and appear to have a global impact.     

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.     

REV-ERB ALPHA Polymorphism Is Associated with Obesity in the Spanish Obese Male Population

REV-ERB ALPHA has been shown to link metabolism with circadian rhythms. We aimed to identify new polymorphisms in the promoter of REV-ERB ALPHA and tested whether these polymorphisms could be associated with obesity in the Spanish population. Of the 1197 subjects included in our study, 779 were obese (BMI 34.38±3.1 kg/m²) and 418 lean (BMI 23.27±1.5 kg/m²). In the obese group, 469 of the 779 had type 2 diabetes. Genomic DNA from all the subjects was obtained from peripheral blood cells and the genotyping in the REV-ERB ALPHA promoter was analyzed by High Resolution Melting. We found six polymorphisms in the REV-ERB ALPHA promoter and identified rs939347 as a SNP with the highest frequency in the total population. We did not find any association between rs939347 and type 2 diabetes (p = 0.101), but rs939347 was associated with obesity (p = 0.036) with the genotype AA exhibiting higher frequency in the obese (5.2% in total obese vs 2.4% in lean). This association was found only in men (p = 0.031; 6.5% AA-carriers in obese men vs 1.9% AA-carriers in lean men), with no association found in the female population (p = 0.505; 4.4% AA-carriers in obese women vs 2.7% AA-carriers in lean women). Our results suggest that the REV-ERB ALPHA rs939347 polymorphism could modulate body fat mass in men. The present work supports the role of REV-ERB ALPHA in the development of obesity as well as a potential target for the treatment of obesity.     

Melanocortin-4 receptor gene variant I103 is negatively associated with obesity

Several rare mutations in the melanocortin-4 receptor gene (MC4R) predispose to obesity. For the most common missense variant V103I (rs2229616), however, the previously reported similar carrier frequencies in obese and nonobese individuals are in line with in vitro studies, which have not shown a functional implication of this variant. In the present study, we initially performed a transmission/disequilibrium test on 520 trios with obesity, and we observed a lower transmission rate of the I103 allele (P=.017), which was an unexpected finding. Therefore, we initiated two large case-control studies (N=2,334 and N=661) and combined the data with those from 12 published studies, for a total of 7,713 individuals. The resulting meta-analysis provides evidence for a negative association of the I103 allele with obesity (odds ratio 0.69; 95% confidence interval 0.50-0.96; P=.03), mainly comprising samples of European origin. Additional screening of four other ethnic groups showed comparable I103 carrier frequencies well below 10%. Genomic sequencing of the MC4R gene revealed three polymorphisms in the noncoding region that displayed strong linkage disequilibrium with V103I. In our functional in vitro assays, the variant was indistinguishable from the wild-type allele, as was the result in previous studies. This report on an SNP/haplotype that is negatively associated with obesity expands the successful application of meta-analysis of modest effects in common diseases to a variant with a carrier frequency well below 10%. The respective protective effect against obesity implies that variation in the MC4R gene entails both loss and gain of function.     

Genetic association of ADIPOQ gene variants with type 2 diabetes,obesity and serum adiponectin levels in south Indian population

Objective

To investigate the genetic association of eight variants of the adiponectin gene with type 2 diabetes mellitus (T2DM), obesity and serum adiponectin level in the south Indian population.

Methods

The study comprised of 1100 normal glucose tolerant (NGT) and 1100 type 2 diabetic, unrelated subjects randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Fasting serum adiponectin levels were measured by radioimmunoassay. The variants were screened by polymerase chain reaction-restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotype frequencies.

Results

Of the 8 variants, four SNPs namely, + 276 G/T (rs1501299), − 4522 C/T (rs822393), − 11365 C/G (rs266729), and + 712 G/A (rs3774261) were significantly associated with T2DM in our study population. The −3971 A/G (rs822396) and − 11391 G/A (rs17300539) SNPs' association with T2DM diabetes was mediated through obesity (where the association with type 2 diabetes was lost after adjusting for BMI). There was an independent association of + 276 G/T (rs1501299) and − 3971 A/G (rs822396) SNPs with generalized obesity and + 349 A/G (rs2241767) with central obesity. Four SNPs, −3971 A/G (rs822396), + 276 G/T (rs1501299), − 4522 C/T (rs822393) and Y111H T/C (rs17366743) were significantly associated with hypoadiponectinemia. The haplotypes GCCATGAAT and AGCGTGGGT conferred lower risk of T2DM in this south Indian population.

Conclusion

The adiponectin gene variants and haplotype contribute to the genetic risk towards the development of type 2 diabetes, obesity and hypoadiponectinemia in the south Indian population.     

SLC30A8 (ZnT8) variations and type 2 diabetes in the Chinese Han population

In recent genome-wide association studies, variants in the SLC30A8 gene have been found to be associated with risk for type 2 diabetes. We examined a possible association of tag SNPs spanning SLC30A8 and their haplotypes with type 2 diabetes in the Chinese Han population. There were 1508 Chinese Han type 2 diabetes patients and 1500 age- and gender-matched control subjects; all were genotyped for three tagging SNPs (rs2466295, rs4876703, and rs11558471) of the human SLC30A8 gene. The AA genotype of rs11558471 was found significantly more frequently in type 2 diabetes patients than in controls (46 vs 24%). The frequency of the A-C-A haplotype was significantly higher in type 2 diabetes patients than in controls (0.331 vs 0.120). The frequency of the A-C-G haplotype was significantly lower in type 2 diabetes patients than in controls (0.160 vs 0.365). We conclude that type 2 diabetes is associated with the AA genotype of rs11558471 in the human SLC30A8 gene. The A-C-A haplotype appears to be a risk factor and the A-C-G haplotype may be a protective factor against type 2 diabetes in Chinese Han.     

Potential association of obesity with IL6 G-174C polymorphism and TTV infections

Polymorphisms in IL6, ACE and ATR genes are associated with obesity. Torque Teno virus (TTV) seems to be able to interfere with production of some proinflammatory cytokines associated with obesity and related phenotypes. The aim of this study was to test the potential association between obesity, TTV infection and the IL6 G-174C (rs1800795), ACE I/D (rs4646994), AT1R A1166C (rs5186) polymorphisms. The polymorphisms and the presence of TTV were detected in blood samples from 150 obese and 150 normal-weight, healthy subjects using PCR based methods. IL6-174 CC genotype was more frequent in all obese patients (P=0.02) and in patients without TTV infections (P=0.03) than in controls. Obese women had more frequent TTV infections compared with normal-weight women (P=0.046). Obese subjects, regardless of gender (women P=0.03, men P=0.04), and healthy normal-weight men (P<0.01) carriers of AT1R C allele had higher triglycerides levels compared with non-carriers. The frequency of TTV in the control group (70.67%) was similar to data reported in other populations. The present study indicated that IL6-174 CC genotype and TTV infections in women could be associated with the common form of obesity.     

FTO polymorphisms are associated with obesity but not diabetes risk in postmenopausal women

The FTO gene was recently identified as a susceptibility locus for both obesity and type 2 diabetes by whole-genome association analyses of several European populations. We tested for an association between FTO risk alleles and obesity and diabetes in a well-characterized multiethnic cohort of postmenopausal women in the United States. We genotyped two most significantly associated single-nucleotide polymorphisms (SNPs) (rs9939609 and rs8050136) in intron 1 of FTO gene in a nested case-control study of 1,517 diabetes cases and 2,123 controls from the Women's Health Initiative-Observational Study (WHI-OS). The allelic frequencies of either rs9939609 or rs8050136 differed widely across four ethnic groups. The frequency of the rare allele A of rs9939609 among controls was much lower in Asians/Pacific Islanders (17%) than in blacks (45%), whites (40%), and Hispanics (31%). We found significant associations of rs9939609 with BMI and waist circumference in white and Hispanic women, but not among black and Asian/Pacific Islander women. On average, each copy of the risk-allele A at rs9939609 was significantly associated with 0.45 kg/m(2) increase in BMI (95% confidence interval (CI): 0.16-0.74; P = 0.004) and 0.97 cm increase in waist circumference (95% CI: 0.21-0.65; P = 0.0002). Similar results were observed for rs8050136. However, we found no significant genetic associations with diabetes risk, either within the full study sample or in any ethnic group. In conclusion, common genetic variants in the intron 1 of FTO gene may confer a modest susceptibility to obesity in an ethnicity-specific manner, but may be unlikely to contribute to a clinically significant diabetes risk.