Analysis of MTNR1B gene polymorphisms in relationship with IRS2 gene variants,epicardial fat thickness,glucose homeostasis and cognitive performance in the elderly

Genome-wide association studies pinpointed common variants in or near the MTNR1B gene encoding MT2 melatonin receptor to be strongly associated with fasting glucose levels. IRS2 gene polymorphisms impact insulin resistance and epicardial fat (EF) thickness, which in turn is correlated with visceral adiposity, cognitive ability and risk for metabolic plus cardiovascular disease. We aimed to discover the interactions between MTNR1B and IRS2 gene polymorphisms, insulin sensitivity, EF thickness and cognitive performance in the elderly. In 60 subjects aged 60 years and older, we evaluated five single nucleotide polymorphisms (SNPs) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638), the Gly1057Asp variant of IRS2 gene (rs1805097), biochemical parameters, cognitive performance by the Mini Mental State Examination (MMSE) and EF thickness by transthoracic echocardiography. We found that MTNR1B and IRS2 gene variants impacted EF thickness, lipid profile and glucose homeostasis. IRS2 but not MTNR1B variants impacted MMSE scores. In conclusion, MTNR1B SNPs interact with IRS2 gene variant, correlate with the amount of epicardial adipose tissue and impact glucose homeostasis and lipid profile influencing cardiometabolic risk.     

Polymorphism analysis of the Gly972Arg IRS-1 and Gly1057Asp IRS-2 genes in obese pregnant women

Genes encoding insulin receptor substrates IRS-1 and IRS-2 perform key functions in the insulin pathway. Numerous authors have suggested that single-nucleotide polymorphism (SNP) changes in the DNA sequence may be associated with the development of obesity, insulin resistance and type 2 diabetes. The Gly972Arg polymorphism of the IRS-1 gene and the Gly1057Asp polymorphism of the IRS-2 gene are believed to be associated with the occurrence of insulin resistance and obesity according to many sources. The aim of our study was to investigate the influence of these polymorphisms on the clinical parameters and to assess their correlations in obese Polish pregnant women. A total of 154 pregnant Caucasian women from the Wielkopolska region were analyzed: 78 diagnosed with overweight or obesity (study group) and 76 with normal body mass (controls). The analysis of the polymorphisms was performed using the PCR-restriction fragment length polymorphism (PCR-RFLP) method. The IRS-2 Gly1057Asp polymorphism revealed no significant correlations with excessive weight gain during pregnancy. The analysis of the IRS-1 Gly972Arg polymorphism showed an association with obesity between the study and control groups (GG-80.77%, GR-17.95%, RR-1.28% vs GG-94.74%, GR-5.26%; p = 0.023). We also observed slightly increased BMI values ​​and higher values ​​of the waist and hip circumference before pregnancy in the case of the IRS-1 Gly972Arg polymorphism. The analysis of the clinical and anthropometric parameters demonstrated no significant relationships between the genotypes of the polymorphic variants of the IRS-1 and IRS-2 genes but suggested an association between the IRS-1 Gly972Arg polymorphism and the risk for obesity.     

IRS1 phosphorylation does not mediate mTORC1-induced insulin resistance

Increased mammalian target of rapamycin complex 1 (mTORC1) activity has been suggested to play important roles in development of insulin resistance in obesity. mTORC1 hyperactivity also increases endoplasmic reticulum (ER) stress, which in turn contributes to development of insulin resistance and glucose intolerance. Increased IRS1 phosphorylation at Ser307 in vitro is correlated with mTORC1- and ER stress-induced insulin resistance. This phosphorylation site correlates strongly with impaired insulin receptor signaling in diabetic mice and humans. In contrast, evidence from knock-in mice suggests that phosphorylation of IRS1 at Ser307 is actually required to maintain insulin sensitivity. To study the involvement of IRS1^Ser307 phosphorylation in mTORC1-mediated glucose intolerance and insulin sensitivity in vivo, we investigated the effects of liver specific TSC1 depletion in IRS1^Ser307Ala mice and controls. Our results demonstrate that blockade of IRS1^Ser307 phosphorylation in vivo does not prevent mTORC1-mediated glucose intolerance and insulin resistance.     

Insulin receptor substrate-2 is not necessary for insulin- and exercise-stimulated glucose transport in skeletal muscle.

Insulin receptor substrate-2-deficient (IRS2(-/-)) mice develop type 2 diabetes. The purpose of this study was to determine whether there is a defect in basal, insulin-, and exercise-stimulated glucose transport in the skeletal muscle of these animals. IRS2(-/-) and wild-type (WT) mice (male, 8-10 weeks) exercised on a treadmill for 1 h or remained sedentary. 2-Deoxyglucose (2DG) uptake was measured in isolated soleus muscles incubated in vitro in the presence or absence of insulin. Resting blood glucose concentration in IRS2(-/-) mice (10.3 mM) was higher than WT animals (4.1 mM), but there was a wide range among the IRS2(-/-) mice (3-25 mM). Therefore, IRS2(-/-) mice were divided into two subgroups based on blood glucose concentrations (IRS2(-/-)L < 7.2 mM, IRS2(-/-)H > 7.2 mM). Only IRS2(-/-)H had lower basal, exercise-, and submaximally insulin-stimulated 2DG uptake, while maximal insulin-stimulated 2DG uptake was similar among the three groups. The ED(50) for insulin to stimulate 2DG uptake above basal in IRS2(-/-)H was higher than WT and IRS2(-/-)L mice, suggesting insulin resistance in the skeletal muscle from the IRS2(-/-) mice with high blood glucose concentrations. Furthermore, resting blood glucose concentrations from all groups were negatively correlated to submaximally insulin-stimulated 2DG uptake (r(2) = 0.33, p < 0.01). Muscle GLUT4 content was significantly lower in IRS2(-/-)H mice compared with WT and IRS2(-/-)L mice. These results demonstrate that the IRS2 protein in muscle is not necessary for insulin- or exercise-stimulated glucose transport, suggesting that the onset of diabetes in the IRS2(-/-) mice is not due to a defect in skeletal muscle glucose transport; hyperglycemia may cause insulin resistance in the muscle of IRS2(-/-) mice.     

Polymorphisms in vitamin D receptor,toll-like receptor 2 and Toll-Like receptor 4 genes links with Dengue susceptibility

Host genetic factors are known to determine disease susceptibility in dengue virus infection. Therefore, in this study association of gene polymorphisms of Vitamin D Receptor [rs731236 (Taq) and rs7975232 (Apa1)], Toll-like receptor 2 [rs5743708 (Arg735Gln) and rs5743704 (Pro631His)] and Toll-like receptor 4 [rs4986790A/G(Asp299Gly13843) and rs4986791 C/T(Thr399Ile)] were studied in cases with dengue as compared to controls. Total 98 cases of confirmed dengue virus infection and 98 age, sex and geographically matched healthy controls were enrolled and their genetic polymorphisms for the above mentioned regions were studied by Sanger sequencing. Mutant genotypes CC of VDR rs731236 (Taq1) [(OR 3.808, p value =0.02, CI 1.160-12.498)], GG of VDR rs7975232 (Apa1) [(OR 3.485, p value =0.02, CI 1.162-10.45)] and heterozygous genotypes of TLR4 rs4986790 A/G Asp299Gly [OR 2.40, p value= 0.02, CI 1.12-5.14], TLR4 rs4986791 C/T Thr399Ile [OR 2.09, p value=0.02, CI 1.12-5.14] were found to be significantly more in cases with dengue virus infection as compared to the controls. Also, at these positions mutant alleles were observed in significantly higher number of cases than controls. The values for C allele at VDR rs731236 (Taq1) were OR 1.86, p value 0.009, CI 1.162-3.001; for allele G at rs7975232( Apa1) were OR 2.71, p value 0.006, CI 1.196-2.98 for allele G at TLR4s rs4986790 A/G Asp299Gly were OR 2.35, p value 0.009, CI 1.23-4.50 and for allele T at rs4986791 C/T Thr399Ile were OR 2.36, p value=0.006, CI 1.28-4.38. VDR and TLR4 but not TLR2 gene polymorphisms were found to be associated with dengue susceptibility in Indian population.     

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.     

Lack of support for the association between GAD2 polymorphisms and severe human obesity

The demonstration of association between common genetic variants and chronic human diseases such as obesity could have profound implications for the prediction, prevention, and treatment of these conditions. Unequivocal proof of such an association, however, requires independent replication of initial positive findings. Recently, three (-243 A>G, +61450 C>A, and +83897 T>A) single nucleotide polymorphisms (SNPs) within glutamate decarboxylase 2 (GAD2) were found to be associated with class III obesity (body mass index > 40 kg/m2). The association was observed among 188 families (612 individuals) segregating the condition, and a case-control study of 575 cases and 646 lean controls. Functional data supporting a pathophysiological role for one of the SNPs (-243 A>G) were also presented. The gene GAD2 encodes the 65-kDa subunit of glutamic acid decarboxylase-GAD65. In the present study, we attempted to replicate this association in larger groups of individuals, and to extend the functional studies of the -243 A>G SNP. Among 2,359 individuals comprising 693 German nuclear families with severe, early-onset obesity, we found no evidence for a relationship between the three GAD2 SNPs and obesity, whether SNPs were studied individually or as haplotypes. In two independent case-control studies (a total of 680 class III obesity cases and 1,186 lean controls), there was no significant relationship between the -243 A>G SNP and obesity (OR = 0.99, 95% CI 0.83-1.18, p = 0.89) in the pooled sample. These negative findings were recapitulated in a meta-analysis, incorporating all published data for the association between the -243G allele and class III obesity, which yielded an OR of 1.11 (95% CI 0.90-1.36, p = 0.28) in a total sample of 1,252 class III obese cases and 1,800 lean controls. Moreover, analysis of common haplotypes encompassing the GAD2 locus revealed no association with severe obesity in families with the condition. We also obtained functional data for the -243 A>G SNP that does not support a pathophysiological role for this variant in obesity. Potential confounding variables in association studies involving common variants and complex diseases (low power to detect modest genetic effects, overinterpretation of marginal data, population stratification, and biological plausibility) are also discussed in the context of GAD2 and severe obesity.     

Association between BH3 interacting domain death agonist (BID) gene polymorphism and ossification of the posterior longitudinal ligament in Korean population

The purpose of this study was to investigate single nucleotide polymorphisms (SNPs) of the BH3 interacting domain death agonist (BID) gene as a risk factor in Korean patients with ossification of the posterior longitudinal ligament (OPLL). To investigate the genetic association, two coding SNPs (rs8190315, Ser10Gly; rs2072392, Asp60Asp) of BID were genotyped in 157 OPLL patients and 209 control subjects. SNPStats, SNPAnalyzer Pro, Helixtree, and Haploview 4.2 programs were used for association analysis. Multiple logistic regression models (codominant, dominant, and recessive) were calculated for the odds ratios (ORs), 95 % confidence intervals (CIs), and corresponding P values. For multiple testing, Bonferroni correction was performed. After Bonferroni correction, genotype analysis of both rs8190315 and rs2072392 showed association between the OPLL group and the control group in the codominant model (P = 0.042, OR 1.86, 95 % CI 1.10–3.15). A complete linkage disequilibrium block was estimated between the two SNPs. Both of the G allele of rs8190315 and C allele of rs2072392 were strongly associated with an increased risk in the development of OPLL (P = 0.0052, OR 2.66, 95 % CI 1.51–4.68). These results suggest that BID is associated with OPLL, and both the G allele of a missense SNP (rs8190315, Ser10Gly) and C allele of a synonymous SNP (rs2072392, Asp60Asp) are risk factors for the development of OPLL in Korean population.     

Polymorphisms in insulin-related genes predispose to specific KRAS2 and TP53 mutations in colon cancer

Risk factors for colon cancer may not only influence the overall risk of cancer but also the risk for specific types of mutations. We evaluated the effect of polymorphisms in four insulin-related genes (G972R in IRS1, G1057D in IRS2, a CA repeat in IGFI and an A/C polymorphism at -202 of IGFBP3) on the risk of microsatellite instability and KRAS2 and TP53 mutations in a population-based set of 1788 cases of colon cancer and 1981 controls. The GR/RR IRS1 genotypes were associated with an increased risk of colon cancers with the KRAS2 G12D mutation (OR 2.3, 95% CI 1.5, 3.5 versus controls, OR 1.7, 95% CI 1.1, 2.6 versus KRAS2 wild type), the "no 192" IGFI genotype increased the risk of the KRAS2 G13D mutation (OR 2.3, 95% CI 1.2, 4.2 versus controls, OR 2.1, 95% CI 1.1, 4.0 versus wild type), and the DD IRS2 genotype increased the risk of the G12V KRAS2 mutation (OR 1.8, 95% CI 0.9, 3.5 versus controls, OR 2.0, 95% CI 1.0, 4.0 versus wild type). Polymorphisms in IRS1 and IGF1 were also associated with an approximately two-fold increased risk of specific TP53 mutations relative to controls without cancer. We conclude that polymorphisms in some insulin-related genes are associated with an increased risk of colon cancer with specific KRAS2 and TP53 mutations, implying a link between these genetic changes and specific mutational pathways in carcinogenesis.     

The R453Q and D151A polymorphisms of hexose-6-phosphate dehydrogenase gene (H6PD) influence the polycystic ovary syndrome (PCOS) and obesity

Hexose-6-phosphate dehydrogenase (H6PDH) influences 11β-hydroxysteroid dehydrogenase activity, a key enzyme in the peripheral metabolism of cortisol that modulates insulin sensitivity in adipose tissue. To study the associations of R453Q and D151A polymorphisms in the H6PDH gene (H6PD) with polycystic ovary syndrome (PCOS) and their influence on clinical and metabolic variables, we genotyped 237 patients with PCOS and 135 control women for the R453Q (rs6688832) and D151A (rs34603401) variants in H6PD. The R453Q genotypes were distributed differently in patients and controls (χ(2)=9.55, P=0.002). Genotypes of D151A were distributed evenly in women with PCOS and controls, but showed a different distribution in non-obese and obese women (χ(2)=3.95, P=0.047), especially within the PCOS subgroup (χ(2)=4.65, P=0.031). A backward stepwise likelihood ratio logistic regression model (Nagelkerke's R(2)=0.490; χ(2)=164; P<0.0001) retained free testosterone (OR=1.13; 95% CI: 1.10-1.17) and H6PD Q453 alleles (OR=0.46; 95% CI: 0.27-0.79) as statistically significant predictors for PCOS, whereas homeostasis model assessment of insulin resistance and the H6PD D151A variant were excluded by the model. Both H6PD variants were associated with several phenotypic variables, including fasting insulin, homeostasis model assessment of insulin resistance and androstenedione levels. In summary, the R453Q and D151A variants of the H6PD gene are associated with PCOS and obesity, respectively, and may contribute to the PCOS phenotype by influencing obesity, insulin resistance and hyperandrogenism.     

Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance

Insulin regulates glucose homeostasis by binding and activating the insulin receptor, and defects in insulin responses (insulin resistance) induce type 2 diabetes. SH2-B, an Src homology 2 (SH2) and pleckstrin homology domain-containing adaptor protein, binds via its SH2 domain to insulin receptor in response to insulin; however, its physiological role remains unclear. Here we show that SH2-B was expressed in the liver, skeletal muscle, and fat. Systemic deletion of SH2-B impaired insulin receptor activation and signaling in the liver, skeletal muscle, and fat, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and IRS2 and activation of the phosphatidylinositol 3-kinase/Akt and the Erk1/2 pathways. Consequently, SH2-B-/- knockout mice developed age-dependent hyperinsulinemia, hyperglycemia, and glucose intolerance. Moreover, SH2-B directly enhanced autophosphorylation of insulin receptor and tyrosine phosphorylation of IRS1 and IRS2 in an SH2 domain-dependent manner in cultured cells. Our data suggest that SH2-B is a physiological enhancer of insulin receptor activation and is required for maintaining normal insulin sensitivity and glucose homeostasis during aging.     

Haplotypes in the promoter region of the ADIPOQ gene are associated with increased diabetes risk in a German Caucasian population.

Adiponectin, which is encoded by the ADIPOQ gene, has been shown to modulate insulin sensitivity and glucose homeostasis. Plasma adiponectin levels are decreased in type 2 diabetes and obesity. Genetic variations within the ADIPOQ gene are associated with decreased adiponectin hormone levels. To analyze specific single-nucleotide polymorphisms (SNPs) and their association with T2D, 365 German subjects with T2D and 323 control subjects were screened. Three common SNPs - +45T>G in exon 2, and 2 promoter variants SNPs -11391G>A and -11377C>G - were analyzed. We found that the variant allele of SNP -11391G>A was significantly more frequent in the diabetic patient group than in the control group (p=0.003). Carrying the haplotype of SNP -11391A and SNP -11377C was associated with a 1.50-fold (p=0.03) increase in diabetes risk. The combination of the A-C haplotype and the G-C haplotype was associated with significantly elevated diabetes risk (OR=2.82 (95% CI: 1.35-5.91), p=0.006) after correction for BMI and age. Our observations suggest that diploid combinations of haplotype in the adiponectin gene promoter region contribute to the genetic risk of T2D in individuals from a German Caucasian population.     

CARD15 and TLR4 genes polymorphisms in atopic bronchial asthma

In order to investigate whether single nucleotide polymorphisms G(+2722)C and 3020insC in CARD15 gene and Asp299Gly in TLR4 gene contribute to atopic bronchial asthma we performed a comparative analysis of alleles and genotypes frequencies of these polymorphisms in Russian patients from Moscow. DNA samples from 283 patients with atopic bronchial asthma and 227 healthy donors were genotyped. There were associations neither of G(+2722)C and 3020insC in CARD15 gene and Asp299Gly in TLR4 gene with asthma nor of markers of CARD15 gene with asthma severity. Haplotype frequency analysis of CARD15 gene polymorphisms did not reveal significant difference between groups. However, a strong association was found between Asp299Gly and asthma severity. Allele Asp of this marker showed association with mild atopic bronchial asthma and allele Gl--with moderate/severe asthma = 0.47, 95% CI [0.24-0.93] i OR = 2.12, 95% CI [1.08-4.18] respectively).     

Race, childhood insulin, childhood caloric intake, and class 3 obesity at age 24: 14-year prospective study of schoolgirls

The prevalence of Class 3 obesity (BMI ≥40 kg/m²) has more than doubled in the past 25 years. In a 14‐year prospective study from age 10 to 24 of a biracial schoolgirl cohort (293 black, 256 white), we assessed childhood correlates of Class 3 BMI at age 24. Of 42 girls with Class 3 BMI at age 24, 36 (86%) were black. By logistic regression, significant explanatory variables of Class 3 BMI at age 24 included top decile waist circumference at age 11 (odds ratio (OR) 5.7, 95% confidence interval (CI) 2.3–13.9, P = 0.0002), age 10 BMI ≥ the Center for Disease Control (CDC) 2000 top 15% (OR 7.0, 95% CI 2.5–19.3, P = 0.0002), and a three‐way interaction between race, childhood insulin, and average caloric intake from age 10 to age 19 (for each unit increase, OR 1.7 95% CI 1.3–2.2, P = 0.0003). Age 10 BMI, age 11 waist circumference, and interaction of race, childhood insulin, and childhood caloric intake predict Class 3 obesity in young adulthood, facilitating childhood identification of girls at high risk for developing Class 3 obesity.     

Altered Circulating Levels of Retinol Binding Protein 4 and Transthyretin in Relation to Insulin Resistance,Obesity, and Glucose Intolerance in Asian Indians

Objective: Retinol binding protein 4 (RBP4) has been implicated in metabolic disorders including type 2 diabetes mellitus (T2DM), but few studies have looked at transthyretin (TTR) with which RBP4 is normally bound to in the circulation. We report on the systemic levels of RBP4 and TTR and their associations with insulin resistance, obesity, prediabetes, and T2DM in Asian Indians.Methods: Age-matched individuals with normal glucose tolerance (NGT, n = 90), impaired glucose tolerance (IGT, n = 70) and T2DM (n = 90) were recruited from the Chennai Urban Rural Epidemiology Study (CURES). Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). RBP4 and TTR levels were measured by enzyme-linked immunosorbent assay (ELISA).Results: Circulatory RBP4 and TTR levels (in μg/mL) were highest in T2DM (RBP4: 13 ± 3.9, TTR: 832 ± 310) followed by IGT (RBP4: 10.5 ± 3.2; TTR: 720 ± 214) compared to NGT (RBP4: 8.7 ± 2.5; TTR: 551 ± 185; P<.001). Compared to nonobese NGT individuals, obese NGT, nonobese T2DM, and obese T2DM had higher RBP4 (8.1 vs. 10.6, 12.1, and 13.2 μg/mL, P<.01) and TTR levels (478 vs. 737, 777, and 900 μg/mL, P<.01). RBP4 but not TTR was significantly (P<.001) correlated with insulin resistance even among NGT subjects. In regression analysis, RBP4 and TTR showed significant associations with T2DM after adjusting for confounders (RBP4 odds ratio [OR]: 1.107, 95% confidence interval [CI]: 1.008–1.216; TTR OR: 1.342, 95% CI: 1.165–1.547).Conclusion: Circulatory levels of RBP4 and TTR showed a significant associations with glucose intolerance, obesity, T2DM and RBP4 additionally, with insulin resistance.Abbreviations: BMI = body mass index CI = confidence interval HDL = high-density lipoprotein IGT = impaired glucose tolerance LDL = low-density lipoprotein NGT = normal glucose tolerance OGTT = oral glucose tolerance test OR = odds ratio RBP4 = retinol binding protein 4 T2DM = type 2 diabetes mellitus TTR = transthyretin WC = waist circumference     

Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms in cancer: a meta-analysis

Toll-like receptor 4 (TLR4) is critical in the recognition of Gram-negative bacteria serving as a key immune system effector. Recently, a number of case-control studies were conducted to investigate the association between TLR4 gene polymorphism and cancer risk, especially Asp299Gly and Thr399Ile polymorphisms. However, published data were still conflicting. In this paper, we summarized 9463 cancer cases and 10,825 controls from 22 studies and attempted to assess the susceptibility of TLR4 gene polymorphism to cancers by a synthetical meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the relationship. Our results suggested that Asp299Gly represented a risk factor on cancers in digestive system (G allele versus A allele, OR=1.64, 95% CI: 1.02-2.64; GA+GG versus AA, OR=1.64, 95% CI: 1.00-2.71) but tend to have a protective effect on prostate cancer (GG versus AA, OR=0.37, 95% CI: 0.14-0.98; GG versus GA+AA, OR=0.37, 95% CI: 0.14-0.98). Thr399Ile polymorphism was significantly associated with an elevated cancer risk in overall analysis (T allele versus C allele, OR=1.72, 95% CI: 1.27-2.33; TC versus CC, OR=1.63, 95% CI: 1.18-2.26; TT+TC versus CC, OR=1.70, 95% CI: 1.24-2.34) and especially in gastrointestinal subgroup (T allele versus C allele, OR=2.01, 95% CI: 1.40-2.89; TC versus CC, OR=1.86, 95% CI: 1.26-2.74; TT+TC versus CC, OR=1.97, 95% CI: 1.35-2.88). Further prospective researches with larger numbers of worldwide participants are warranted to draw comprehensive and true conclusions.     

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.     

ADRB2 Haplotype Is Associated With Glucose Tolerance and Insulin Sensitivity in Obese Postmenopausal Women

The β₂‐adrenergic receptor (ADRB2) mediates obesity, cardiorespiratory fitness, and insulin resistance. We examined the hypothesis that ADRB2 Arg16Gly‐Gln27Glu haplotype is associated with body composition, glucose tolerance, and insulin sensitivity in obese, postmenopausal women. Obese (>35% body fat), postmenopausal (age 45–75 years) women (n = 123) underwent genotyping, dual‐energy X‐ray absorptiometry, and computed tomography scans, exercise testing (VO_2max), 2‐h oral glucose tolerance tests (OGTTs), and hyperinsulinemic‐euglycemic clamps (80 mU/m²/min). Analysis of covariance (ANCOVA) tested for differences among haplotypes, with race, % body fat, and VO_2max as covariates. We found that ADRB2 haplotype was independently associated with % body fat, abdominal fat distribution, VO_2max, insulin sensitivity (M/ΔInsulin), and glucose tolerance (ANOVA, P < 0.05 for all). Women homozygous for Gly16–Gln27 haplotype had the highest % body fat (52.7 ± 1.9%), high abdominal fat, low M/ΔInsulin (0.49 ± 0.08 mg/kg/min/pmol/l/10²), and impaired glucose tolerance (IGT) during an OGTT (G₁₂₀ = 10.2 ± 0.9 mmol/l). Women homozygous for Gly16–Glu27 haplotype also had low M/ΔInsulin (0.51 ± 0.05 mg/kg/min/pmol/l/10²) and IGT (G₁₂₀ = 8.2 ± 0.7 mmol/l). Subjects with Arg16–Gln27/Gly16–Gln27 haplotype combination had the highest VO_2max (1.84 ± 0.07 l/min) and M/ΔInsulin (0.7 ± 0.04 mg/kg/min/pmol/l/10²), and normal glucose tolerance (G₁₂₀ = 6.4 ± 0.4 mmol/l), despite being obese. These data show associations of the ADRB2 Arg16Gly‐Gln27Glu haplotype with VO_2max and body composition, and an independent association with glucose metabolism, which persists after controlling for body composition and fitness. This suggests that ADRB2 haplotypes may mediate insulin action, glucose tolerance, and potentially risk for type 2 diabetes mellitus (T2DM) in obese, postmenopausal women.