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Evaluation of DOK5 as a susceptibility gene for type 2 diabetes and obesity in North Indian population.

ABSTRACT: BACKGROUND: Type 2 diabetes is a complex metabolic disorder with obesity being a major contributing factor in its development. Susceptibility loci for type 2 diabetes and obesity have been localized on different chromosomal regions by various genome-wide linkage scans. Of these chromosomal regions, 20q13 is one of the strongest linked regions for type 2 diabetes as well as obesity. On 20q13 lies DOK5 that seems to be a strong functional and positional candidate for type 2 diabetes and obesity because of its involvement in insulin signaling and immune responses. Hence, for the first time, we explored DOK5 as a potential type 2 diabetes and obesity susceptibility gene. METHODS: We sequenced 43 subjects for polymorphisms in functionally relevant regions of DOK5. A total of 10 SNPs that included 5 that were identified by sequencing and 5 additional SNPs from NCBI Variation Database were genotyped in 2,115 participants comprising of 1,073 patients with type 2 diabetes and 1,042 controls of Indo-European ethnicity from North India. RESULTS: We identified a novel variant in intron 7 referred to as DK176673. We found nominal association of three SNPs-rs6064099 (OR = 0.75, P = 0.019), rs873079 (OR = 0.76, P = 0.036) and DK176673 (OR = 1.55, P = 0.037) with type 2 diabetes among normal-weight subjects [BMI < 23 kg/m2]. The haplotype GGC harboring rs6068916, rs6064099 and rs873079 showed strong association with type 2 diabetes among normal-weight subjects (OR = 1.37, P/Pperm = 5.8 x 10-3/0.037). Association analysis with obesity revealed that rs6064099 is associated with reduced susceptibility for obesity (OR = 0.48, P = 6.8 x 10-3). Also, haplotype GGC conferred increased susceptibility for obesity (OR = 1.27, P/Pperm = 9.0 x 10-3/0.039). Also, rs6064099 was significantly associated with reduced BMI [median(IQR) = 24.0(20.7-27.1) vs 23.9(20.2-26.8) vs 21.8(19.2-24.7) for GG vs GC vs CC, P = 7.0 x 10-3]. CONCLUSIONS: We identified DOK5 as a novel susceptibility gene for obesity and type 2 diabetes in North Indian subjects. Association of DOK5 variants both with obesity and type 2 diabetes suggests that these variants might modulate type 2 diabetes susceptibility through obesity.

SUBMITTER: Tabassum R

PROVIDER: S-EPMC2848002 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Evaluation of DOK5 as a susceptibility gene for type 2 diabetes and obesity in North Indian population.

Tabassum Rubina R Mahajan Anubha A Chauhan Ganesh G Dwivedi Om Prakash OP Ghosh Saurabh S Tandon Nikhil N Bharadwaj Dwaipayan D

BMC medical genetics 20100227

<h4>Background</h4>Type 2 diabetes is a complex metabolic disorder with obesity being a major contributing factor in its development. Susceptibility loci for type 2 diabetes and obesity have been localized on different chromosomal regions by various genome-wide linkage scans. Of these chromosomal regions, 20q13 is one of the strongest linked regions for type 2 diabetes as well as obesity. On 20q13 lies DOK5 that seems to be a strong functional and positional candidate for type 2 diabetes and obe ...[more]

PMID: 20187968

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Project description:Our previous studies have implicated genes mainly involved in the activity of pancreatic ? cells in type 2 diabetes (T2D) susceptibility in the North Indian population. Recent literature on the role of SIRT1 as a potential master switch modulating insulin secretion and regulating gene expression in pancreatic ? cells has warranted an evaluation of SIRT1 promoter region polymorphisms in the North Indian population, which is the main focus of the present study. 1542 samples (692 T2D patients and 850 controls) were sequenced for the 1.46 kb region upstream the translation start site of the SIRT1 gene. We performed a functional characterization of the SIRT1 promoter region polymorphisms using luciferase assay and observed a single-nucleotide polymorphism (SNP), rs12778366, in association with SIRT1 expression. We propose that TT, the high-expressing genotype of SNP rs12778366 in the SIRT1 promoter region and present in >80% of the North Indian population, was favored under conditions of feast-famine cycles in evolution, which has turned out to be a cause of concern in the present sedentary lifestyle under ad libitum conditions. Case-control association analysis did not implicate rs12778366 in T2DM per se in the studied population. However, our earlier reported risk genotype combinations of mt-ND3, PGC1?, and UCP2-866, when compared with the protective genotype combinations, in the background of the high-expressing TT genotype of SIRT1 SNP rs12778366, showed a very high additive risk [corrected odd ratio (OR)?=?8.91; p?=?6.5×10(-11)]. The risk level was considerably low in the genotype backgrounds of TX (OR?=?6.68; p?=?2.71×10(-12)) and CX (OR?=?3.74; p?=?4.0×10(-3)). In addition, we screened other reported T2D-associated polymorphisms: PIK3R1 rs3730089, IRS1 rs1801278, and PPP1R3 rs1799999, which did not show any significant association in North Indian population. The present paper emphasizes the importance of gene interactions in the biological pathways of T2D, a complex lifestyle disease.

Project description:Background & objectives:Diabetes genomics research has illuminated single nucleotide polymorphism (SNP) in several genes including, fat mass and obesity associated (FTO) (rs9939609 and rs9926289), potassium voltage-gated channel subfamily J member 11 (rs5219), SLC30A 8 (rs13266634) and peroxisome proliferator-activated receptor gamma 2 (rs1805192). The present study was conducted to investigate the involvement of these polymorphisms in conferring susceptibility to type 2 diabetes (T2D) in the North East Indian population, and also to establish their association with anthropometric parameters. Methods:DNA was extracted from blood samples of 155 patients with T2D and 100 controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. To confirm the association between the inheritance of SNP and T2D development, logistic regression analysis was performed. Results:For the rs9939609 variant (FTO), the dominant model AA/(AT+TT) revealed significant association with T2D [odds ratio (OR)=2.03, P=0.021], but was non-significant post correction for multiple testing (P=0.002). For the rs13266634 variant (SLC30A 8), there was considerable but non-significant difference in the distribution pattern of genotypic polymorphisms between the patients and the controls (P=0.004). Significant association was observed in case of the recessive model (CC+CT)/TT (OR=4.56 P=0.001), after adjusting for age, gender and body mass index. In addition, a significant association (P=0.001) of low-density lipoprotein (mg/dl) could be established with the FTO (rs9926289) polymorphism assuming dominant model. Interpretation & conclusions:The current study demonstrated a modest but significant effect of SLC30A8 (rs13266634) polymorphisms on T2D predisposition. Considering the burgeoning prevalence of T2D in the Indian population, the contribution of these genetic variants studied, to the ever-increasing number of T2D cases, appears to be relatively low. This study may serve as a foundation for performing future genome-wide association studies (GWAS) involving larger populations.

Project description:Background and aimsAt present obesity and metabolic syndrome (MetS) in India are the most challenging health problems. It is also well accepted that obesity is a significant risk factor for the development of metabolic syndrome and other degenerative diseases. Many studies have reported that single-nucleotide polymorphisms (SNPs) of the adiponectin (ADIPOQ) gene have been associated with obesity and its related disorders. Here, we aimed to investigate the association of two intronic variants in ADIPOQ gene, -3971A>G (rs822396) and +276G>T (rs1501299) with obesity and metabolic syndrome.MethodsBiochemical and anthropometric measurements were obtained from a total of 550 unrelated subjects (obese = 250 and non-obese = 300) of North Indian Punjabi population. Genotyping for the intron variants were performed by polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) methods. After genotyping, as a quality control measure 10% of the samples for each polymorphism were confirmed by Sanger Sequencing method. The distributions of genotypic and allelic frequencies among obese and non-obese groups were compared by chi-square test and the corresponding risk was calculated using binary logistic regression. The effects of multiple testing were controlled by applying Bonferroni corrections.ResultsAll the anthropometric and biochemical parameters except triglycerides (TG) and very low-density lipoproteins cholesterol (VLDL-C) have shown significant association with both GG and TT genotypes of -3971A>G (rs822396) and +276G>T (rs1501299) polymorphisms respectively. The frequencies of GG (-3971A>G) and TT (+276G>T) genotypes were higher among obese cases (p = 0.008 and p = 0.035 respectively). However, no significant association was found between allelic frequencies of ADIPOQ rs822396 and obesity, whereas the association of ADIPOQ rs1501299 attenuated and became marginally significant after Bonferroni correction (p>0.025). Both the variant genotypes of ADIPOQ gene polymorphisms (-3971GG and +276TT) significantly increased the risk of development of obesity (OR: 1.52, p = 0.03; OR: 1.58, p = 0.04 respectively) and MetS (OR: 1.42, p = 0.03; OR: 1.57, p = 0.01 respectively) in the present population, after adjusting the various covariates. The G-T haplotype model (possessing -3971G and +276T alleles) was shown toprovide ~ 3 fold risk towards the obesity susceptibility (OR: 2.69, p = 0.009) and MetS risk (OR: 2.73, p = 0.009) and the association persisted after adjusting for different confounding variables.ConclusionThe present study has confirmed that ADIPOQ -3971A>G (rs822396) and +276G>T (rs1501299) polymorphism may be clinically helpful to estimate obesity and MetS risk in North Indian Punjabi population.

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Evaluation of DOK5 as a susceptibility gene for type 2 diabetes and obesity in North Indian population.

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Evaluation of DOK5 as a susceptibility gene for type 2 diabetes and obesity in North Indian population.

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