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Obesity involves alterations in transcriptional programs that can change in response to genetic and environmental signals through chromatin modifications. Since chromatin modifications involve different biochemical, neurological and molecular signaling pathways related to energy homeostasis, we hypothesize that genetic variations in chromatin modifier genes can predispose to obesity. Here, we assessed the associations between 179 variants in 35 chromatin modifier genes and overweight/obesity in 1283 adolescents (830 normal weight and 453 overweight/obese). This was followed up by the replication analysis of associated signals (18 variants in 8 genes) in 2247 adolescents (1709 normal weight and 538 overweight/obese). Our study revealed significant associations of two variants rs6598860 (OR = 1.27, P = 1.58 × 10–4) and rs4589135 (OR = 1.22, P = 3.72 × 10–4) in ARID1A with overweight/obesity. We also identified association of rs3804562 (β = 0.11, P = 1.35 × 10–4) in KAT2B gene with BMI. In conclusion, our study suggests a potential role of ARID1A and KAT2B genes in the development of obesity in adolescents and provides leads for further investigations.

Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes–associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10−9). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10−12) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D.

Common variants near melanocortin 4 receptor (MC4R) gene are shown to be associated with adiposity but have varied effects in different age groups. Among Indians, studies have shown association of these variants with obesity in adults, but their association in children is yet to be confirmed. We evaluated association of rs17782313 and rs12970134 near MC4R with adiposity and related traits in Indians including 1362 children and 4077 adults (consisting of 2049 diabetic and 2028 nondiabetic adult subjects). Both variants rs17782313 and rs12970134 showed strong association with adiposity measures (weight, body mass index and waist circumference) in children (P-range 7.6 × 10(-5)-3.8 × 10(-12)) and nominal association in nondiabetic adults (P-range 0.05-0.003). Effect sizes on adiposity measures in children (β range 0.22-0.26 Z-score) were ~3-fold higher compared with adults (β range 0.06-0.08). The minor alleles of both variants showed borderline association (P-range 0.08-0.04) with risk of type 2 diabetes in adults. Meta-analysis of rs12970134 in12 000 Indian adults corroborated its association with adiposity (P≤2.2 × 10(-9)), homeostasis model assessment-estimated insulin resistance (P=4.0 × 10(-5)) and type 2 diabetes (P=0.003) with only moderate heterogeneity, suggesting similar effect on adult Indians residing in different geographical regions. In conclusion, the study demonstrates association of variants near MC4R with obesity and related traits in Indian children and adults, with higher impact during childhood.

OBJECTIVE Common variants in PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 genes have been shown to be associated with type 2 diabetes in European populations by genome-wide association studies. We have studied the association of common variants in these eight genes with type 2 diabetes and related traits in Indians by combining the data from two independent case–control studies. RESEARCH DESIGN AND METHODS We genotyped eight single nucleotide polymorphisms (PPARG-rs1801282, KCNJ11-rs5219, TCF7L2-rs7903146, SLC30A8-rs13266634, HHEX-rs1111875, CDKN2A-rs10811661, IGF2BP2-rs4402960, and CDKAL1-rs10946398) in 5,164 unrelated Indians of Indo-European ethnicity, including 2,486 type 2 diabetic patients and 2,678 ethnically matched control subjects. RESULTS We confirmed the association of all eight loci with type 2 diabetes with odds ratio (OR) ranging from 1.18 to 1.89 (P = 1.6 × 10−3 to 4.6 × 10−34). The strongest association with the highest effect size was observed for TCF7L2 (OR 1.89 [95% CI 1.71–2.09], P = 4.6 × 10−34). We also found significant association of PPARG and TCF7L2 with homeostasis model assessment of β-cell function (P = 6.9 × 10−8 and 3 × 10−4, respectively), which looked consistent with recessive and under-dominant models, respectively. CONCLUSIONS Our study replicates the association of well-established common variants with type 2 diabetes in Indians and shows larger effect size for most of them than those reported in Europeans.

Six common genetic variants (rs2229094, rs1041981, rs1800630, rs1800629, rs361525, and rs1800610) in the TNF-LTA locus encoding the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and lymphotoxin-α have been shown to be associated with various metabolic traits including susceptibility to type 2 diabetes, metabolic syndrome, insulin resistance, and increased body mass index (BMI) in Caucasians from different geographic locations and have yielded mixed results. We tested for the association of these variants with type 2 diabetes in North Indians by studying 2,115 participants comprising of 1,073 type 2 diabetes patients and 1,042 controls. We report the association of a promoter region variant of TNF: rs1800630 and non-synonymous LTA variant: rs2229094 with type 2 diabetes [OR = 0.83 (95% CI 0.72–0.95), P = 0.005 and OR = 0.86 (95% CI 0.75–0.98), P = 0.02, respectively]. Although these associations were BMI-dependent, no interactive effect of BMI and variants on type 2 diabetes was detectable. Further, the haplotype carrying all the six major alleles conferred susceptibility to type 2 diabetes [OR = 1.23 (95% CI 1.06–1.42), P = 0.005; P permuted = 0.02], with the effect much enhanced in non-obese subjects [OR = 1.45 (95% CI 1.19–1.78), P = 2 × 10−4: P permuted = 3 × 10−4]. The minor allele of rs2229094 was associated with lower hsCRP, BMI, and waist circumference (WC), while the minor allele of rs1800630 showed association with lower BMI and WC (all P

Here, we examined the association of genetic variants of FOXA2, an upstream activator of the beta-cell transcription factor network, with type 2 diabetes and related phenotypes in North India. We genotyped three SNPs (rs1212275, rs1055080, rs6048205) and the (TCC)( n ) repeat polymorphism in 1,656 participants comprising 1,031 patients with type 2 diabetes and 625 controls. SNPs rs1212275 and rs6048205 were uncommon (MAF5%) with similar distribution among patients and controls. We found a strong association of (TCC)( n ) common allele A5 with type 2 diabetes [OR = 1.66 (95% CI 1.36-2.04, p = 5.9 x 10(-7)) for A5 homozygotes]. Obese individuals with A5A5 genotype had enhanced risk when segregated from normal-weight subjects [OR = 1.92 (95% CI 1.47-2.51), p = 1.6 x 10(-6)]. A5 was also nominally associated with higher fasting glucose (p = 0.02) and lower fasting insulin (p = 0.0028) and C-peptide (p = 0.036) levels among controls. At the rs1055080 locus, GG was found to provide reduced risk among normal-weight subjects [OR = 0.59 (95% CI 0.40-0.88), p = 0.011]. Combination of protective GG and non-risk genotypes of (TCC)( n ) showed reduced risk of type 2 diabetes both among normal-weight [OR = 0.43 (95% CI 0.29-0.65), p = 1.2 x 10(-6)] and obese individuals [0.47 (95% CI 0.34-0.64), p = 4.3 x 10(-5)]. For the first time we demonstrated that FOXA2 variants may affect risk of type 2 diabetes and metabolic traits in North India, however replication analyses in other cohorts are required to confirm the findings.

Background FTO variants are robustly associated with obesity and related traits in many population and shown to have variable impact during life course. Although studies have shown association of FTO variants with adiposity in adult Indian, its association in Indian children is yet to be confirmed. Methods Here we examined association of FTO variants (rs9939609 and rs8050136) with obesity and related anthropometric and biochemical traits in 3,126 Indian children (aged 11–17 years) including 2,230 normal-weight and 896 over-weight/obese children. We also compared effects observed in the present study with that observed in previous studies on South Asian adults and children of other ethnic groups. Results The variant rs9939609 showed significant association with risk of obesity [OR = 1.21, P = 2.5×10−3] and its measures BMI, weight, waist circumference and hip circumference [β range = 0.11 to 0.14 Z-score units; P range = 1.3×10−4 to 1.6×10−7] in children. The observed effect sizes in Indian children were similar to those reported for European children. Variant rs9939609 explained 0.88% of BMI variance in Indian children. The effect sizes of rs9939609 on BMI and WC were ∼2 fold higher in children than adults. Interestingly rs9939609 was also associated with serum levels of thyroid stimulating hormone (TSH) [β = 0.10 Z-score, P = 5.8×10−3]. The other variant rs8050136 was in strong linkage disequilibrium with rs9939609 (r2 = 0.97) and provided similar association results. Conclusion The study provides first report of association of FTO variants with obesity and related anthropometric traits in Indian children with higher impact in children compared to adults. We also demonstrated association of FTO variant with serum levels of TSH, indicating putative influence of FTO in hypothalamic-pituitary-thyroid axis.

Background Hyperhomocysteinemia is regarded as a risk factor for cardiovascular diseases, diabetes and obesity. Manifestation of these chronic metabolic disorders starts in early life marked by increase in body mass index (BMI). We hypothesized that perturbations in homocysteine metabolism in early life could be a link between childhood obesity and adult metabolic disorders. Thus here we investigated association of common variants from homocysteine metabolism pathway genes with obesity in 3,168 urban Indian children. Methodology/Principal Findings We genotyped 90 common variants from 18 genes in 1,325 children comprising of 862 normal-weight (NW) and 463 over-weight/obese (OW/OB) children in stage 1. The top signal obtained was replicated in an independent sample set of 1843 children (1,399 NW and 444 OW/OB) in stage 2. Stage 1 association analysis revealed association between seven variants and childhood obesity at P

Though multiple studies link chromosomal regions 1q21-q23 and 20q13 with type 2 diabetes, fine mapping of these regions is yet to confirm gene(s) explaining the linkages. These candidate regions remain unexplored in Indians, which is a high-risk population for type 2 diabetes. Hypothesizing regulatory regions to have a more important role in complex disorders, we examined association of 207 common variants in proximal promoter and untranslated regions of genes on 1q21-23 and 20q13 with type 2 diabetes in 2115 North Indians. Further, top signals were replicated in an independent group of 2085 North Indians. Variants-rs11265455-SLAMF1 (odds ratios (OR)=1.32, P=1.1 × 10(-3)), rs1062827-F11R (OR=1.36, P=1.7 × 10(-3)) and rs12565932-F11R (OR=1.35, P=1.8 × 10(-3)) were top signals for association with type 2 diabetes whereas rs1333062-ITLN1 (OR=1.28, P=3.4 × 10(-3)) showed strongest association in body mass index-stratified analysis. Replication of these four variants confirmed associations of rs11265455-SLAMF1 (OR=1.27, P=9.1 × 10(-3)) and rs1333062-ITLN1 (OR=1.25, P=1.1 × 10(-3)) with type 2 diabetes. Meta-analysis further corroborated the association of rs11265455-SLAMF1 (OR random effect=1.29, P random effect=3.9 × 10(-5)) and rs1333062-ITLN1 (OR random effect=1.19, P random effect=1.8 × 10(-4)). In conclusion, the study demonstrates that variants of SLAMF1 and ITLN1, both implicated in inflammation, are associated with type 2 diabetes in Indians.

The increasing prevalence of obesity in urban Indian children is indicative of an impending crisis of metabolic disorders. Although perturbations in the secretion of adipokines and inflammatory molecules in childhood obesity are well documented, the contribution of common variants of genes encoding them is not well investigated. We assessed the association of 125 common variants from 21 genes, encoding adipocytokines and inflammatory markers in 1,325 urban Indian children (862 normal weight [NW group] and 463 overweight/obese [OW/OB group]) and replicated top loci in 1,843 Indian children (1,399 NW children and 444 OW/OB children). Variants of four genes (PBEF1 [rs3801266] [P = 4.5 × 10−4], IL6 [rs2069845] [P = 8.7 × 10−4], LEPR [rs1137100] [P = 1.8 × 10−3], and IL6R [rs7514452] [P = 2.1 × 10−3]) were top signals in the discovery sample. Associations of rs2069845, rs1137100, and rs3801266 were replicated (P = 7.9 × 10−4, 8.3 × 10−3, and 0.036, respectively) and corroborated in meta-analysis (P = 2.3 × 10−6, 3.9 × 10−5, and 4.3 × 10−4, respectively) that remained significant after multiple testing corrections. These variants also were associated with quantitative measures of adiposity (weight, BMI, and waist and hip circumferences). Allele dosage analysis of rs2069845, rs1137100, and rs3801266 revealed that children with five to six risk alleles had an approximately four times increased risk of obesity than children with less than two risk alleles (P = 1.2 × 10−7). In conclusion, our results demonstrate the association of the common variants of IL6, LEPR, and PBEF1 with obesity in Indian children.

Hyperhomocysteinemia, a risk factor for cardiovascular disorder, obesity, and type 2 diabetes, is prevalent among Indians who are at high risk of these metabolic disorders. We evaluated association of common variants of genes involved in homocysteine metabolism or its levels with type 2 diabetes, obesity, and related traits in North Indians. We genotyped 90 variants in initial phase (2.115 subjects) and replicated top signals in an independent sample set (2.085 subjects). The variantMTHFR-rs1801133 was the top signal for association with type 2 diabetes (OR=0.78(95% CI=0.67–0.92),P=0.003) and was also associated with 2 h postload plasma glucose (P=0.04), high-density lipoprotein cholesterol (P=0.004), and total cholesterol (P=0.01) in control subjects. These associations were neither replicated nor significant after meta-analysis. Studies involving a larger study population and different ethnic groups are required before ruling out the role of these important candidate genes in type 2 diabetes, obesity, and related traits.

Whole genome sequencing of personal genomes has revealed a large repertoire of genomic variations and has provided a rich template for identification of common and rare variants in genomes in addition to understanding the genetic basis of diseases. The widespread application of personal genome sequencing in clinical settings for predictive and preventive medicine has been limited due to the lack of comprehensive computational analysis pipelines. We have used next-generation sequencing technology to sequence the whole genome of a self-declared healthy male of Indian origin. We have generated around 28X of the reference human genome with over 99% coverage. Analysis revealed over 3 million single nucleotide variations and about 490,000 small insertion-deletion events including several novel variants. Using this dataset as a template, we designed a comprehensive computational analysis pipeline for the systematic analysis and annotation of functionally relevant variants in the genome. This study follows a systematic and intuitive data analysis workflow to annotate genome variations and its potential functional effects. Moreover, we integrate predictive analysis of pharmacogenomic traits with emphasis on drugs for which pharmacogenomic testing has been recommended. This study thus provides the template for genome-scale analysis of personal genomes for personalized medicine.

Common variants of fat mass and obesity-associated gene (FTO, fat mass- and obesity-associated gene) have been shown to be associated with obesity and type 2 diabetes in population of European and non-European ethnicity. However, studies in Indian population have provided inconsistent results. Here, we examined association of eight FTO variants (rs1421085, rs8050136, rs9939609, rs9930506, rs1861867, rs9926180, rs2540769 and rs708277) with obesity and type 2 diabetes in 5364 North Indians (2474 type 2 diabetes patients and 2890 non-diabetic controls) in two stages. None of the variants including previously reported intron 1 variants (rs1421085, rs8050136, rs9939609 and rs9930506) showed body mass index (BMI)-dependent/independent association with type 2 diabetes. However, rs1421085, rs8050136 and rs9939609 were associated with obesity status and measures of obesity (BMI, waist circumference and waist-to-hip ratio) in stage 2 and combined study population. Meta-analysis of the two study population results also revealed that rs1421085, rs8050136 and rs9939609 were significantly associated with BMI both under the random- and fixed-effect models (P (random/fixed)=0.02/0.0001, 0.004/0.0006 and 0.01/0.01, respectively). In conclusion, common variants of FTO were associated with obesity, but not with type 2 diabetes in North Indian population.

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/P perm = 5.8 × 10-3/0.037). Association analysis with obesity revealed that rs6064099 is associated with reduced susceptibility for obesity (OR = 0.48, P = 6.8 × 10-3). Also, haplotype GGC conferred increased susceptibility for obesity (OR = 1.27, P/P perm = 9.0 × 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 × 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.

Context: Elevated high-sensitivity C-reactive protein (hsCRP) levels have frequently been shown to be associated with type 2 diabetes (T2D); however, very little is known about this in Asian Indians, a high-risk group. Objective: The aim of the study was to assess the association of hsCRP with T2D and to determine its correlates in North Indians of Indo-European origin. Design and Patients: A cross-sectional population-based study of 2520 urban subjects, comprising 1410 T2D patients and 1110 nondiabetic subjects, was carried out and 18 metabolic traits were assessed. Results: Median hsCRP levels were significantly higher in both diabetic men and women as compared to their nondiabetic counterparts (P < 0.0001). Elevated hsCRP was positively associated with T2D (odds ratio, 1.66; 95% confidence interval, 1.21–2.28; P = 0.002) even after adjusting for markers of obesity. After adjustments for age, sex, and BMI, HbA1c was the major correlate of hsCRP in nondiabetic subjects (β = 0.28; P = 0.03). We observed that T2D patients were at higher risk for cardiovascular disease compared to nondiabetic subjects when classified into low-, intermediate-, and high-risk groups based on hsCRP levels (ptrend = 3.8 ×10−15). Conclusions: We demonstrate the association of low-grade systemic inflammation, as indicated by elevated hsCRP levels, with T2D in North Indian population. This association was independent of obesity. Obesity and glycemic control were the major correlates of hsCRP levels. Future studies are required to evaluate the influence of modulators including genetic variations on the elevation of hsCRP levels in this population.

BackgroundHigh sensitivity C-reactive protein (hsCRP) levels are shown to be influenced by genetic variants in Europeans; however, little is explored in Indian population.MethodsHerein, we comprehensively evaluated association of all previously reported genetic determinants of hsCRP levels, including 18 cis (proximal to CRP gene) and 73 trans-acting (distal to CRP gene) variants in 4,200 North Indians of Indo-European ethnicity. First, we evaluated association of 91 variants from 12 candidate loci with hsCRP levels in 2,115 North Indians (1,042 non-diabetic subjects and 1,073 patients with type 2 diabetes). Then, cis and trans-acting variants contributing maximally to hsCRP level variation were further replicated in an independent 2,085 North Indians (1,047 patients with type 2 diabetes and 1,038 non-diabetic subjects).ResultsWe found association of 12 variants from CRP, LEPR, IL1A, IL6, and IL6R with hsCRP levels in non-diabetic subjects. However, only rs3093059-CRP [β = 0.33, P = 9.6×10⁻⁵] and the haplotype harboring rs3093059 risk allele [β = 0.32 µg/mL, P = 1.4×10⁻⁴/P(perm) = 9.0×10⁻⁴] retained significance after correcting for multiple testing. The cis-acting variant rs3093059-CRP had maximum contribution to the variance in hsCRP levels (1.14%). Among, trans-acting variants, rs1892534-LEPR was observed to contribute maximally to hsCRP level variance (0.59%). Associations of rs3093059-CRP and rs1892534-LEPR were confirmed by replication and attained higher significance after meta-analysis [β(meta) = 0.26/0.22; P(meta) = 4.3×10⁻⁷/7.4×10⁻³ and β(meta) = -0.15/-0.12; P(meta) = 2.0×10⁻⁶/1.6×10⁻⁶ for rs3093059 and rs1892534, respectively in non-diabetic subjects and all subjects taken together].ConclusionIn conclusion, we identified rs3093059 in CRP and rs1892534 in LEPR as major cis and trans-acting contributor respectively, to the variance in hsCRP levels in North Indian population.

Background There has been no systematic evaluation of the association between genetic variants of type 2 receptor for TNFα (TNFR2) and type 2 diabetes, despite strong biological evidence for the role of this receptor in the pathogenesis of this complex disorder. In view of this, we performed a comprehensive association analysis of TNFRSF1B variants with type 2 diabetes in 4,200 Indo-European subjects from North India. Methods The initial phase evaluated association of seven SNPs viz. rs652625, rs496888, rs6697733, rs945439, rs235249, rs17883432 and rs17884213 with type 2 diabetes in 2,115 participants (1,073 type 2 diabetes patients and 1,042 control subjects). Further, we conducted replication analysis of three associated SNPs in 2,085 subjects (1,047 type 2 diabetes patients and 1,038 control subjects). Results We observed nominal association of rs945439, rs235249 and rs17884213 with type 2 diabetes (P < 0.05) in the initial phase. Haplotype CC of rs945439 and rs235249 conferred increased susceptibility for type 2 diabetes [OR = 1.19 (95%CI 1.03-1.37), P = 0.019/P perm = 0.076] whereas, TG haplotype of rs235249 and rs17884213 provided protection against type 2 diabetes [OR = 0.83 (95%CI 0.72-0.95, P = 7.2 × 10-3/P perm = 0.019]. We also observed suggestive association of rs496888 with plasma hsCRP levels [P = 0.042]. However, the association of rs945439, rs235249 and rs17884213 with type 2 diabetes was not replicated in the second study population. Meta-analysis of the two studies also failed to detect any association with type 2 diabetes. Conclusions Our two-stage association analysis suggests that TNFRSF1B variants are not the determinants of genetic risk of type 2 diabetes in North Indians.