Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

We replicated the association of well-established common variants with Type 2 diabetes in Indians and observed a similar association as reported in Western populations. Combined analysis of 32 variants aids identification of subgroups at increased risk of Type 2 diabetes, but adds only a minor advantage over conventional risk factors.

Aims/hypothesisEvaluation of the association of 31 common single nucleotide polymorphisms (SNPs) with fasting glucose, fasting insulin, HOMA-beta cell function (HOMA-β), HOMA-insulin resistance (HOMA-IR) and type 2 diabetes in the Indian population.MethodsWe genotyped 3,089 sib pairs recruited in the Indian Migration Study from four cities in India (Lucknow, Nagpur, Hyderabad and Bangalore) for 31 SNPs in 24 genes previously associated with type 2 diabetes in European populations. We conducted within-sib-pair analysis for type 2 diabetes and its related quantitative traits.ResultsThe risk-allele frequencies of all the SNPs were comparable with those reported in western populations. We demonstrated significant associations of CXCR4 (rs932206), CDKAL1 (rs7756992) and TCF7L2 (rs7903146, rs12255372) with fasting glucose, with β values of 0.007 (p = 0.05), 0.01 (p = 0.01), 0.007 (p = 0.05), 0.01 (p = 0.003) and 0.08 (p = 0.01), respectively. Variants in NOTCH2 (rs10923931), TCF-2 (also known as HNF1B) (rs757210), ADAM30 (rs2641348) and CDKN2A/B (rs10811661) significantly predicted fasting insulin, with β values of −0.06 (p = 0.04), 0.05 (p = 0.05), −0.08 (p = 0.01) and −0.08 (p = 0.02), respectively. For HOMA-IR, we detected associations with TCF-2, ADAM30 and CDKN2A/B, with β values of 0.05 (p = 0.04), −0.07 (p = 0.03) and −0.08 (p = 0.02), respectively. We also found significant associations of ADAM30 (β = −0.05; p = 0.01) and CDKN2A/B (β = −0.05; p = 0.03) with HOMA-β. THADA variant (rs7578597) was associated with type 2 diabetes (OR 1.5; 95% CI 1.04, 2.22; p = 0.03).Conclusions/interpretationWe validated the association of seven established loci with intermediate traits related to type 2 diabetes in an Indian population using a design resistant to population stratification.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2355-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference (P < .05). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers (P for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity.

BackgroundGenome wide association studies (GWAS), mostly in Europeans have identified several common variants as associated with key lipid traits. Replication of these genetic effects in South Asian populations is important since it would suggest wider relevance for these findings. Given the rising prevalence of metabolic disorders and heart disease in the Indian sub-continent, these studies could be of future clinical relevance.MethodsWe studied seven common variants associated with a variety of lipid traits in previous GWASs. The study sample comprised of 3178 sib-pairs recruited as participants for the Indian Migration Study (IMS). Associations with various lipid parameters and quantitative traits were analyzed using the Fulker genetic association model.ResultsWe replicated five of the 7 main effect associations with p-values ranging from 0.03 to 1.97x10-7. We identified particularly strong association signals at rs662799 in APOA5 (beta=0.18 s.d, p=1.97 x 10-7), rs10503669 in LPL (beta =−0.18 s.d, p=1.0 x 10-4) and rs780094 in GCKR (beta=0.11 s.d, p=0.001) loci in relation to triglycerides. In addition, the GCKR variant was also associated with total cholesterol (beta=0.11 s.d, p=3.9x10-4). We also replicated the association of rs562338 in APOB (p=0.03) and rs4775041 in LIPC (p=0.007) with LDL-cholesterol and HDL-cholesterol respectively.ConclusionsWe report associations of five loci with various lipid traits with the effect size consistent with the same reported in Europeans. These results indicate an overlap of genetic effects pertaining to lipid traits across the European and Indian populations.

Obesity is an established risk factor for type 2 diabetes (T2D) and they are metabolically related through the mechanism of insulin resistance. In order to explore how common genetic variants associated with T2D correlate with body mass index (BMI), we examined the influence of 25 T2D associated loci on obesity risk. We used 5056 individuals (2528 sib-pairs) recruited in Indian Migration Study and conducted within sib-pair analysis for six obesity phenotypes. We found associations of variants in CXCR4 (rs932206) and HHEX (rs5015480) with higher body mass index (BMI) (β = 0.13, p = 0.001) and (β = 0.09, p = 0.002), respectively and weight (β = 0.13, p = 0.001) and (β = 0.09, p = 0.001), respectively. CXCR4 variant was also strongly associated with body fat (β = 0.10, p = 0.0004). In addition, we demonstrated associations of CXCR4 and HHEX with overweight/obesity (OR = 1.6, p = 0.003) and (OR = 1.4, p = 0.002), respectively, in 1333 sib-pairs (2666 individuals). We observed marginal evidence of associations between variants at six loci (TCF7L2, NGN3, FOXA2, LOC646279, FLJ3970 and THADA) and waist hip ratio (WHR), BMI and/or overweight which needs to be validated in larger set of samples. All the above findings were independent of daily energy consumption and physical activity level. The risk score estimates based on eight significant loci (including nominal associations) showed associations with WHR and body fat which were independent of BMI. In summary, we establish the role of T2D associated loci in influencing the measures of obesity in Indian population, suggesting common underlying pathophysiology across populations.