Smita R. Kulkarni

Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population

Aims and hypothesisIndia has the greatest number of diabetic subjects in any one country, but the genetic basis of type 2 diabetes mellitus in India is poorly understood. Common non-coding variants in the transcription factor 7-like 2 gene (TCF7L2) have recently been strongly associated with increased risk of type 2 diabetes in European populations. We investigated whether TCF7L2 variants are also associated with type 2 diabetes mellitus in the Indian population.Materials and methodsWe genotyped type 2 diabetes patients (n = 955) and ethnically matched control subjects (n = 399) by sequencing three single nucleotide polymorphisms (SNPs) (rs7903146, rs12255372 and rs4506565) in TCF7L2.ResultsWe observed a strong association with all the polymorphisms, including rs12255372 (odds ratio [OR] 1.50 [95% CI = 1.24–1.82], p = 4.0 × 10−5), rs4506565 (OR 1.48 [95% CI = 1.24–1.77], p = 2.0 × 10−5) and rs7903146 (OR 1.46 [95% CI = 1.22–1.75], p = 3.0 × 10−5). All three variants showed increased relative risk when homozygous rather than heterozygous, with the strongest risk for rs12255372 (OR 2.28 [95% CI = 1.40–3.72] vs OR 1.43 [95% CI = 1.11–1.83]). We found no association of the TCF7L2 genotypes with age at diagnosis, BMI or WHR, but the risk genotype at rs12255372 was associated with higher fasting plasma glucose (p = 0.001), higher 2-h plasma glucose (p = 0.0002) and higher homeostasis model assessment of insulin resistance (HOMA-R; p = 0.012) in non-diabetic subjects.ConclusionsOur study in Indian subjects replicates the strong association of TCF7L2 variants with type 2 diabetes in other populations. It also provides evidence that variations in TCF7L2 may play a crucial role in the pathogenesis of type 2 diabetes by influencing both insulin secretion and insulin resistance. TCF7L2 is an important gene for determining susceptibility to type 2 diabetes mellitus and it transgresses the boundaries of ethnicity.

FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians

Aims and hypothesisVariants of the FTO (fat mass and obesity associated) gene are associated with obesity and type 2 diabetes in white Europeans, but these associations are not consistent in Asians. A recent study in Asian Indian Sikhs showed an association with type 2 diabetes that did not seem to be mediated through BMI. We studied the association of FTO variants with type 2 diabetes and measures of obesity in South Asian Indians in Pune.MethodsWe genotyped, by sequencing, two single nucleotide polymorphisms, rs9939609 and rs7191344, in the FTO gene in 1,453 type 2 diabetes patients and 1,361 controls from Pune, Western India and a further 961 population-based individuals from Mysore, South India.ResultsWe observed a strong association of the minor allele A at rs9939609 with type 2 diabetes (OR per allele 1.26; 95% CI 1.13–1.40; p = 3 × 10−5). The variant was also associated with BMI but this association appeared to be weaker (0.06 SDs; 95% CI 0.01–0.10) than the previously reported effect in Europeans (0.10 SDs; 95% CI 0.09–0.12; heterogeneity p = 0.06). Unlike in the Europeans, the association with type 2 diabetes remained significant after adjusting for BMI (OR per allele for type 2 diabetes 1.21; 95% CI 1.06–1.37; p = 4.0 × 10−3), and also for waist circumference and other anthropometric variables.ConclusionsOur study replicates the strong association of FTO variants with type 2 diabetes and similar to the study in North Indians Sikhs, shows that this association may not be entirely mediated through BMI. This could imply underlying differences between Indians and Europeans in the mechanisms linking body size with type 2 diabetes.

Impact of Common Variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the Risk of Type 2 Diabetes in 5,164 Indians

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.

Maternal Lipids Are as Important as Glucose for Fetal Growth: Findings from the Pune Maternal Nutrition Study

OBJECTIVE To study the relationship between maternal circulating fuels and neonatal size and compare the relative effects of glucose and lipids. RESEARCH DESIGN AND METHODS The Pune Maternal Nutrition Study (1993–1996) investigated the influence of maternal nutrition on fetal growth. We measured maternal body size and glucose and lipid concentrations during pregnancy and examined their relationship with birth size in full-term babies using correlation and regression techniques. RESULTS The mothers (n = 631) were young (mean age 21 years), short (mean height 151.9 cm), and thin (BMI 18.0 kg/m2) but were relatively more adipose (body fat 21.1%). Their diet was mostly vegetarian. Between 18 and 28 weeks’ gestation, fasting glucose concentrations remained stable, whereas total cholesterol and triglyceride concentrations increased and HDL-cholesterol concentrations decreased. The mean birth weight of the offspring was 2666 g. Total cholesterol and triglycerides at both 18 and 28 weeks and plasma glucose only at 28 weeks were associated directly with birth size. One SD higher maternal fasting glucose, cholesterol, and triglyceride concentrations at 28 weeks were associated with 37, 54, and 36 g higher birth weights, respectively (P < 0.05 for all). HDL-cholesterol concentrations were unrelated to newborn measurements. The results were similar if preterm deliveries also were included in the analysis (total n = 700). CONCLUSIONS Our results suggest an influence of maternal lipids on neonatal size in addition to the well-established effect of glucose. Further research should be directed at defining the clinical relevance of these findings.

Analysis of 32 common susceptibility genetic variants and their combined effect in predicting risk of Type 2 diabetes and related traits in Indians

Diabet. Med. 29, 121–127 (2012)

Response to Comment on: Chauhan et al. (2010) Impact of Common Variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the Risk of Type 2 Diabetes in 5,164 Indians. Diabetes;59:2068–2074

We read with interest the letter by Gupta and Ebrahim (1) complimenting our article (2) published recently in Diabetes . As mentioned rightly by the authors, there have not been many well-powered association studies on type 2 diabetes in the Indian population; hence this collaborative effort, even though as a replication of established genome-wide association study (GWAS) signals, is indeed exemplary. While thanking the authors for acknowledging our contribution, we believe that the issue raised by them of spurious association because of population stratification has limited scientific basis. The issue of population …

Determinants of Incident Hyperglycemia 6 Years After Delivery in Young Rural Indian Mothers The Pune Maternal Nutrition Study (PMNS)

OBJECTIVE—To study determinants of incident hyperglycemia in rural Indian mothers 6 years after delivery. RESEARCH DESIGN AND METHODS—The Pune Maternal Nutrition Study collected information in six villages near Pune on prepregnant characteristics and nutrition, physical activity, and glucose tolerance during pregnancy. An oral glucose tolerance test (OGTT) was repeated 6 years after delivery. RESULTS—A total of 597 mothers had an OGTT at 28 weeks’ gestation; 3 had gestational diabetes (by World Health Organization 1999 criteria). Six years later, 42 of 509 originally normal glucose-tolerant mothers were hyperglycemic (8 diabetic, 20 with impaired glucose tolerance, and 14 with impaired fasting glucose). The hyperglycemic women had shorter legs and thicker skinfolds before pregnancy (P < 0.01, both), were less active and more hyperglycemic (2-h plasma glucose 4.8 vs. 4.4 mmol/l, P < 0.001) during pregnancy, and gained more weight during follow-up (6.0 vs. 2.7 kg, P < 0.001). Multivariate analysis revealed that total leukocyte count and blood pressure during pregnancy were additional independent predictors of 2-h glucose concentration at follow-up. CONCLUSIONS—Our results suggest that compromised linear growth, adiposity, inflammation, and less physical activity predispose to hyperglycemia in young rural Indian women. International cut points of diabetes risk factors are largely irrelevant in these women.

Response to Comment on Kulkarni et al. Maternal Lipids Are as Important as Glucose for Fetal Growth: Findings From the Pune Maternal Nutrition Study. Diabetes Care 2013;36:2706–2713

We thank Sahoo et al. (1) for their interest in our article (2) and for their comments. Our study did not show an association between HDL cholesterol levels and birth size (2). Sahoo et al. allude to three articles (3–5) that suggest that our findings are unusual. However, we believe our results are compatible with these studies. In the study by Misra et al. (3), there was an inverse relationship between HDL cholesterol and birth weight only in overweight/obese women (i.e., BMI >25 kg/m2). In our study, the average BMI was ∼18 kg/m2, and this may explain …