<strong>Common and distinct genetic architecture of age at diagnosis of diabetes in South Indian and European populations</strong>

OBJECTIVE South Asians are diagnosed with type 2 diabetes (T2D) more than a decade earlier in life than seen in European populations. We hypothesised that studying the genomics of age of diagnosis in these populations may give insight into earlier age diagnosis of T2D among individuals of South Asian descent.  RESEARCH DESIGN AND METHODS  We conducted a meta-analysis of GWAS of age at diagnosis of T2D in 34,001 individuals from four independent cohorts of European and South Asian Indians.  RESULTS  We identified two signals near the TCF7L2 and CDKAL1 associated with age at the onset of T2D. The strongest genome-wide significant variants at chromosome 10q25·3 in TCF7L2 (rs7903146; p = 2·4 ×10-12, Beta = -0·436; SE = 0·02) and chromosome 6 p22·3 in CDKAL1 (rs9368219; p = 2·29 ×10-8; Beta = -0·053; SE=0·01) were directionally consistent across ethnic groups and present at similar frequencies, however both loci harboured additional independent signals that were only present in the South Indian Cohorts. A genome wide signal was also obtained at chromosome 10q26·12 in WDR11 (rs3011366; p = 3.255 ×10-8; Beta = 1·44; SE=0·25) specifically in the South Indian cohorts. Heritability estimates for the age diagnosis were much stronger in South Indian compared to Europeans, and a polygenic risk score was constructed using a South Indians, which explained about 2% trait variance. CONCLUSIONS  Our findings provide a better understanding of ethnic differences in the age at diagnosis and indicate the potential importance of ethnic differences in the genetic architecture underpinning T2D.   </p

Interaction of the <i>TCF7L2</i> gene polymorphism (rs12255372) with fat (g) intake, PUFA intake and Alpha Linolenic Acid (g) intake on HDL-C.

<p>Individuals carrying the ‘XT’ genotype had 2.26 mg/dl higher HDL-C in the lowest fat tertile (P = 0.008), while those in the highest tertile had 1.87 mg/dl lower HDL-C (P = 0.017) than those who carry the ‘GG’ allele. Carriers of the ‘XT’ genotype had 1.96 mg/dl higher HDL-C in the 1^st tertile of PUFA intake (g) (P = 0.024), while those in the 3^rd tertile had 1.64 mg/dl lower HDL-C in comparison to the carriers of the ‘GG’ genotype (P = 0.028). In the 1^st tertile of Alpha Linolenic acid intake (g), individuals with the ‘XT’ genotype had 2.42 mg/dl higher HDL-C than the ‘GG’ homozygotes (P = 0.004).</p

Interactions of <i>TCF7L2</i> SNPs rs12255372 and rs7903146 with carbohydrate, fibre and protein intake on HDL-C, fasting blood glucose and diastolic blood pressure.

<p>Interactions of <i>TCF7L2</i> SNPs rs12255372 and rs7903146 with carbohydrate, fibre and protein intake on HDL-C, fasting blood glucose and diastolic blood pressure.</p

Additional file 1: Table S1a. of Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India

Sample information and clinical characteristics. Table S1b. Summary of clinical characteristics of MODY patient samples. Table S2a. Sequencing statistics of combined exome and WGS. Table S2b. Sequencing statistics of targeted exome samples. Table S3. Targeted gene panel. Table S4. Candidate variants identified in MODY samples. Table S5. Differentially expressed genes - NKX6–1 (XLS 292 kb

Additional file 2: Figure S1. of Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India

Box plot showing (a) fasting plasma glucose, (b) fasting insulin, (c) C-peptide fasting, (d) C-peptide stimulated and (e) creatinine in MODY and control samples. The median value is shown as a line with the whiskers extending from the highest value within 1.5 * IQR of the third quartile to the lowest value within 1.5 * IQR of the first quartile where IQR is the inter-quartile range. Figure S2. Heatmap depicting the genotype based identity of the discovery and validation MODY cohort and control samples. Genomic regions for which we obtained data for the validation cohort samples and corresponding regions from the discovery set samples using GATK joint-variant caller. The sample identity was computed based on the high-confidence set of single nucleotide variants (SNVs) that passed GATK Hard-Filtering criteria. Figure S3. Expression level of mouse Nkx6–1 (top) or human NKX6–1 (bottom) following induction in cells stably expressing the indicated variant or wildtype. Figure S4. Western blot showing the expression of NKX6–1 48 h post dox induction. Hsp90 was used as a loading control. (ZIP 5136 kb