Burden of Type 2 Diabetes and Associated Cardiometabolic Traits and Their Heritability Estimates in Endogamous Ethnic Groups of India: Findings From the INDIGENIUS Consortium

Abstract

To assess the burden of type 2 diabetes (T2D) and its genetic profile in endogamous populations of India given the paucity of data, we aimed to determine the prevalence of T2D and estimate its heritability using family-based cohorts from three distinct Endogamous Ethnic Groups (EEGs) representing Northern (Rajasthan [Agarwals: AG]) and Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India. For comparison, family-based data collected previously from another North Indian Punjabi Sikh (SI) EEG was used. In addition, we examined various T2D-related cardiometabolic traits and determined their heritabilities. These studies were conducted as part of the Indian Diabetes Genetic Studies in collaboration with US (INDIGENIUS) Consortium. The pedigree, demographic, phenotypic, covariate data and samples were collected from the CH, AG, and RE EEGs. The status of T2D was defined by ADA guidelines (fasting glucose ≥ 126 mg/dl or HbA1c ≥ 6.5% and/or use of diabetes medication/history). The prevalence of T2D in CH (N = 517, families = 21, mean age = 47y, mean BMI = 27), AG (N = 530, Families = 25, mean age = 43y, mean BMI = 27), and RE (N = 500, Families = 22, mean age = 46y, mean BMI = 27) was found to be 33%, 37%, and 36%, respectively, Also, the study participants from these EEGs were found to be at increased cardiometabolic risk (e.g., obesity and prediabetes). Similar characteristics for the SI EEG (N = 1,260, Families = 324, Age = 51y, BMI = 27, T2D = 75%) were obtained previously. We used the variance components approach to carry out genetic analyses after adjusting for covariate effects. The heritability (h2) estimates of T2D in the CH, RE, SI, and AG were found to be 30%, 46%, 54%, and 82% respectively, and statistically significant (P ≤ 0.05). Other T2D related traits (e.g., BMI, lipids, blood pressure) in AG, CH, and RE EEGs exhibited strong additive genetic influences (h2 range: 17% [triglycerides/AG and hs-CRP/RE] - 86% [glucose/non-T2D/AG]). Our findings highlight the high burden of T2D in Indian EEGs with significant and differential additive genetic influences on T2D and related traits.

Polygenic scores of diabetes-related traits in subgroups of type 2 diabetes in India: a cohort study

“… 52 Population studies have revealed a historic admixture pattern mirroring a North-South gradient [Ancestral North Indians (ANI) vs. Ancestral South Indians (ASI)]. 53 , 54 , 55 A gene-flow from Europe to North India has been indicated in the manifestation of external phenotypes such as skin colour, 56 which could potentially be extended to metabolism. It could be speculated that there would be a higher degree of similarity between findings in Europe and North India whereas this would tend to reduce as one moves further South, given the increasing genetic diversity between the different geographies.…”

Susceptibility Loci for Type 2 Diabetes in the Ethnically Endogamous Indian Sindhi Population: A Pooled Blood Genome-Wide Association Study

“…In the same year, Saxena et al [ 44 ] published a study on the Punjabi Sikh population with a novel signal at the SGCG gene. Recently, a study [ 45 ] published on the genetic basis of T2D in three ethnically endogamous Indian populations based in Tamil Nadu, Rajasthan and Andhra Pradesh states (the INDIGENIUS Consortium) also demonstrated substantial population-specificity in the genetic basis of T2D within Indian populations. It is therefore a need to conduct T2D GWAS studies in ethnically coherent subgroups within India.…”

The Real DAPSI: A Real-World Retrospective Study on Assessing the Efficacy and Safety of a Fixed-Dose Combination of Dapagliflozin and Sitagliptin in the Indian Population

“…The Indian population exhibits unique characteristics, such as a higher prevalence of insulin resistance, a distinct genetic profile, and disparities in healthcare access and quality. These unique characteristics of the Indian population make it imperative to evaluate the efficacy and safety of anti-diabetic agents in this population [9]. Furthermore, T2DM is often associated with comorbidities such as obesity, dyslipidemia, and hypertension, which further complicate management and may require multiple therapeutic interventions [10].…”