Burden of Type 2 Diabetes and Its Genetic Determinants in Indian Populations: Findings from the INDIGENIUS Consortium

To address the public health issue of type 2 diabetes (T2D) and its genetic profile in India, we aimed to evaluate genetic determinants of T2D using family-based cohorts from four distinct Endogamous Ethnic Groups (EEGs) representing two Northern (Punjab [Sikhs: SI] and Rajasthan [Agarwals: AG]) and two Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India, and to examine whether genetic variants found through targeted sequencing of the previously established 8 South Asian T2D risk loci (including the one from the Sikh population) are relevant to the AG, CH, and RE EEGs. In this study, we report the findings of T2D occurrence and genetic basis of T2D/related traits from the EEGs, as part of the INDIGENIUS (Indian Diabetes Genetic Studies in collaboration with U.S.) consortium studies, supported by an Indo-U.S. Collaborative Research Partnership on T2D. Data and samples were collected from three EEGs: AG (N=530, Families=25, mean age=43y, mean BMI=27, T2D=37%); CH (N=518, families=21, Age=47y, BMI=27, T2D=33%), and RE (N=500, Families=22, Age=46y, BMI=27, T2D=36%). Each of the families from an EEG was ascertained by a proband with T2D. The status of T2D was defined by ADA 2018 guidelines (fasting glucose≥126 mg/dl or HbA1c≥6.5% and/or use of diabetes medication/history). Similar characteristics for the SI EEG (N=1260, Families=324, Age=51y, BMI=27, T2D=75%) were obtained previously. We used the variance components method as implemented in the program SOLAR to carry out genetic analyses. All analyses were adjusted for age and sex effects. In all cohorts, T2D heritability (h2) (p<0.05) ranged from 30% (CH) to 81% (AG). Other T2D-related traits (e.g., BMI, lipids, blood pressure, insulin, glucose) in AG, CH, and RE EEGs exhibited strong genetic influences (h2 range: 15% [triglycerides] - 90% [glucose; non-T2D]). Our findings highlight high burden of T2D in Indian EEGs with significant additive genetic influences on T2D and its related traits. Disclosure V. Venkatesan: None. J.C. Lopez-Alvarenga: None. R. Arya: None. T. Koshy: None. U. Ravichandran: None. S. Sharma: None. S. Lodha: None. A.R. Ponnala: None. K.K. Sharma: None. M.V. Shaik: None. R.G. Resendez: None. D. Ramu: None. P. Venugopal: None. P. R.: None. N. S.: None. J.A. Ezeilo: None. C.A. Bejar: None. S. Mummidi: None. C. Natesan: None. J. Blangero: None. K.M. Medicherla: None. S. Thanikachalam: None. T. Sadras Panchatcharam: None. D. K.: None. R. Gupta: None. D.K. Sanghera: None. R. Duggirala: None. S.F. Paul: None. Funding Indian Council of Medical Research (55/6/2/Indo-US/2014-NCD-II); National Institute of Diabetes and Digestive and Kidney Diseases (R21DK105913)