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Genetic polymorphism affecting triglyceride metabolism as an independent determinant of insulin resistance and type2 diabetes in Indian patients: Use of Mendelian Randomisation Principle (WELLGEN)


Funded By:  The Wellcome Trust, UK
Month & Year of Commencement:  Mar 2005
Current Status:  Ongoing (Number of subjects being expanded. This study has created a resource for further genetic studies)

Principal Investigator: Dr. C.S.Yajnik, Director, Diabetes Unit, KEM Hospital & Research Centre, Pune, India
Co-Investigator: Prof.Andrew Hattersley, Prof. of Diabetes and Vascular Medicine, Penninsula Medical School, University of Exeter, UK
Dr. G. R. Chandak- Medical Geneticist ,Center for Cellular and Molecular Biology, Andhra Pradesh,India
» Background
» Objectives
» Methodology and Design
» Results


Background

The contribution of genetic factors to the rising epidemic of diabetes in Indians is only beginning to be studied. We have taken the initial step in this direction by setting up a tripartite collaborations with Centre for Cellular and Molecular Biology (CCMB, Hyderabad, Dr G Chandak) and Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, UK (Prof. Andrew Hattersley). The first study endeavours to collect DNA samples and phenotypic information from young type 2 diabetes patients (diagnosed < 45y of age) from the Diabetes Clinics of KEM Hospital and the attending consultants. Control samples are drawn from the well characterised subjects in various studies in the Diabetes Unit (Pune Maternal Nutrition Study, CRISIS etc). We are planning to extend the collection and collaborate with other groups to increase the number of patients and controls, and create a large repository for genetic research. As part of this we have collaborated with PBMA's HV Desai Eye Hospital, Pune.

The first grant was from the Wellcome Trust & was for the study of genetic polymorphisms in the triglyceride metablism to test the idea that hypertriglyceridemia may be causally related to incident diabetes. We have used the Mendelian Randomisation method to test this hypothesis. For this purpose we chose the genetic variant -1131T>C (of the gene ApoAV) which is present in 36 % of the Indian population and raises TG levels by 20%. Possession of such a genetic variant is effectively randomized at conception and results in long term exposure to the intermediate phenotype of interest viz raised circulating TG levels.



Objectives

To test whether ApoAV -1131T>C, a genetic variant is an independent determinant of insulin resistance (IR) and T2DM.


Methdology and Design

We studied more than 2300 young onset T2DM patients and a similar number of non-diabetic controls for the ApoAV genotype. Additional phenotypic information includes glycemic control, lipid levels, family history of diabetes and various clinical details and measurements. We will analyse if the ApoAV genotype distribution is different in patients and controls.
Results

Sample collection is ongoing. Genetic and other analysis is in progress. During this time we analyzed some more genetic markers of type 2 diabetes like TCF7L2, FTO etc with very exciting results.

(Ref: Chandak GR et al. Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia 2007;50:63-7 Yajnik CS, Janipalli CS, Bhaskar S et al. FTO gene variants are strongly associated with type 2 diabetes in South Asian Indians. Diabetologia 2009;52:247-52. Chauhan G, Spurgeon CJ, Tabassum R et al. 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 2010;59:2068-74.)


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