Identification of genetic variants underlying Type 2 Diabetes in UK Indian Asians

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

Diabetes is a leading cause of death world-wide. Indian Asians are almost 4 times more likely to develop diabetes than Europeans. This is thought to be genetic, but no specific genetic factors have been identified so far. We have assembled a large population study of Indian Asians and Europeans in West London (LOLIPOP), and will have complete high density genetic (?genome wide association?) data on 5200 Indian Asians, including 1600 with diabetes, by the end of 2007. We will capitalise on this unique Indian Asian genetic data, to complete the first well-powered genetic investigation of diabetes in Asians. We will integrate our genetic datasets to produce an Indian specific genetic map, then perform three rounds of further genetic testing in a progressively focused way. In total, we will be looking at genetic variants in over 20,000 Indian Asians, and a similar number of Europeans. With these large numbers we will be able to detect even small genetic effects. The results of our study will allow us to identify the genetic factors underlying diabetes in Indian Asians, and to identify which are specifc to Asians, and which are shared with Europeans. Our findings will advance our understanding of diabetes, and in the future may enable risk prediction in Indian Asians, allowing early intervention to prevent diabetes and its complications.

Technical Summary

Type 2 diabetes (T2D) is a leading cause of death world-wide. The prevalence of T2D in UK Indian Asians is 2-4 fold higher in Indian Asians than Europeans. Little is known about the genetic basis for T2D amongst Indian Asians, who constitute approximately ~30% of persons with T2D worldwide. We hypothesise that the higher prevalence of T2D amongst Indian Asians compared to Europeans is explained in part by i. Indian Asian specific T2D genetic variants, and ii Shared variants that are either a) more prevalent, or b) carry increased relative risk, in Indian Asians compared with Europeans. We have assembled the London Life Sciences Population (LOLIPOP) cohort of 36K Indian Asians and Europeans in West London, and will have complete genome wide association (GWA) data in 5218 Indian Asians, 1621 with T2D. We will capitalise on this available resource of unique Indian Asian GWA data, to complete the first well-powered investigation of the genetic variants underlying T2D in Indian Asians. We will carry out a four-stage study. In stage one, we will integrate our available Indian Asian GWA data, impute missing genotypes using established methodology, and select ~20K SNPs showing association with T2D. In stage two, these 20K SNPs will be genotyped in a cohort of 4800 Indian Asians (1600 with T2D), and analysed for association with T2D. In stage three, SNPs showing association with T2D at P 10-2 (from stage two, ~200) will be tested in 4000 Indian Asians with T2D, and 8000 Indian Asian controls. This provides an overall 80% power to detect an OR 1.15 for T2D in Indian Asians, with an overall false positive rate of 0.05. Finally, to identify population specific and shared variants, SNPs associated / top-ranked with T2D in Indian Asians will be genotyped in our European cohorts, and validated / top ranked SNPs associated with T2D in our European case-control consortia of 20K subjects will be tested in Indian Asians. Allele frequencies and risk ratios will be compared between the ethnic groups. Results of this study will identify the population specific and shared genetic variants underlying T2D in Indian Asians.

Publications

10 25 50

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C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC) (2011) Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. in BMJ (Clinical research ed.)

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Chambers JC (2010) Genetic variation in SCN10A influences cardiac conduction. in Nature genetics

 
Description Health
Amount € 2,999,000 (EUR)
Funding ID 279143 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2012 
End 12/2014
 
Description Program Grant
Amount £1,800,000 (GBP)
Funding ID RP-PG-0407-10371 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 06/2007 
End 06/2013