ArticlesEpigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study
Introduction
Type 2 diabetes is a major public health problem worldwide, particularly in rapidly urbanising countries such as India.1, 2 Indian Asians (ie, people originating from India, Pakistan, Bangladesh, or Sri Lanka), who comprise a quarter of the world's population, are at higher risk of type 2 diabetes than are North Americans and Europeans.2, 3, 4 Type 2 diabetes is estimated to affect more than 100 million people in India alone by 2030.1
Diet, obesity, and physical inactivity are major risk factors for type 2 diabetes in Indian Asians, as they are in other populations, but differences in the prevalence of these behaviours between Indian Asians and Europeans do not seem to account for their increased risk of type 2 diabetes.5, 6 Genome-wide association studies among Indian Asians and Europeans have identified common genetic variants at about 80 genetic loci that affect the risk of type 2 diabetes,4, 7, 8, 9, 10 although these only explain about 5% of type 2 diabetes risk in both populations.11, 12 Improved understanding of the mechanisms underlying the high incidence of type 2 diabetes among Indian Asians is needed to help reverse the epidemic of type 2 diabetes in this population.
DNA methylation at cytosine–guanine nucleotide pair (CpG) sites affects gene expression, cellular differentiation, and molecular response to environmental stressors.13, 14, 15, 16 Methylation at the FTO locus and other loci containing genetic variants linked to type 2 diabetes is associated with prevalent type 2 diabetes in Ashkenazi Jews, and baseline methylation of FTO was used as a marker to predict the likelihood of progressing from normal to impaired glucose metabolism in a follow-up study.17 Additionally, disturbances in methylation at the PPARG, KCNQ1, TCF7L2, and IRS1 loci have been reported in adipose and pancreatic tissue from people with prevalent type 2 diabetes.18, 19, 20 These findings raise the possibility that alterations in DNA methylation might be involved in the biological pathways underlying development of type 2 diabetes.
Therefore, in this study, we aimed to investigate whether variations in DNA methylation are associated with future type 2 diabetes among Indian Asians, and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes.
Section snippets
Patients
In this nested case-control study, we did epigenome-wide association of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. LOLIPOP4 was a prospective population study of Indian Asian (n=17 606) and European (n=7766) men and women, recruited at age 35–75 years from the lists of 58 family doctors in west London, UK, between May 1, 2002,
Results
The appendix lists baseline characteristics of the 13 535 Indian Asians and 7066 Europeans who did not have type 2 diabetes at enrolment into the LOLIPOP study. Despite lower BMI (p=0·01) and younger age (p<0·0001), Indian Asians had higher waist circumference (p<0·0001), waist:hip ratio (p<0·0001), HbA1c (p<0·0001), and glucose (p=0·01), insulin (p<0·0001), and triglyceride (p<0·0001) concentrations, and lower HDL cholesterol concentrations (p<0·0001) compared with Europeans. Family history of
Discussion
Methylation of DNA at CpG sites regulates gene expression and mediates the biological response to environmental exposures.13, 14, 15, 16 Although previous studies have investigated the association between methylation and type 2 diabetes, these have been largely limited to the study of patients with established disease.17, 18, 19, 20, 28, 29 In this large, prospective, nested case-control study, we identified an association between differential methylation at five genetic loci (ABCG1, PHOSPHO1,
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