Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study

Abstract

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP , ABCG1 , and SREBF1 ). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A , with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

Epigenetic Changes in Islets of Langerhans Preceding the Onset of Diabetes

“…Furthermore, PTPRN2 (receptor-type tyrosine-protein phosphatase N2), one of the top five predictive genes in our study, is required for the accumulation of normal levels of insulin-containing vesicles, preventing their degradation, and plays a role in glucose-stimulated insulin secretion ( 37 ). None of our 105 candidates were genome-wide statistically significant in the two largest prospective epigenetic-wide association studies ( 38 , 39 ). In a nested case-control study, Chambers et al ( 39 ) identified an association between differential methylation at five genetic loci ( ABCG1 , PHOSPHO1 , SOCS3 , SREBF1 , and TXNIP ) with T2D incidence among Indian Asians and Europeans.…”

Differential DNA methylation profile in infants born small-for-gestational-age: association with markers of adiposity and insulin resistance from birth to age 24 months

“… 38 39 Inversely, overexpression of CPT1A in the liver of obese mice reduces inflammation and improves insulin signaling. 40 Recently, epigenome-wide association studies have disclosed the causal role of CPT1A methylation in type 2 diabetes 41 and the association between intron 1 CPT1A methylation and gestational BMI. 42 …”

Epigenetic regulation of insulin action and secretion – role in the pathogenesis of type 2 diabetes

“…Several studies have shown that DNA methylation in blood is associated with future risk of T2D using prospective population‐based cohorts [13,66,74,75]. Methylation of the ABCG1 , PHOSPHO1 , TXNIP and CPT1 locus could be replicated in independent prospective cohorts.…”

“…Some studies have taken on the challenging task to examine if epigenetic mechanisms may cause T2D. These studies have used both mathematical modelling such as causal inference tests (CITs) and Mendelian randomization analyses as well as experimental approaches including epigenetic editing [64‐67] (Fig. 3a).…”

“…Cardona et al found that methylation of a CpG site at CPT1A has a possible direct causal role in T2D when they used Mendelian randomization analyses [66]. CPT1A encodes an enzyme regulating the carnitine‐dependent transport across the mitochondrial inner membrane and its deficiency results in reduced fatty acid beta‐oxidation.…”