Epigenome-Wide Association Study of Fasting Measures of Glucose, Insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network Study

Abstract

Known genetic susceptibility loci for type 2 diabetes (T2D) explain only a small proportion of heritable T2D risk. We hypothesize that DNA methylation patterns may contribute to variation in diabetes-related risk factors, and this epigenetic variation across the genome can contribute to the missing heritability in T2D and related metabolic traits. We conducted an epigenome-wide association study for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study, divided into discovery (N = 544) and replication (N = 293) stages. Cytosine guanine dinucleotide (CpG) methylation at ∼470,000 CpG sites was assayed in CD4+ T cells using the Illumina Infinium HumanMethylation 450 Beadchip. We fit a mixed model with the methylation status of each CpG as the dependent variable, adjusting for age, sex, study site, and T-cell purity as fixed-effects and family structure as a random-effect. A Bonferroni corrected P value of 1.1 × 10−7 was considered significant in the discovery stage. Significant associations were tested in the replication stage using identical models. Methylation of a CpG site in ABCG1 on chromosome 21 was significantly associated with insulin (P = 1.83 × 10−7) and HOMA-IR (P = 1.60 × 10−9). Another site in the same gene was significant for HOMA-IR and of borderline significance for insulin (P = 1.29 × 10−7 and P = 3.36 × 10−6, respectively). Associations with the top two signals replicated for insulin and HOMA-IR (P = 5.75 × 10−3 and P = 3.35 × 10−2, respectively). Our findings suggest that methylation of a CpG site within ABCG1 is associated with fasting insulin and merits further evaluation as a novel disease risk marker.

An Epigenome-Wide Association Study of Inflammatory Response to Fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network

“…The protocol was approved by the Institutional Review Boards of University of Minnesota, University of Utah, Tufts University/New England Medical Center, and the University of Alabama at Birmingham. More details about the GOLDN study have been published in earlier reports [17][18][25][26][27]. Baseline and postfenofibrate intervention data were available for 750 participants with DNA methylation measurements.…”

“…Random subsets of 10,000 CpGs per run were run after normalization, in which each array of 12 samples were used as batch. Correction for differing probe chemistry was performed on Illumina Infinium HumanMethylation450 Bead chip, normalizing the probes separately from the Infinium I and II [26][27]29,31].…”

Adipose ABCG1: A potential therapeutic target in obesity?

“…7 Interestingly, a recent epigenome-wide association study among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study suggested that cytosine guanine dinucleotide (CpG) methylation at CpG sites in ABCG1 locus in CD4C T cells was significantly associated with insulin levels and HOMA-IR. 8 Those latter studies would suggest that pharmacological inhibition of ABCG1 could exert potentially deleterious effects on insulin resistance (IR), This possibility is however weakened by the observation that Abcg1 -/-mice fed a highfat diet did not exhibit glucose intolerance or liver steatosis, in contrast to control Abcg1 C/C littermates 4 , suggesting that total Abcg1 deficiency should rather protect against IR rather than deteriorate it. However, our analysis of ABCG1 SNPs in 1320 morbidly obese patients revealed that both rs1378577 and rs1893590 were not associated with HOMA index independently of BMI.…”

“…Low amounts of membrane SM ensures optimal LPL activity and hydrolysis of triacylglycerol-rich lipoproteins (TRL) (3), contributing to the release of free fatty acids (FA) (4). Released FFAs are then taken up by the cell (5) and used for triglycerides synthesis (6), leading to TG storage (7) and to increased lipid droplet size in adipocytes (8). Optimal LPL activity is also accompanied by TRL uptake, ensuing increase of intracellular cholesterol content (5).…”

Non-coding genome functions in diabetes

“…The first T2D epigenome-wide association studies (EWASs) are now starting to be performed (Dick et al 2014, Hidalgo et al 2014, Petersen et al 2014, Chambers et al 2015, Kulkarni et al 2015. However, so far, T2D EWAS have only been performed with wholeblood cells instead of pancreatic islets or other diseaserelevant tissues, only being able to grasp early developmental epigenetic changes, which can be present in multiple tissues, and alterations derived from inflammatory processes, which are often detectable in circulating blood.…”