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- Title
Epigenome-Wide Association Study of Fasting Measures of Glucose, Insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network Study.
- Authors
Hidalgo, Bertha; Irvin, M. Ryan; Jin Sha; Degui Zhi; Aslibekyan, Stella; Absher, Devin; Tiwari, Hemant K.; Kabagambe, Edmond K.; Ordovas, Jose M.; Arnett, Donna K.
- 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 In nium 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 x 107 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 x 10-7) and HOMA-IR (P = 1.60 x 10-9). Another site in the same gene was significant for HOMA-IR and of borderline significance for insulin (P =1.29 x 10-7 and P = 3.36 x 10-6, respectively). Associations with the top two signals replicated for insulin and HOMA-IR (P = 5.75 x 10-3 and P = 3.35 x 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.
- Subjects
TYPE 2 diabetes; FASTING; HERITABILITY; GLUCOSE; INSULIN resistance
- Publication
Diabetes, 2014, Vol 63, Issue 2, p801
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db13-1100