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.
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.
authors.affiliation: Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Bertha
authors.initials: B
authors.lastname: Hidalgo
authors.forename: M Ryan
authors.initials: MR
authors.lastname: Irvin
authors.forename: Jin
authors.initials: J
authors.lastname: Sha
authors.forename: Degui
authors.initials: D
authors.lastname: Zhi
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.forename: Edmond K
authors.initials: EK
authors.lastname: Kabagambe
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000502:physiology*; D057890:Epigenomics; D005786:Gene Expression Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology*; D015203:Reproducibility of Results; D012307:Risk Factors; D059467:Transcriptome
chemical_list: D001786:Blood Glucose; D007328:Insulin