Epigenome-Wide Association Study of Fasting Measures of Glucose, Insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network Study
- Bertha Hidalgo1⇑,
- M. Ryan Irvin2,
- Jin Sha2,
- Degui Zhi1,
- Stella Aslibekyan2,
- Devin Absher3,
- Hemant K. Tiwari1,
- Edmond K. Kabagambe4,
- Jose M. Ordovas5 and
- Donna K. Arnett2
- 1Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL
- 2Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL
- 3Hudson Alpha Institute for Biotechnology, Huntsville, AL
- 4Department of Medicine, Vanderbilt University, Nashville, TN
- 5Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Medford, MA
- Corresponding author: Bertha Hidalgo, .
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.
- Received July 16, 2013.
- Accepted October 7, 2013.
- © 2014 by the American Diabetes Association.
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