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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

Author
item HIDALGO, BERTHA - University Of Alabama
item IRVIN, IRVIN - University Of Alabama
item SHA, JIN - University Of Alabama
item ZHI, DEGUI - University Of Alabama
item ASLIBEKYAN, STELLA - University Of Alabama
item ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology
item TIWARI, HERMANT - University Of Alabama
item KABAGAMBE, EDMOND - Vanderbilt University
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item ARNETT, DONNA - University Of Alabama

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/7/2013
Publication Date: 2/1/2014
Citation: Hidalgo, B., Irvin, I.M., Sha, J., Zhi, D., Aslibekyan, S., Absher, D., Tiwari, H.K., Kabagambe, E.K., Ordovas, J.M., Arnett, D.K. 2014. Epigenome-wide association study of fasting measures of glucose, insulin, and HOMA-IR in the genetics of lipid lowering drugs and diet Network Study. Diabetes. 63(2):801-807.

Interpretive Summary: The risk of type 2 diabetes (T2D) is partially driven by genetic factors; however, known genes for T2D explain only a small proportion of heritable T2D risk. We hypothesize that epigenetics (the study of heritable changes in gene activity), and specifically 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. Cytosine guanine dinucleotide (CpG) methylation at around 470,000 CpG sites across the entire genome was assayed in white blood cells. Methylation of a CpG site in ABCG1 on chromosome 21 was significantly associated with insulin and HOMA-IR. 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.

Technical 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.