Abstract P366: Promoter Methylation of the Monoamine Oxidase a Gene is Associated With Fasting Plasma Glucose: A Monozygotic Twin Study

Abstract

Background: Epigenetic factors play an important role in complex diseases including diabetes. The monoamine oxidase A (MAOA) gene codes for the enzyme MAOA that plays a key role in the metabolism of neurotransmitters including dopamine, norepinephrine, and serotonin. These neurotransmitters are known to be involved in the pathogenesis of diabetes. No study has examined the association of MAOA methylation with fasting plasma glucose (FPG), independent of genetic factors. Objective: To examine whether MAOA promoter methylation variation is associated with FPG, independent of familiar factors. Methods: We studied 69 middle-aged, male-male monozygotic twin pairs drawn from the Vietnam Era Twin Registry. All twins were free of overt diabetes. DNA methylation at seven CpG sites in the MAOA promoter region was quantified by bisulfite pyrosequencing using genomic DNA isolated from peripheral blood leukocytes. To examine whether MAOA promoter methylation variation influences FPG, we first calculated the intra-pair difference, defined as the difference in DNA methylation level at each CpG site between members of a twin pair. The intra-pair differences in FPG and other potential confounding factors were similarly calculated. We then conducted a matched pair analysis by regressing the intra-pair difference in FPG (dependent variable) on the intra-pair difference in DNA methylation level at each CpG site (independent variable), adjusting for intra-pair differences in body mass index (BMI), smoking pack-years, physical activity and depressive symptoms assessed by beck depression inventory (BDI). Multiple testing was corrected by the FDR p-value (or q-value) with a significant threshold of q<0.05. Results: The mean age of the twins was 55 years old. DNA methylation at the seven examined CpG sites varied from 1.6% to 19.0% with a mean methylation level of 5.0%. Intra-pair difference in FPG was significantly and positively correlated with intra-pair difference in methylation level at 3 out of the 7 CpG sites (r2 ranges 0.10 to 0.18, all P<0.025) as well as the mean methylation level (r2=0.10, p=0.026). Matched-pair analysis showed that methylation variation at 3 CpG sites was significantly associated with FPG (β ranges 1.83 to 2.33, all P<0.015), independent of BMI, smoking, physical activity and depressive symptoms. On average, a 1% increase in the intra-pair difference in mean methylation level was associated with a 2.21 mg/dl increase in the intra-pair difference in FPG (P=0.015). Conclusion: Methylation variation in the MAOA gene promoter is associated with FPG, independent of genetic and other clinical factors. This finding suggests a novel mechanism through which MAOA methylation variation, and perhaps its resulting changes in neurotransmitters, may contribute to diabetes.