Effects of vitamin D genes on measures of insulin secretion, insulin sensitivity and adiposity: An ancillary study to the Insulin Resistance Atherosclerosis Study (IRAS) Family Study

Vitamin D is associated with type 2 diabetes (T2D) quantitative traits. Three genes, the vitamin D receptor (VDR), the vitamin D binding protein (DBP), and the vitamin D 1alpha-hydroxylase (CYP27B1) have been implicated in insulin secretion, insulin sensitivity and obesity. Physical activity also plays an important role in T2D quantitative traits. The goal of this work was to determine the association between these vitamin D related genes in interaction with each other and, separately, physical activity and T2D quantitative traits. Thirty single nucleotide polymorphisms (SNPs) in these 3 genes were genotyped in 604 African Americans (42 families) from Los Angeles, 715 Hispanics (30 families) from the San Luis Valley, CO, and 710 Hispanics (60 families) from San Antonio, TX, recruited in the Insulin Resistance Atherosclerosis (IRAS) Family Study. Using the family based association test (FBAT) and the quantitative pedigree disequilibrium test (QPDT), this work investigated the association of the SNPs with acute insulin response to glucose (AIRG ) and the insulin sensitivity index (SI), calculated from a frequently-sampled intravenous glucose tolerance test; waist-to-hip ratio (WHR); abdominal visceral-to-subcutaneous fat ratio (VSR), measured by computed tomography; and the metabolic syndrome. SNPs associated with these traits by both QPDT and FBAT were examined in a generalized estimating equations model to test for gene-gene and gene-physical activity interactions. Several individual polymorphisms were associated with these traits in at least one population. There was evidence for an interaction between DBP2 and VDR1 in LA African Americans and SLV Hispanics (P=0.007 and 0.05, respectively) and between DBP2 and VDR9 in SLV Hispanics (P<0.0001). There was evidence for an interaction between DBP8 and VDR6 in SLV and SA Hispanics (P=0.0008 and 0.0002, respectively) for WHR and between DBP1 and VDR13 in SLV Hispanics (P=0.0005) for WHR. There was also evidence for an interaction between DBP8 and quartiles of estimated energy expenditure in LA African Americans (P=0.0003) for VSR and between DBP7 and quartiles of estimated energy expenditure in LA African Americans (P<0.0001) for SI. In summary, interactions between the DBP and VDR genes and between the DBP gene and physical activity play an important role in these traits.