1691-P: A Variant in the Melanocortin-4 Receptor (MC4R) Locus Is Associated with Glycemic Control and Insulin Resistance (IR) in Type 1 Diabetes (T1D)

The MC4R gene (18q21.32) plays a role in regulating appetite and energy homeostasis and is consistently linked with obesity. A variant near MC4R (rs12970134) has also been associated with IR and type 2 diabetes, independent of BMI. We examined the association of rs12970134 with HbA1c, IR, and BMI in the Pittsburgh Epidemiology of Diabetes Complications study, a prospective T1D cohort (mean age 27, T1D duration 18 years at baseline, 1986-88). In 422 EDC participants of European ancestry with available DNA, we assessed associations between 16 published IR SNPs, including rs12970134, and longitudinal measures of HbA1c, estimated glucose disposal rate (eGDR, an inverse measure of IR), and BMI over 18 years of follow-up (1986-88 to 2004-06). General additive mixed models were adjusted for sex, T1D duration, and principal components of ancestry. The rs12970134 SNP was associated with longitudinal HbA1c (β=0.33, p=5x10^-5, see Figure) and eGDR (β=-0.31, p=0.008) trajectories, but not BMI (β=0.21, p=0.38). The associations remained significant after adjusting for BMI and insulin dose. There was no evidence for a SNP x time interaction (p>0.25 for both); all groups showed a similar fall in HbA1c after publication of the DCCT results. Thus, the rs12970134 SNP near MC4R is associated with glycemic control and insulin resistance, despite no association with BMI, in this T1D cohort.