1535-P: An Insulin Resistance Genetic Risk Score (IR_GRS) Is Associated with Mortality in Type 1 Diabetes (T1D)

Abstract

Many SNPs in multiple loci are associated with IR in the general population. IR itself is associated with increased complication and mortality risk in T1D. We thus assessed whether a genetic risk score derived from IR SNPs (IR_GRS) is associated with mortality in the T1D prospective Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. In 422 participants of European ancestry, with available DNA, a weighted IR_GRS based on 16 published IR-associated SNPs was calculated. First, for each SNP, the effect size of the association between each SNP and estimated glucose disposal rate (eGDR, an inverse measure of insulin resistance) was estimated using a general additive linear model. This effect size was then multiplied by the risk allele count to obtain the IR-weighted count. The IR_GRS was calculated as the sum of the 16 weighted counts. All deaths were classified by a physician committee yielding underlying and contributing causes. IR_GRS was related to 25-year total, any mention of cardiovascular disease (CVD), and any end-stage renal disease (ESRD) mortality in Cox models adjusted for sex, principal components for ancestry, and T1D duration and baseline (1986-88) clinical risk factors, including HbA1c, lipids, blood pressure, albumin excretion rate (AER), estimated glomerular filtration rate, and white blood cell count. IR_GRS was associated with increased risk of mortality outcomes: total (99 deaths, p=0.003), any CVD (71 deaths, p=0.01), and any ESRD (49 deaths, p=0.01). Adjustment for clinical risk factors attenuated these associations: total mortality (p=0.04), CVD mortality (p=0.17), ESRD mortality (p=0.10), largely as a result of adjustment for log-transformed AER, which was significantly associated with the IR_GRS (p=0.0003). These results, while needing validation in other cohorts, suggest that an IR_GRS may help to identify individuals with T1D who are at increased risk of mortality and vascular damage (i.e., AER) due to IR. Disclosure R.G. Miller: None. T. Costacou: None. S. Onengut-Gumuscu: None. W. Chen: None. S.S. Rich: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. Funding National Institutes of Health; Rossi Memorial Fund; JDRF