Abstract 16596: Genetic Variation in Vitamin D Metabolism and Changes in Body Weight and Insulin Resistance in a 2-Year Weight-Loss Trial: The Pounds Lost Trial

Abstract

Background Vitamin D status has been associated with obesity, insulin resistance and diabetes. A recent genome-wide association study identified genetic variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1), and vitamin D transport (GC) affecting vitamin D status. We examined whether weight-loss diets varying in macronutrient content might modify the effect of these variants on changes in body weight and insulin resistance in a 2-year randomized intervention study: the Pounds Lost Trial. Methods Three SNPs (DHCR7 rs12785878, CYP2R1 rs10741657, and GC rs2282679) were genotyped in 732 overweight or obese adults who were randomly assigned to one of four weight-loss diets differing in the percentages of energy derived from fat, protein and carbohydrate (20, 15, and 65%; 20, 25, and 55%; 40, 15, and 45%; and 40, 25, and 35%) for 2 years. We assessed the effect of genotypes on changes in weight, fasting insulin and HOMA-IR at 6 months and 2 years in two-by-two factorial comparison of low (20%) versus high fat (40%), and low (15%) versus high protein (25%) content. Results We found significant interactions between DHCR7 rs12785878 genotypes and intervention varying in diet protein on changes in fasting insulin and HOMA-IR at 6 months (P for interaction =0.0004, 0.0003, respectively). The T-allele (vitamin D increasing-allele) of rs12785878 was associated with greater decreases in fasting insulin (P=0.0007) and HOMA-IR (P=0.001) among participants who were assigned to the high-protein diet, while there was no significant genotype effect on changes in these traits in the low-protein diet group (all P>0.19). The results on changes in fasting insulin and HOMA-IR remained significant after correction for multiple tests (12 independent tests, significant P=0.004). At 2 years, most participants regained body weight, probably due to diminished adherence that occurred between 6 months and 2 years in the intervention, and the genotype-diet interactions on changes in fasting insulin and HOMA-IR were attenuated (P for interaction =0.02 and 0.01, respectively). Conclusions Our data suggest that the T-allele of DHCR7 rs12785878 was associated with greater improvement of insulin resistance among individuals by choosing a high-protein diet.