Abstract 17844: Genetic Variant of Body Iron Metabolism Modifies Insulin Resistance and Cell Function Response to Weight-Loss Diets in a 2-Year Randomized Trial: the POUNDS LOST Trial

Abstract

Aims ─ Excess body iron store was associated with obesity, and risk of type 2 diabetes. Recent genome-wide associations studies (GWAS) identified SNPs on TMPRSS6 and PCSK7 were related to iron homeostasis. We aimed to assess whether genetic variants in these loci modify changes in insulin resistance and beta-cell function in response to weight-loss diets among obese patients. Methods ─ The PCSK7 rs236918 (C/G) and TMPRSS6 rs855791 (C/T) was genotyped in 730 obese adults who were randomly assigned to one of four diets differing in the target percentages of energy derived from fat, protein, and carbohydrates. Results ─ We found that PCSK7 rs236918 genotypes modified the effects of fat diet (low vs. high) on the changes in HOMA_IR and HOMA_β. Among the participants carrying C allele, the low-fat diet induced greater decrease in HOMA-IR from baseline to 6 months (period of weight loss; p=0.024) but greater increase in HOMA-IR from 6 months to 2 years (period of weight regain; p=0.05), compared to the high-fat diet. However, in those without C allele, no significant difference between the diet groups was observed. In addition, we found that in participants without C allele, the high fat diet led to greater decrease in HOMA_ β index across 2-years of intervention (p=0.006), but no difference in HOMA_β was found between diet groups in participants with C allele (p for interaction=0.039). TMPRSS6 genotype did not modify dietary intervention on HOMA_IR and HOMA_β. Conclusions ─ PCSK7 genotypes may modify changes in insulin resistance and beta-cell function by weight-loss diets. Keywords:PCSK7, gene-diet interaction, HOMA_IR, HOMA_beta, Iron