PCSK7 Genotype Modifies Effect of a Weight-Loss Diet on 2-Year Changes of Insulin Resistance: The POUNDS LOST Trial

OBJECTIVE A common variant rs236918 in the PCSK7 gene has the strongest association with iron homeostasis and is related to insulin resistance. Dietary carbohydrate (CHO) modulates the genetic effect on insulin resistance. We examined whether 2-year weight-loss diets modify the effect of PCSK7 genetic variants on changes in fasting insulin levels and insulin resistance in a randomized, controlled trial. RESEARCH DESIGN AND METHODS Data were analyzed in the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial, which is a randomized, controlled 2-year weight-loss trial using diets that differed in macronutrient proportions. PCSK7 rs236918 was genotyped in 730 overweight or obese adults (80% whites) in this trial. We assessed the progression in fasting insulin and glucose levels, and insulin resistance by genotypes. RESULTS During the 6-month weight-loss phase, the PCSK7 rs236918 G allele was significantly associated with greater decreases in fasting insulin levels in the high-dietary CHO group (P for interaction = 0.04), while the interaction for changes in HOMA-insulin resistance (HOMA-IR) (P for interaction = 0.06) did not reach significant levels in white subjects. The G allele was significantly associated with a greater decrease in fasting insulin levels and HOMA-IR in response to high dietary CHO levels (P = 0.02 and P = 0.03, respectively). From 6 months to 2 years (weight-regain phase), the interactions became attenuated due to the regaining of weight (P for interactions = 0.08 and 0.06, respectively). In addition, we observed similar and even stronger results in the whole-study samples from the trial. CONCLUSIONS Our data suggest that PCSK7 genotypes may interact with dietary CHO intake on changes in insulin sensitivity in the white Americans.