IRS1 Genotype Modulates Metabolic Syndrome Reversion in Response to 2-Year Weight-Loss Diet Intervention

Abstract

OBJECTIVEGenetic variants near IRS1 are associated with features of the metabolic syndrome (MetS). We examined whether genetic variants near IRS1 might modulate the effects of diets varying in fat content on the MetS status in a 2-year weight-loss trial.RESEARCH DESIGN AND METHODSTwo variants near IRS1, rs1522813 and rs2943641, were genotyped in 738 overweight/obese adults (age 60 ± 9 years; BMI 32.7 ± 3.9 kg/m2) randomly assigned to one of four weight-loss diets (a deficit of 750 kcal/day of caloric intake from baseline) varying in macronutrient contents for 2 years. We compared MetS status of high-fat (40% of caloric intake; n = 370) and low-fat (20% caloric intake; n = 368) diet groups differentiated by genotypes (rs1522813 A-allele carriers and noncarriers and rs2943641T-allele carriers and noncarriers).RESULTSAmong rs1522813 A-allele carriers, the reversion rates of the MetS were higher in the high-fat diet group than those in the low-fat diet group over the 2-year intervention (P = 0.002), while no significant difference between diet groups was observed among noncarriers (P = 0.27). The genetic modulation on dietary effect was independent of weight changes. The odds ratio (OR) for the 2-year reversion of the MetS was 2.88 (95% CI 1.25–6.67) comparing the high-fat and low-fat diets among rs1522813 A-allele carriers, while the corresponding OR was 0.83 (0.36–1.92) in noncarriers. The variant rs2943641 was not observed to modulate dietary effects on the MetS status.CONCLUSIONSOur data suggest that high-fat weight-loss diets might be more effective in the management of the MetS compared with low-fat diets among individuals with the A-allele of the rs1522813 variant near IRS1.

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

“…Thus, either CHO or dietary fat may modulate the effect of the PCSK7 rs236918. Second, the power to detect the effect of genotype on insulin resistance in response to the real difference in macronutrients intake was reduced because of the decline of adherence to various diets after 6 months, which is similar to most of the long-term diet intervention trials reported ( 14 , 23 ). Finally, 80% of the participants in our study are white, and further studies are required to determine whether our findings are generalizable to other ethnic groups.…”

Gene-Diet Interaction and Precision Nutrition in Obesity

“…It has been reported that how genetic variants modifies effect of dietary intake on weight loss among overweight and obese individuals. In participants of the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) Trial [ 68 ] and the Dietary Intervention Randomized Controlled Trial (DIRECT) [ 69 ], we have performed a series of analyses on gene–diet interactions in obesity and metabolic risk factors ( Table 2 ) [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. There have been debates about which dietary intervention is more effective in losing body weight.…”

Gene–diet interaction and weight loss

“…In the Pounds Lost trial, we have reported interactions between diet intervention and genetic variants in relation to several metabolic traits (Table 1) [13 ▪ ,33–36,38–40,43 ▪ ,44 ▪▪ ,45,46,47 ▪ ,48 ▪ ,49] In one study, we found the T allele of the GIPR SNP rs2287019 was associated with greater decreases in fasting glucose, fasting insulin, and HOMA-IR (all P <0.03) in participants assigned to low-fat diets, whereas there was no significant genotype effect on changes in these traits in those assigned to the high-fat diet ( P -interaction =0.04, 0.10, and 0.07, respectively) [13 ▪ ]. In another study [43 ▪ ], we found that dietary fat modified genotype effects of APOA5 rs964184 on changes in total-cholesterol, LDL-cholesterol, and HDL-cholesterol ( P -interaction =0.007, 0.017, and 0.006, respectively).…”