IRS1 Genotype Modulates Metabolic Syndrome Reversion in Response to 2-Year Weight-Loss Diet Intervention: The POUNDS LOST trial

OBJECTIVE

Genetic 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 METHODS

Two 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).

RESULTS

Among 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.

CONCLUSIONS

Our 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.The metabolic syndrome (MetS) is a constellation of metabolic abnormalities including abdominal obesity, dyslipidemia (low HDL cholesterol levels, and hypertriglyceridemia), elevated blood pressure, and hyperglycemia (1). It has been well-documented that the MetS increases the risk of diabetes, cardiovascular disease, and all-cause mortality (2). Several clinical trials have suggested that dietary intervention is an effective way to manage the MetS (3–9), though a specific therapeutic diet for the MetS remains to be determined. We have previously shown that weight-loss diets varying in macronutrient components had similar effectiveness in reducing the prevalence of the MetS in a 2-year randomized clinical trial, the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial (10).Genetic factors may play an important role in the development of the MetS. Insulin receptor substrate 1 (IRS1), encoded by the IRS1 gene, plays a key role in the insulin signaling pathway (11–13). Recent genome-wide association studies have identified common genetic variants near the IRS1 gene associated with multiple features of the MetS, such as insulin resistance, abdominal obesity, and dyslipidemia, as well as risk of diabetes and coronary heart disease (14–17). Moreover, our previous gene–diet interaction analysis has shown that the genetic variant rs2943641 near IRS1 might modulate the effect of diets varying in fat content on weight loss and the improvement of insulin resistance (18). Thus, we hypothesized that genetic variation near IRS1 may also modify the effect of weight-loss diets varying in fat content on the MetS status.In the current study, we genotyped another genetic variant, rs1522813, for which occurrence is independent of the previously investigated genetic variant rs2943641 (r² < 0.01) and is also near IRS1, and compared the effects of the high-fat and low-fat diets on the reversion of the MetS according to genotypes of the two variants over a 2-year intervention in 738 overweight or obese adults from the POUNDS LOST trial.