Obesity Epidemiology

478 EPIDEMIOLOGIC STUDIES OF DETERMINANTS OF OBESITYsubjects with the insulin receptor substrate-1 gene (IRS1) Gly972Arg (G972R) genotype thanthose with G972G, but the difference was not statistically significant (P = .06).Hauner et al. 77 investigated whether genetic variants modified the effects of a weight lossdrug, Sibutramine (a centrally acting noradrenaline and serotonin reuptake inhibitor), in111 subjects participating in a randomized placebo-controlled clinical trial. They found thatthe G-protein b3 subunit gene (GNB3) 825C > T polymorphism was highly predictive ofweight loss induced by sibutramine treatment. Specifically, a 15 mg sibutramine treatmentwas more effective in individuals with the CC genotype than in subjects with the TT/TCgenotypes (weight loss: 7.2 ± 2.2 kg vs. 4.1 ± 2.1 kg, P = .0013, sibutramine vs. placebo).More recently, Franks et al. 78 examined whether the PPARG2 P12A polymorphismmodified obesity-related traits in a 1-year randomized trial of treatment with metformin,troglitazone or lifestyle modification relative to placebo for diabetes prevention in highriskindividuals. In the metformin and lifestyle groups, weight loss occurred acrossgenotypes, but was significantly greater in the A allele carriers. Troglitazone treatmentinduced weight gain, which tended to be greater in the A allele carriers (P = 0.08). Thisstudy suggests that genetic variability may modify adverse responses (i.e., weight gain)of diabetes treatment.Methodological IssuesSimilar to the literature on the main genetic variants predisposing to obesity, lack ofreplication is a common problem in studies on gene-environment interactions of obesityand its related phenotypes. Replication is more challenging for gene-environment interactionsthan main effects because such studies involve the assessment of joint effects ofgenetic variants that typically have modest marginal effects and environmental variablesthat are often difficult to measure. The problem of multiple testing is exacerbated ingene-environment studies because numerous subgroups can be compared. In addition,most studies are small and underpowered. In the subsequent sections, we discuss severalcommon methodological issues in gene-environment studies.Sample Size RequirementInadequate sample size has been a major limiting factor in genetic epidemiologic studies,especially those on gene-environment interactions. A rule of thumb is that the samplesize necessary to test departure from a multiplicative gene-environment interaction is atleast four times that needed to evaluate the main genetic or environmental associations. 79Larger samples are needed to compensate for measurement error associated with environmentalexposures. 80 Inadequate power has been a common problem with many geneticstudies—an important reason for the high number of false-positives and non-reproduciblefindings. 81 Hunter 82 estimated that in most scenarios, thousands of cases and controls areneeded to detect multiplicative interactions with ORs ranging from 1.5 to 2, even underthe assumption of a common variation (minor allele frequency >5%) and sizable geneticand environmental effects (an OR of 1.5 for both). Unfortunately, most observational studieshave been limited to a sample size of a few hundred subjects. The sample size for mostof the intervention trials has been even smaller. Small underpowered studies contributeto both false-positive and false-negative findings. Thus, there is an urgent need for large,well-powered, and carefully designed observational studies to examine gene-environmentinteractions in the development of obesity. Larger and longer-term intervention studies arealso needed to test the effects of gene-diet interactions on weight loss and maintenance.