The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women

Abstract

Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR) = 1.17; 95% confidence interval (CI): 1.03-1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91-1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.

Figure 1. Association of the FTO rs9939609 with endometrial carcinoma risk in non-Hispanic white women.

Forest plot of the ORs and 95% CIs comparing endometrial carcinoma risk for the FTO rs9939609 rare allele homozygotes (AA genotype) versus common allele homozygotes (TT genotype) for nine studies included in the pooled analysis. The pooled^a OR for all studies was 1.17 [95% CI: 1.03–1.34; p (1 d.f.)  = 0.01.] P for heterogeneity of effects by study = 0.87. The pooled^b OR for studies including incident cases only (excluding TORONTO study) was 1.18 [95% CI: 1.03–1.35; p (1 d.f.)  = 0.02]. P for heterogeneity of effects between studies with incident cases vs. prevalent cases (TORONTO)  = 0.78. Pooling was performed by combining all data using study as fixed and random effects (results were the same).

Figure 2. Association of the MC4R rs17782313 with endometrial carcinoma risk in non-Hispanic white women.

Forest plot of the ORs and 95% CIs comparing endometrial carcinoma risk for the MC4R rs17782313 rare allele homozygotes (CC genotype) versus common allele homozygotes (TT genotype) for eight studies included in the pooled analysis. The pooled^a OR for all studies combined was 0.97 [95% CI: 0.81–1.18; p (1 d.f.)  = 0.78]. P for heterogeneity of effects by study = 0.49. The pooled^b OR for studies including incident cases only (excluding TORONTO study) was 0.99 [95% CI: 0.81–1.22; p (1 d.f.)  = 0.94]. P for heterogeneity of effects between studies with incident cases vs. prevalent cases (TORONTO)  = 0.68. Pooling was performed by combining all data using study as fixed and random effects (results were the same).