Introduction: Obesity and diabetes are known risk factors for endometrial cancer; thus, the genetic risk factors of these phenotypes might also be associated with endometrial cancer risk. To evaluate this hypothesis, we genotyped tag-single nucleotide polymorphisms (SNP) and candidate SNPs in FTO and HHEX in a primary set of 417 endometrial cancer cases and 406 population-based controls, and validated significant findings in a replication set of approximately 2,347 cases and 3,140 controls from three additional studies. Methods: We genotyped 189 tagSNPs in FTO (including rs8050136) and five tagSNPs in HHEX (including rs1111875) in the primary set and one SNP each in FTO (rs12927155) and HHEX (rs1111875) in the validation set. Per allele odds ratios (OR) and 95% confidence intervals (CI) were calculated to estimate the association between the genotypes of each SNPs (as an ordinal variable) and endometrial cancer risk using unconditional logistic regression models, controlling for age and site. Results: In the primary study, the most significant finding in FTO was rs12927155 (OR, 1.56; 95% CI, 1.21-2.01; P = 5.8 × 10-4), and in HHEX, it was rs1111875 (OR, 0.80; 95% CI, 0.66-0.97; P = 0.026). In the validation studies, the pooled per allele OR, adjusted for age and study for FTO, was rs12927155 (OR, 0.94; 95% CI, 0.83-1.06; P = 0.29), whereas for HHEX, it was rs1111875 (OR, 1.00; 95% CI, 0.92-1.10; P = 0.96). Conclusion: Our data indicate that common genetic variants in two genes previously related to obesity (FTO) and diabetes (HHEX) by genome-wide association scans were not associated with endometrial cancer risk. Impact: Polymorphisms in FTO and HHEX are unlikely to have large effects on endometrial cancer risk but may have weaker effects.
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