The characteristics of cases and controls in the MEC and the WHI are shown in . The mean ages of cases and controls were similar in each study. The majority of women in the WHI were European American (93.2% of cases and 80.3% of controls); there were very few Asian/Pacific Islander (n
8) and Latino (n
20) cases. The MEC included sizable proportions of women from other racial/ethnic groups: 20.5% African American, 30.3% Japanese, and 18.7% Latino. Compared to controls, cases were heavier, more likely to have fewer births, and to be diabetic. Cases were less likely to have used OCs or to have ever smoked.
Characteristics of Cases and Controls in the Multiethnic Cohort Study (MEC) and the Women's Health Initiative Study (WHI).
We found that rs4430796 and rs7501939 were associated with risk of endometrial cancer in European Americans in the MEC and the WHI (). The combined ORper allele
was 0.83 (95% CI: 0.75, 0.92; P
) for rs4430796 (G
allele) and 0.79 (95% CI: 0.71, 0.88; P
) for rs7501939 (A
allele). No heterogeneity between studies was observed (P≥0.59). The rs4430796 and rs7501939 were in strong linkage disequilibrium (LD) in our European-American controls (r2
0.61 in the MEC; r2
0.66 in the WHI).
Association between HNF1B variants and endometrial cancer.
In the MEC, consistent associations were observed in African Americans, Hawaiians, Japanese and Latinos, i.e. reduced risk associated with the G
allele of rs4430796 or with the A
allele of rs7501939 (). There were limited numbers of non-European descent women in the WHI, especially the Asian/Pacific Islander group (8 cases and 161 controls). In African Americans and Latinos, we observed consistent associations with those observed among European Americans. No evidence was observed of heterogeneity in the ORs by race/ethnicity (P≥0.21). Combining the MEC and the WHI results, the ORper allele
ranged between 0.74 and 0.80 for rs4430796 and between 0.73 and 0.80 for rs7501939 in African Americans, Asians/Pacific Islanders, and Latinos. The two SNPs were in high LD in Asians (r2
0.80) and Latinos (r2
0.65) and in lower LD in African Americans (r2
In the analysis of all race/ethnicity groups combined, the ORper allele
for rs4430796 was 0.80 (95% CI: 0.69, 0.93; P
0.0048) and 0.83 (95% CI: 0.75, 0.92; P
0.00059) in the MEC and the WHI, respectively (). The all groups' ORper allele
for rs7501939 was 0.80 (95% CI: 0.68, 0.94; P
0.0068) and 0.79 (95% CI: 0.71, 0.88; P
) in the MEC and the WHI, respectively. When we combined the results from the MEC and the WHI, the ORper allele
was 0.82 (95% CI: 0.75, 0.89; P
) for rs4430796 and 0.79 (95% CI: 0.73, 0.87; P
) for rs7501939. No heterogeneity between studies was observed (P≥0.70). Further adjustment for parity, oral contraceptive use, menopausal hormone use, smoking status, diabetes status and clinical trial participation (dietary modification, hormone therapy, or observational study) for the WHI had little effect on the results.
The associations of HNF1B
SNPs with Type I and Type II tumors are shown in . In both studies, rs4430796 and rs7501939 were significantly associated with Type I tumors. Both SNPs were also associated with reduced risk of Type II tumors, but the association was only significant for rs4430796 in the MEC. No evidence of heterogeneity between studies was observed (P≥0.18). The combined ORper allele
for rs4430796 was 0.83 (95% CI: 0.76, 0.90; P
) for Type I tumors and 0.78 (95% CI: 0.61, 0.99; P
0.041) for Type II tumors. The combined ORper allele
for rs7501939 was 0.80 (95% CI: 0.73, 0.87; P
) for Type I tumors and 0.75 (95% CI: 0.58, 0.95; P
0.020) for Type II tumors. Neither study found significant differences between the associations of HNF1B
SNPs with Type I and Type II tumors (P≥0.19 in the MEC; P≥0.80 in the WHI).
Association between HNF1B variants and Type I and Type II endometrial cancer.
To determine whether the associations of HNF1B
variants and endometrial cancer were influenced by diabetes, we examined the OR for the SNP-endometrial cancer relationship among diabetics and non-diabetics separately (). Significant associations were observed only among non-diabetics in both studies. In the WHI, the test for interaction was statistically significant for rs4430796 (P
0.028) and borderline significant for rs7501939 (P
0.054). No significant interaction was observed in the MEC.
Association between HNF1B variants and endometrial cancer by diabetes status.
We also examined effect modification of the association between HNF1B
SNPs and endometrial cancer by BMI, parity, OC use, menopausal hormone use and smoking status (Table S1
) and found no significant interaction.