Abstract C80: The interaction between menopausal hormone replacement therapy and the 2q35 (rs13387042) breast cancer risk variant explains the effect modification by genetic ancestry among Hispanic women
Authors: Fejerman Laura , Stern Mariana C. , Ziv Elad , John Esther M. , Torres-Mejia Gabriela , Hines Lisa M. , Wolff Roger , Baumgartner Kathy B. , Giuliano Anna , Slattery Martha L. 
Published: May 2015

Background: Breast cancer genome-wide association studies published to date are mostly based on samples of European or Asian origin. There have been few published studies in African American women and none in Latinas. In a previous study we reported statistically significant interactions between genetic ancestry and genotypes for 3 out of 10 GWAS-discovered breast cancer risk variants, in 4,694 Hispanics from the U.S. and Mexico who participated in one of three population-based case-control studies of breast cancer (Single nucleotide polymorphisms (SNPs): rs13387042-2q35 region, rs17157903-RELN gene and rs7696175-TLR1 gene). For these three SNPs, the risk allele showed stronger associations among women of higher Indigenous American (IA) ancestry. In the present study, we investigated multiple know reproductive and lifestyle related breast cancer risk factors to evaluate if the previously observed heterogeneity could be due to the correlation between those factors and ancestry.

Methods: Genetic ancestry was previously estimated with a set of 104 ancestry-informative markers (AIMs) selected to discriminate between IA and European ancestry. We used stratified logistic regression analyses to compare the associations with different genetic variants by proportion of IA ancestry (low, intermediate, high) and questionnaire based information on menopausal status, family history of breast cancer, number of full-term pregnancies, age at first full-term pregnancy, breast feeding, body mass index, height, alcohol intake, smoking, menopausal hormone replacement therapy, age at menarche, diabetes and use of oral contraceptives.

Results: The three investigated SNPs showed suggestive interactions with the reproductive/lifestyle related breast cancer risk factors. For SNP rs13387042 the interaction with menopausal hormone replacement therapy explained the previously observed interaction with ancestry. This SNP was associated with breast cancer risk only among postmenopausal women who never used hormone replacement therapy, and this association was apparent in all ancestry categories [AA genotype vs. GG genotype OR 3.01, 95%CI 1.06-8.52 in the low Indigenous American ancestry category; OR 1.61, 95%CI 1.04-2.51 in the intermediate ancestry category; OR 3.37, 95%CI 1.34-8.46 in the high ancestry category, p value interaction 0.96]. For the other two SNPs, we saw interactions with non-genetic risk factors, but those did not explain the previously reported heterogeneity by ancestry.

Conclusions: Our results showed that the correlation between genetic ancestry and a non-genetic factor might explain the previously reported interaction between a breast cancer risk variant and genetic ancestry in Latinas for at least one out of three SNPs. Future studies should investigate the possibility that for some variants that have been associated with breast cancer risk, the effect heterogeneity by ancestry might be due to differences between populations in the genetic architecture of the regions were the variants are located.

Citation Format: Laura Fejerman, Mariana C. Stern, Elad Ziv, Esther M. John, Gabriela Torres-Mejia, Lisa M. Hines, Roger Wolff, Kathy B. Baumgartner, Anna Giuliano, Martha L. Slattery. The interaction between menopausal hormone replacement therapy and the 2q35 (rs13387042) breast cancer risk variant explains the effect modification by genetic ancestry among Hispanic women. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C80. doi:10.1158/1538-7755.DISP13-C80