Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25

Abstract

The genetic contributions to breast cancer development among Latinas are not well understood. Here, we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5’ of the Estrogen Receptor 1 gene (ESR1) (6q25 region). The minor allele for this variant is strongly protective (rs140068132: OR 0.60, 95%CI 0.53-0.67, P=9×10−18), originates from Indigenous Americans, and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for estrogen receptor negative disease (OR 0.34 95% CI 0.21-0.54) than estrogen receptor positive disease (OR 0.63 95% CI 0.49-0.80) (P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.

Human Demographic History Impacts Genetic Risk Prediction across Diverse Populations

“…[20][21][22][23][24][25] Studies of admixed populations have been particularly fruitful in identifying genetic adaptations and risk for diseases that are stratified across diverged ancestral origins. [26][27][28][29][30][31] Admixture patterns became especially complex during the peopling of the Americas, with extensive recent admixture spanning multiple continents. Processes shaping structure in these admixed populations include sex-biased migration and admixture, isolationby-distance, differential drift in mainland versus island populations, and variable admixture timing.…”

Association of lifestyle and demographic factors with estrogenic and glucocorticogenic activity in Mexican American women

“…Indigenous American ancestry has consistently been associated with breast cancer risk, with lower risk among women with high Indigenous American ancestry (50,51). A genome-wide association study in Latinas reported the existence of a single nucleotide polymorphism, only present in Indigenous American populations, and associated with protection against breast cancer (52). In addition to this protective variant, non-genetic factors are likely to contribute to the decreased breast cancer risk in highly Indigenous American women, given that genetic ancestry is correlated with sociodemographic, reproductive and lifestyle factors such as education, neighborhood SES, use of HT and alcohol intake (53).…”

Diversity in Clinical and Biomedical Research: A promise yet to be fulfilled

“…Breast cancer Differences in Native American ancestry at the estrogen receptor locus led to discovery of a genetic variant that was protective against breast cancer in Latinas [11].…”