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

Laura Fejerman, Nasim Ahmadiyeh, Donglei Hu, Scott Huntsman, Kenneth B. Beckman, Jennifer L. Caswell, Karen Tsung, Esther M. John, Gabriela Torres-Mejia, Luis Carvajal-Carmona, María Magdalena Echeverry, Anna Marie D Tuazon, Carolina Ramirez, Mabel Elena Bohórquez, Rodrigo Prieto, Ángel Criollo, Carolina Ramírez, Ana Patricia Estrada, John Jairo Suáres, Gilbert MateusJorge Mario Castro, Yesid Sánchez, Raúl Murillo, Martha Lucia Serrano, Carolina Sanabria, Justo Germán Olaya, Alejandro Vélez, Jenny Andrea Carmona, Nancy Guerrero Rodríguez, Cristina Serón Sousa, Cesar Eduardo Alvarez Mendez, Ana Isabel Orduz Galviz, Christopher R. Gignoux, Celeste Eng, Esteban Gonzalez-Burchard, Brian Henderson, Loic Le Marchand, Charles Kooperberg, Lifang Hou, Ilir Agalliu, Peter Kraft, Sara Lindström, Eliseo J. Perez-Stable, Christopher A. Haiman, Elad Ziv

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82 Scopus citations

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: odds ratio (OR) 0.60, 95% confidence interval (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 oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen 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.

Original languageEnglish (US)
Article number5260
JournalNature communications
Volume5
DOIs
StatePublished - Oct 20 2014

Bibliographical note

Funding Information:
We want to thank the study participants. This work was supported by the National Cancer Institute (K01 CA160607 to L.F., R01 CA120120 and K24 CA169004 to E.Z. and R01 CA132839 to C.A.H.), the Center for Aging in Diverse Communities (CADC) under the Resource Centers for Minority Aging Research programme by the National Institute on Aging (P30-AG15272) and the National Cancer Institute grant from the Special Population Network programme to the University of Texas, San Antonio (Redes En Acción no. U01CA86117). The San Francisco Bay Area Breast Cancer Study was supported by the National Cancer Institute (CA63446 and CA77305), the US Department of Defense (DAMD17-96-1-6071) and the California Breast Cancer Research Program (7PB-0068). The Northern California Breast Cancer Family Registry was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR. The Multiethnic Cohort Study was supported by the National Institutes of Health grants R01 CA63464 and R37 CA54281, R01 CA132839, 5UM1CA164973. The GALA1 study was supported by The National Institutes of Health (HL078885, AI077439 and HL088133). The Mexico Breast Cancer Study was funded by Consejo Nacional de Ciencia y Tecnología (SALUD-2002-C01-7462). The COLUMBUS study receives support from GSK Oncology (Ethnic Research Initiative), University of Tolima, University of California Davis and The V Foundation. L.C.-C. is a V Foundation V Scholar. A.M.D.T. is supported by the Howard Hughes Medical Institute, Integrating Medicine into Basic Science fellowship. The WHI programme is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. Genotyping of MEC samples was also supported by the Slim Initiative in Genomic Medicine for the Americas (SIGMA), a joint US–Mexico project funded by the Carlos Slim Health Institute.

Publisher Copyright:
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