Journal
GENETIC EPIDEMIOLOGY
Volume 38, Issue 1, Pages 84-93Publisher
WILEY
DOI: 10.1002/gepi.21771
Keywords
breast cancer risk; gene-environment interaction; polymorphisms; body mass index; case-control study
Funding
- European Community [223175]
- Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692]
- National Institutes of Health [CA128978]
- Post-Cancer GWAS initiative (the GAME-ON initiative) [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]
- Department of Defence [W81XWH-10-1-0341]
- Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer
- Komen Foundation for the Cure
- Breast Cancer Research Foundation
- Ovarian Cancer Research Fund
- Cancer Research UK [16561, 11022, 10118, 16565, 16563] Funding Source: researchfish
- The Francis Crick Institute [10124] Funding Source: researchfish
- National Breast Cancer Foundation [IF-12-06] Funding Source: researchfish
- NATIONAL CANCER INSTITUTE [UM1CA164920, U01CA069638, U19CA148065, U19CA148537, ZIACP010126, P50CA116201, P30CA015083, U19CA148112, U01CA069417, R01CA128978, U01CA069467] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [Z01AI000732] Funding Source: NIH RePORTER
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Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G x E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 x 10(-07)), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 x 10(-05)). Our findings confirm comparable power of the recent methods for detecting G x E interaction and the utility of using G x E interaction analyses to identify new susceptibility loci.
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