title: Genetic ancestry modifies the association between genetic risk variants and breast cancer risk among Hispanic and non-Hispanic white women.
abstract: Hispanic women in the USA have lower breast cancer incidence than non-Hispanic white (NHW) women. Genetic factors may contribute to this difference. Breast cancer genome-wide association studies (GWAS) conducted in women of European or Asian descent have identified multiple risk variants. We tested the association between 10 previously reported single nucleotide polymorphisms (SNPs) and risk of breast cancer in a sample of 4697 Hispanic and 3077 NHW women recruited as part of three population-based case-control studies of breast cancer. We used stratified logistic regression analyses to compare the associations with different genetic variants in NHWs and Hispanics classified by their proportion of Indigenous American (IA) ancestry. Five of 10 SNPs were statistically significantly associated with breast cancer risk. Three of the five significant variants (rs17157903-RELN, rs7696175-TLR1 and rs13387042-2q35) were associated with risk among Hispanics but not in NHWs. The odds ratio (OR) for the heterozygous at 2q35 was 0.75 [95% confidence interval (CI) = 0.50-1.15] for low IA ancestry and 1.38 (95% CI = 1.04-1.82) for high IA ancestry (P interaction 0.02). The ORs for association at RELN were 0.87 (95% CI = 0.59-1.29) and 1.69 (95% CI = 1.04-2.73), respectively (P interaction 0.03). At the TLR1 locus, the ORs for women homozygous for the rare allele were 0.74 (95% CI = 0.42-1.31) and 1.73 (95% CI = 1.19-2.52) (P interaction 0.03). Our results suggest that the proportion of IA ancestry modifies the magnitude and direction of the association of 3 of the 10 previously reported variants. Genetic ancestry should be considered when assessing risk in women of mixed descent and in studies designed to discover causal mutations.
authors.affiliation: Department of Medicine, Division of General Internal Medicine, Institute for Human Genetics and Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, CA 94158, USA. laura.fejerman@ucsf.edu
authors.forename: Laura
authors.initials: L
authors.lastname: Fejerman
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Stern
authors.forename: Elad
authors.initials: E
authors.lastname: Ziv
authors.forename: Esther M
authors.initials: EM
authors.lastname: John
authors.forename: Gabriela
authors.initials: G
authors.lastname: Torres-Mejia
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hines
authors.forename: Roger
authors.initials: R
authors.lastname: Wolff
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Kathy B
authors.initials: KB
authors.lastname: Baumgartner
authors.forename: Anna R
authors.initials: AR
authors.lastname: Giuliano
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
mesh_terms: D001943:Breast Neoplasms / Q000453:epidemiology* / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006579:Heterozygote; D006630:Hispanic or Latino / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D000091042:Reelin Protein; D012306:Risk; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics*
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