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Abstract:
Previous studies have suggested that polymorphisms in CASP8 on
chromosome 2 are associated with breast cancer risk. To clarify the role
of CASP8 in breast cancer susceptibility, we carried out dense
genotyping of this region in the Breast Cancer Association Consortium
(BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region
around CASP8 were genotyped in 46 450 breast cancer cases and 42 600
controls of European origin from 41 studies participating in the BCAC as
part of a custom genotyping array experiment (iCOGS). Missing genotypes
and SNPs were imputed and, after quality exclusions, 501 typed and 1232
imputed SNPs were included in logistic regression models adjusting for
study and ancestry principal components. The SNPs retained in the final
model were investigated further in data from nine genome-wide
association studies (GWAS) comprising in total 10 052 case and 12 575
control subjects. The most significant association signal observed in
European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12
(telomeric to CASP8), with per allele odds ratio and 95% confidence
interval [OR (95% confidence interval, Cl)] for the minor allele of
1.05(1.03-1.07), P = 1 x 10(-5). Three additional independent signals
from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11
(rs59278883) and CFLAR (rs7558475). The association with rs1830298 was
replicated in the imputed results from the combined GWAS (P = 3 x
10(-6)), yielding a combined OR (95% Cl) of 1.06(1.04-1.08), P = 1 x
10(-9). Analyses of gene expression associations in peripheral blood and
normal breast tissue indicate that CASP8 might be the target gene,
suggesting a mechanism involving apoptosis.
