Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk
Open Access
- 28 August 2014
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 24 (1), 285-298
- https://doi.org/10.1093/hmg/ddu431
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, CI)] for the minor allele of 1.05 (1.03–1.07), P = 1 × 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 × 10−6), yielding a combined OR (95% CI) of 1.06 (1.04–1.08), P = 1 × 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.This publication has 19 references indexed in Scilit:
- Fine-Mapping CASP8 Risk Variants in Breast CancerCancer Epidemiology, Biomarkers & Prevention, 2012
- Genotype Imputation with Thousands of GenomesG3 Genes|Genomes|Genetics, 2011
- Genome-wide association study identifies three new melanoma susceptibility lociNature Genetics, 2011
- LocusZoom: regional visualization of genome-wide association scan resultsBioinformatics, 2010
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- Genome-wide association study identifies five new breast cancer susceptibility lociNature Genetics, 2010
- A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association StudiesPLoS Genetics, 2009
- A Breast Cancer Risk Haplotype in the Caspase-8 GeneCancer Research, 2009
- Simultaneous Analysis of All SNPs in Genome-Wide and Re-Sequencing Association StudiesPLoS Genetics, 2008
- A common coding variant in CASP8 is associated with breast cancer riskNature Genetics, 2007