TY - JOUR

T1 - Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk

AU - Lin, Wei-Yu

AU - Camp, Nicola J

AU - Ghoussaini, Maya

AU - Beesley, Jonathan

AU - Michailidou, Kyriaki

AU - Hopper, John L

AU - Apicella, Carmel

AU - Southey, Melissa C

AU - Stone, Jennifer

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Van't Veer, Laura J

AU - Th Rutgers, Emiel J

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Stewart-Brown, Sarah

AU - Siriwanarangsan, Pornthep

AU - Fasching, Peter A

AU - Haeberle, Lothar

AU - Ekici, Arif B

AU - Beckmann, Matthias W

AU - Peto, Julian

AU - Dos-Santos-Silva, Isabel

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Dennis, Joe

AU - Sawyer, Elinor J

AU - Cheng, Timothy

AU - Tomlinson, Ian

AU - Kerin, Michael J

AU - Miller, Nicola

AU - Marmé, Frederik

AU - Surowy, Harald M

AU - Burwinkel, Barbara

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Menegaux, Florence

AU - Mulot, Claire

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - Nielsen, Sune F

AU - Flyger, Henrik

AU - Benitez, Javier

AU - Zamora, M Pilar

AU - Arias Perez, Jose Ignacio

AU - Menéndez, Primitiva

AU - González-Neira, Anna

AU - Pita, Guillermo

AU - GENICA Network

N1 - © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

KW - Breast Neoplasms

KW - CASP8 and FADD-Like Apoptosis Regulating Protein

KW - Case-Control Studies

KW - Caspase 8

KW - Chromosomes, Human, Pair 2

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotyping Techniques

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Proteins

U2 - 10.1093/hmg/ddu431

DO - 10.1093/hmg/ddu431

M3 - Journal article

C2 - 25168388

VL - 24

SP - 285

EP - 298

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 1

ER -