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

Wei-Yu Lin; Nicola J Camp; Maya Ghoussaini; Jonathan Beesley; Kyriaki Michailidou; John L Hopper; Carmel Apicella; Melissa C Southey; Jennifer Stone; Marjanka K Schmidt; Annegien Broeks; Laura J Van't Veer; Emiel J Th Rutgers; Kenneth Muir; Artitaya Lophatananon; Sarah Stewart-Brown; Pornthep Siriwanarangsan; Peter A Fasching; Lothar Haeberle; Arif B Ekici; Matthias W Beckmann; Julian Peto; Isabel Dos-Santos-Silva; Olivia Fletcher; Nichola Johnson; Manjeet K Bolla; Qin Wang; Joe Dennis; Elinor J Sawyer; Timothy Cheng; Ian Tomlinson; Michael J Kerin; Nicola Miller; Frederik Marmé; Harald M Surowy; Barbara Burwinkel; Pascal Guénel; Thérèse Truong; Florence Menegaux; Claire Mulot; Stig E Bojesen; Børge G Nordestgaard; Sune F Nielsen; Henrik Flyger; Javier Benitez; M Pilar Zamora; Jose Ignacio Arias Perez; Primitiva Menéndez; Anna González-Neira; Guillermo Pita; GENICA Network

doi:10.1093/hmg/ddu431

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

Wei-Yu Lin, Nicola J Camp, Maya Ghoussaini, Jonathan Beesley, Kyriaki Michailidou, John L Hopper, Carmel Apicella, Melissa C Southey, Jennifer Stone, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Emiel J Th Rutgers, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A Fasching, Lothar Haeberle, Arif B EkiciMatthias W Beckmann, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Manjeet K Bolla, Qin Wang, Joe Dennis, Elinor J Sawyer, Timothy Cheng, Ian Tomlinson, Michael J Kerin, Nicola Miller, Frederik Marmé, Harald M Surowy, Barbara Burwinkel, Pascal Guénel, Thérèse Truong, Florence Menegaux, Claire Mulot, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, M Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Anna González-Neira, Guillermo Pita, GENICA Network

Department of Clinical Medicine

31 Citations (Scopus)

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.

Original language	English
Journal	Human Molecular Genetics
Volume	24
Issue number	1
Pages (from-to)	285-298
Number of pages	14
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddu431
Publication status	Published - 1 Jan 2015

Keywords

Breast Neoplasms
CASP8 and FADD-Like Apoptosis Regulating Protein
Case-Control Studies
Caspase 8
Chromosomes, Human, Pair 2
European Continental Ancestry Group
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotyping Techniques
Humans
Polymorphism, Single Nucleotide
Proteins

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lin, W.-Y., Camp, N. J., Ghoussaini, M., Beesley, J., Michailidou, K., Hopper, J. L., Apicella, C., Southey, M. C., Stone, J., Schmidt, M. K., Broeks, A., Van't Veer, L. J., Th Rutgers, E. J., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Fasching, P. A., Haeberle, L., ... GENICA Network (2015). Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk. Human Molecular Genetics, 24(1), 285-298. https://doi.org/10.1093/hmg/ddu431

Lin, W-Y, Camp, NJ, Ghoussaini, M, Beesley, J, Michailidou, K, Hopper, JL, Apicella, C, Southey, MC, Stone, J, Schmidt, MK, Broeks, A, Van't Veer, LJ, Th Rutgers, EJ, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, Dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Wang, Q, Dennis, J, Sawyer, EJ, Cheng, T, Tomlinson, I, Kerin, MJ, Miller, N, Marmé, F, Surowy, HM, Burwinkel, B, Guénel, P, Truong, T, Menegaux, F, Mulot, C, Bojesen, SE , Nordestgaard, BG, Nielsen, SF, Flyger, H, Benitez, J, Zamora, MP, Arias Perez, JI, Menéndez, P, González-Neira, A, Pita, G & GENICA Network 2015, 'Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk', Human Molecular Genetics, vol. 24, no. 1, pp. 285-298. https://doi.org/10.1093/hmg/ddu431

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title = "Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk",

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.",

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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

PY - 2015/1/1

Y1 - 2015/1/1

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

SN - 0964-6906

VL - 24

SP - 285

EP - 298

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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