The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10-14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer

CAMPA, DANIELE;
2014

Abstract

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10-14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
Edward J., Saunders; Tokhir, Dadaev; Daniel A., Leongamornlert; Sarah Jugurnauth, Little; Malgorzata, Tymrakiewicz; Fredrik, Wiklund; Ali Amin Al, Olama; Sara, Benlloch; David E., Neal; Freddie C., Hamdy; Jenny L., Donovan; Graham G., Giles; Gianluca, Severi; Henrik, Gronberg; Markus, Aly; Christopher A., Haiman; Fredrick, Schumacher; Brian E., Henderson; Sara, Lindstrom; Peter, Kraft; David J., Hunter; Susan, Gapstur; Stephen, Chanock; Sonja I., Berndt; Demetrius, Albanes; Gerald, Andriole; Johanna, Schleutker; Maren, Weischer; Borge G., Nordestgaard; Federico, Canzian; Campa, Daniele; Elio, Riboli; Tim J., Key; Ruth C., Travis; Sue A., Ingles; Esther M., John; Richard B., Hayes; Paul, Pharoah; Kay Tee, Khaw; Janet L., Stanford; Elaine A., Ostrander; Lisa B., Signorello; Stephen N., Thibodeau; Daniel, Schaid; Christiane, Maier; Adam S., Kibel; Cezary, Cybulski; Lisa Cannon, Albright; Hermann, Brenner; Jong Y., Park; Radka, Kaneva; Jyotsna, Batra; Judith A., Clements; Manuel R., Teixeira; Jianfeng, Xu; Christos, Mikropoulos; Chee, Goh; Koveela, Govindasami; Michelle, Guy; Rosemary A., Wilkinson; Emma J., Sawyer; Angela, Morgan; COGS CRUK GWAS ELLIPSE, Initiative; The UK Genetic Prostate Cancer Study, Collaborators; The UK ProtecT Study, Collaborators; The PRACTICAL, Consortium; Douglas F., Easton; Ken, Muir; Rosalind A., Eeles; Zsofia Kote, Jarai
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/458278
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