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 / Saunders E.J.; Dadaev T.; Leongamornlert D.A.; Jugurnauth-Little S.; Tymrakiewicz M.; Wiklund F.; Al Olama A.A.; Benlloch S.; Neal D.E.; Hamdy F.C.; Donovan J.L.; Giles G.G.; Severi G.; Gronberg H.; Aly M.; Haiman C.A.; Schumacher F.; Henderson B.E.; Lindstrom S.; Kraft P.; Hunter D.J.; Gapstur S.; Chanock S.; Berndt S.I.; Albanes D.; Andriole G.; Schleutker J.; Weischer M.; Nordestgaard B.G.; Canzian F.; Campa D.; Riboli E.; Key T.J.; Travis R.C.; Ingles S.A.; John E.M.; Hayes R.B.; Pharoah P.; Khaw K.-T.; Stanford J.L.; Ostrander E.A.; Signorello L.B.; Thibodeau S.N.; Schaid D.; Maier C.; Kibel A.S.; Cybulski C.; Cannon-Albright L.; Brenner H.; Park J.Y.; Kaneva R.; Batra J.; Clements J.A.; Teixeira M.R.; Xu J.; Mikropoulos C.; Goh C.; Govindasami K.; Guy M.; Wilkinson R.A.; Sawyer E.J.; Morgan A.; Easton D.F.; Muir K.; Eeles R.A.; Kote-Jarai Z.. - In: PLOS GENETICS. - ISSN 1553-7390. - STAMPA. - 10:(2014), pp. e1004129-e1004129. [10.1371/journal.pgen.1004129]
Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer
Severi G.;Aly M.;Albanes D.;
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.
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