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Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer
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نویسنده
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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.
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منبع
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plos genetics - 2014 - دوره : 10 - شماره : 2
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چکیده
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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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آدرس
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the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, department of medical epidemiology and biostatistics,karolinska institute,stockholm, Sweden, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,strangeways laboratory,cambridge, United Kingdom, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,strangeways laboratory,cambridge, United Kingdom, surgical oncology (uro-oncology: s4),university of cambridge,addenbrooke's hospital,cambridge and cancer research uk cambridge research institute,li ka shing centre,cambridge, United Kingdom, nuffield department of surgical sciences,university of oxford,oxford,john radcliffe hospital,oxford, United Kingdom, school of social and community medicine,university of bristol,bristol, United Kingdom, cancer epidemiology centre,the cancer council victoria,carlton,vic,australia,centre for molecular,environmental,genetic and analytic epidemiology,the university of melbourne,melbourne,vic, Australia, cancer epidemiology centre,the cancer council victoria,carlton,vic,australia,centre for molecular,environmental,genetic and analytic epidemiology,the university of melbourne,melbourne,vic, Australia, department of medical epidemiology and biostatistics,karolinska institute,stockholm, Sweden, department of medical epidemiology and biostatistics,karolinska institute,stockholm, Sweden, department of preventive medicine,keck school of medicine,university of southern california/norris comprehensive cancer center,los angeles,ca, United States, department of preventive medicine,keck school of medicine,university of southern california/norris comprehensive cancer center,los angeles,ca, United States, department of preventive medicine,keck school of medicine,university of southern california/norris comprehensive cancer center,los angeles,ca, United States, program in genetic epidemiology and statistical genetics,department of epidemiology,harvard school of public health,boston,ma, United States, program in genetic epidemiology and statistical genetics,department of epidemiology,harvard school of public health,boston,ma, United States, program in genetic epidemiology and statistical genetics,department of epidemiology,harvard school of public health,boston,ma, United States, epidemiology research program,american cancer society,atlanta,ga, United States, division of cancer epidemiology and genetics,national cancer institute,nih,bethesda,md, United States, division of cancer epidemiology and genetics,national cancer institute,nih,bethesda,md, United States, nutritional epidemiology branch,national cancer institute,nih,eps-3044,bethesda,md, United States, division of urologic surgery,washington university school of medicine,st. louis,mo, United States, department of medic biochemistry and genetics,university of turku,turku,finland,institute of biomedical technology and biomeditech,university of tampere and fimlab laboratories,tampere, Finland, department of clinical biochemistry,herlev hospital,copenhagen university hospital,herlev, Denmark, department of clinical biochemistry,herlev hospital,copenhagen university hospital,herlev, Denmark, genomic epidemiology group,german cancer research center (dkfz),heidelberg, Germany, division of cancer epidemiology,german cancer research center (dkfz),heidelberg, Germany, department of epidemiology and biostatistics,school of public health,imperial college london,london, United Kingdom, cancer epidemiology unit,nuffield department of population health,university of oxford,oxford, United Kingdom, cancer epidemiology unit,nuffield department of population health,university of oxford,oxford, United Kingdom, department of preventive medicine,keck school of medicine,university of southern california/norris comprehensive cancer center,los angeles,ca, United States, cancer prevention institute of california,fremont,ca,united states,stanford university school of medicine,stanford,ca, United States, division of epidemiology,department of population health,nyu langone medical center,nyu cancer institute,new york,ny, United States, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,strangeways laboratory,cambridge, United Kingdom, clinical gerontology unit,university of cambridge,cambridge, United Kingdom, department of epidemiology,school of public health,university of washington and division of public health sciences,fred hutchinson cancer research center,seattle,wa, United States, national human genome research institute,national institutes of health,bethesda,md, United States, international epidemiology institute,rockville,md,united states,division of epidemiology,department of medicine,vanderbilt epidemiology center,vanderbilt-ingram cancer center,vanderbilt university school of medicine,nashville,tn, United States, mayo clinic,rochester,mn, United States, mayo clinic,rochester,mn, United States, department of urology,university hospital ulm and institute of human genetics university hospital ulm,ulm, Germany, division of urologic surgery,brigham and women's hospital,dana-farber cancer institute,boston,ma, United States, international hereditary cancer center,department of genetics and pathology,pomeranian medical university,szczecin, Poland, division of genetic epidemiology,department of medicine,university of utah school of medicine,george e. wahlen department of veterans affairs medical center,salt lake city,ut, United States, division of clinical epidemiology and aging research,german cancer research center (dkfz),heidelberg, Germany, department of cancer epidemiology,h. lee moffitt cancer center,tampa,fl, United States, molecular medicine center and department of medical chemistry and biochemistry,medical university - sofia,sofia, Bulgaria, australian prostate cancer research centre-qld,institute of health and biomedical innovation and school of biomedical science,queensland university of technology,brisbane,qld, Australia, australian prostate cancer research centre-qld,institute of health and biomedical innovation and school of biomedical science,queensland university of technology,brisbane,qld, Australia, biomedical sciences institute (icbas),porto university,porto,portugal,department of genetics,portuguese oncology institute,porto, Portugal, center for cancer genomics,wake forest university school of medicine,winston-salem,nc, United States, the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, centre for cancer genetic epidemiology,department of public health and primary care,university of cambridge,strangeways laboratory,cambridge, United Kingdom, warwick medical school,university of warwick,coventry, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom, the institute of cancer research,sutton,surrey, United Kingdom
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Authors
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