Rong Na1,2,3, Brian T Helfand1,4, Haitao Chen5, Carly A Conran1, Susan E Crawford1, Simon W Hayward1, Teuvo L J Tammela6, Judy Hoffman-Bolton7, Siqun L Zheng1, Patrick C Walsh8, Johanna Schleutker9, Elizabeth A Platz7, William B Isaacs8,10, Jianfeng Xu1,2. 1. Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois. 2. Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China. 3. Fudan Universtiy Shanghai Medical College, Shanghai, China. 4. Department of Surgery, NorthShore University HealthSystem, Evanston, Illinois. 5. Fudan University School of Public Health, Shanghai, China. 6. Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland. 7. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland. 8. Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. 9. Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland. 10. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
Abstract
BACKGROUND:Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common conditions. Little is known about their etiologies except that studies have suggested a substantial heritable component. Our objective is to provide a comprehensive, genome-wide evaluation of inherited risks and possible mechanisms of etiology in BPH. METHODS: We performed a three-stage, genome-wide association study (GWAS) of men from three independent populations, the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, the CLUE II cohort, and a Finnish hospital-based population. DNA samples were genotyped using the Illumina HumanOmniExpress BeadChip in REDUCE and CLUE II, and using the Sequenom iPLEX system for the confirmation stage in the Finnish population. A logistic regression model was used to evaluate the association between each SNP and BPH/LUTS. RESULTS: Fourteen SNPs reached P < 5.0 × 10-4 in the meta-analysis of the two GWASs (CLUE II and REDUCE). A total of 773 SNPs were chosen for the confirmation step in the Finish cohort. Only one SNP (rs17144046) located ∼489 kb downstream of GATA3 remained significant after correction for multiple testing (P < 6.5 × 10-5 ). This SNP marginally reached the GWAS significance level after performing a meta-analysis of the three stages (P-meta = 8.89 × 10-7 ). Expression quantitative trait loci (eQTL) analyses showed that the risk allele (G) of rs17144046 was significantly associated with increased expression of GATA3 (P = 0.017). Reported studies indicated a close correlation between GATA3 and BPH pathogenesis and progression. CONCLUSIONS:Rs17144046 located near GATA3 was significantly associated with BPH/LUTS in three independent populations, but did not reach a stringent GWAS significance level. Genetic variants of GATA3 may play a role in the inherited susceptibility and etiology of BPH/LUTS. Further research in this area is needed.
RCT Entities:
BACKGROUND:Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common conditions. Little is known about their etiologies except that studies have suggested a substantial heritable component. Our objective is to provide a comprehensive, genome-wide evaluation of inherited risks and possible mechanisms of etiology in BPH. METHODS: We performed a three-stage, genome-wide association study (GWAS) of men from three independent populations, the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, the CLUE II cohort, and a Finnish hospital-based population. DNA samples were genotyped using the Illumina HumanOmniExpress BeadChip in REDUCE and CLUE II, and using the Sequenom iPLEX system for the confirmation stage in the Finnish population. A logistic regression model was used to evaluate the association between each SNP and BPH/LUTS. RESULTS: Fourteen SNPs reached P < 5.0 × 10-4 in the meta-analysis of the two GWASs (CLUE II and REDUCE). A total of 773 SNPs were chosen for the confirmation step in the Finish cohort. Only one SNP (rs17144046) located ∼489 kb downstream of GATA3 remained significant after correction for multiple testing (P < 6.5 × 10-5 ). This SNP marginally reached the GWAS significance level after performing a meta-analysis of the three stages (P-meta = 8.89 × 10-7 ). Expression quantitative trait loci (eQTL) analyses showed that the risk allele (G) of rs17144046 was significantly associated with increased expression of GATA3 (P = 0.017). Reported studies indicated a close correlation between GATA3 and BPH pathogenesis and progression. CONCLUSIONS:Rs17144046 located near GATA3 was significantly associated with BPH/LUTS in three independent populations, but did not reach a stringent GWAS significance level. Genetic variants of GATA3 may play a role in the inherited susceptibility and etiology of BPH/LUTS. Further research in this area is needed.
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