A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS)

Rong Na; Brian T. Helfand; Haitao Chen; Carly A. Conran; Susan E. Crawford; Simon W. Hayward; Teuvo L.J. Tammela; Judy Hoffman-Bolton; Siqun L. Zheng; Patrick C. Walsh; Johanna Schleutker; Elizabeth A. Platz; William B. Isaacs; Jianfeng Xu

doi:10.1002/pros.23380

A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS)

Rong Na, Brian T. Helfand, Haitao Chen, Carly A. Conran, Susan E. Crawford, Simon W. Hayward, Teuvo L.J. Tammela, Judy Hoffman-Bolton, Siqun L. Zheng, Patrick C. Walsh, Johanna Schleutker, Elizabeth A. Platz, William B. Isaacs, Jianfeng Xu

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1213-1220
Number of pages	8
Journal	Prostate
Volume	77
Issue number	11
DOIs	https://doi.org/10.1002/pros.23380
State	Published - Aug 1 2017

Keywords

BPH
LUTS
genome-wide association study

ASJC Scopus subject areas

Oncology
Urology

Access to Document

10.1002/pros.23380

Cite this

Na, R., Helfand, B. T., Chen, H., Conran, C. A., Crawford, S. E., Hayward, S. W., Tammela, T. L. J., Hoffman-Bolton, J., Zheng, S. L., Walsh, P. C., Schleutker, J., Platz, E. A., Isaacs, W. B., & Xu, J. (2017). A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Prostate, 77(11), 1213-1220. https://doi.org/10.1002/pros.23380

Na, R, Helfand, BT, Chen, H, Conran, CA, Crawford, SE, Hayward, SW, Tammela, TLJ, Hoffman-Bolton, J, Zheng, SL, Walsh, PC, Schleutker, J, Platz, EA , Isaacs, WB & Xu, J 2017, 'A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS)', Prostate, vol. 77, no. 11, pp. 1213-1220. https://doi.org/10.1002/pros.23380

@article{f90fafab95f144e6be374e06ab31bc8b,

title = "A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS)",

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.",

keywords = "BPH, LUTS, genome-wide association study",

author = "Rong Na and Helfand, {Brian T.} and Haitao Chen and Conran, {Carly A.} and Crawford, {Susan E.} and Hayward, {Simon W.} and Tammela, {Teuvo L.J.} and Judy Hoffman-Bolton and Zheng, {Siqun L.} and Walsh, {Patrick C.} and Johanna Schleutker and Platz, {Elizabeth A.} and Isaacs, {William B.} and Jianfeng Xu",

note = "Funding Information: The authors thank the patients enrolled in REDUCE who provided the consent and genetic samples that enabled this study, and the clinicians who contributed their expertise in recruiting study patients for the REDUCE clinical study. Dave Pulford, Jennifer Aponte, Jon Charnecki, and Mary Ellyn Volk participated in consent reconciliation and sample management to enable genetic sample selection for inclusion and genotype determination. Karen King provided data management support for this project. We thank Silviu-Alin Bacanu and Matt Nelson for multiple discussions on power determination, method limitations, and results. We appreciate the assistance of Lauren Marmor in coordinating the support of the Avodart Collaborative Research Team. The assistance of Dr. Tamara Lotan is gratefully acknowledged. This study was supported by Obrien Center Funding (P50-DK082998) from NIDDK, NIH to William B. Isaacs. In addition, this study is partially supported by a National Cancer Institute RC2 grant (CA148463) and a research contract by GlaxoSmithKline to Jianfeng Xu. No known conflict of interest is related to the study. Publisher Copyright: {\textcopyright} 2017 Wiley Periodicals, Inc.",

year = "2017",

month = aug,

day = "1",

doi = "10.1002/pros.23380",

language = "English (US)",

volume = "77",

pages = "1213--1220",

journal = "Prostate",

issn = "0270-4137",

publisher = "Wiley-Liss Inc.",

number = "11",

}

TY - JOUR

T1 - A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS)

AU - Na, Rong

AU - Helfand, Brian T.

AU - Chen, Haitao

AU - Conran, Carly A.

AU - Crawford, Susan E.

AU - Hayward, Simon W.

AU - Tammela, Teuvo L.J.

AU - Hoffman-Bolton, Judy

AU - Zheng, Siqun L.

AU - Walsh, Patrick C.

AU - Schleutker, Johanna

AU - Platz, Elizabeth A.

AU - Isaacs, William B.

AU - Xu, Jianfeng

N1 - Funding Information: The authors thank the patients enrolled in REDUCE who provided the consent and genetic samples that enabled this study, and the clinicians who contributed their expertise in recruiting study patients for the REDUCE clinical study. Dave Pulford, Jennifer Aponte, Jon Charnecki, and Mary Ellyn Volk participated in consent reconciliation and sample management to enable genetic sample selection for inclusion and genotype determination. Karen King provided data management support for this project. We thank Silviu-Alin Bacanu and Matt Nelson for multiple discussions on power determination, method limitations, and results. We appreciate the assistance of Lauren Marmor in coordinating the support of the Avodart Collaborative Research Team. The assistance of Dr. Tamara Lotan is gratefully acknowledged. This study was supported by Obrien Center Funding (P50-DK082998) from NIDDK, NIH to William B. Isaacs. In addition, this study is partially supported by a National Cancer Institute RC2 grant (CA148463) and a research contract by GlaxoSmithKline to Jianfeng Xu. No known conflict of interest is related to the study. Publisher Copyright: © 2017 Wiley Periodicals, Inc.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - BPH

KW - LUTS

KW - genome-wide association study

UR - http://www.scopus.com/inward/record.url?scp=85021447444&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021447444&partnerID=8YFLogxK

U2 - 10.1002/pros.23380

DO - 10.1002/pros.23380

M3 - Article

C2 - 28656603

AN - SCOPUS:85021447444

SN - 0270-4137

VL - 77

SP - 1213

EP - 1220

JO - Prostate

JF - Prostate

IS - 11

ER -

A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS)

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this