Dataset Information

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.

SUBMITTER: Na R

PROVIDER: S-EPMC5565164 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Na Rong R Helfand Brian T BT Chen Haitao H Conran Carly A CA Crawford Susan E SE Hayward Simon W SW Tammela Teuvo L J TLJ Hoffman-Bolton Judy J Zheng Siqun L SL Walsh Patrick C PC Schleutker Johanna J Platz Elizabeth A EA Isaacs William B WB Xu Jianfeng J

The Prostate 20170628 11

<h4>Background</h4>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.<h4>Methods</h4>We performed a three-stage, genome-wide association study (GWAS) of men from three independent populations, the REduc ...[more]

PMID: 28656603

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Project description:BackgroundThe association between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remains controversial, largely due to a detection bias in traditional observational studies.ObjectiveTo assess the association between BPH and PCa using inherited single nucleotide polymorphisms (SNPs).Design setting and participantsThe participants were White men from the population-based UK Biobank (UKB).Outcome measurements and statistical analysisThe association between BPH and PCa was tested for (1) phenotypic correlation using chi-square, (2) genetic correlation (r g) based on genome-wide SNPs using linkage disequilibrium score regression, and (3) cross-disease genetic associations based on known risk-associated SNPs (15 for BPH and 239 for PCa), individually and cumulatively using genetic risk score (GRS).Results and limitationsAmong 214 717 White men in the UKB, 24 623 (11%) and 14 311 (6.7%) had a diagnosis of BPH and PCa, respectively. Diagnoses of these two diseases were significantly correlated (χ2 = 1862.80, p < 0.001). A significant genetic correlation was found (r g = 0.16; 95% confidence interval 0.03-0.28, p = 0.01). In addition, significant cross-disease genetic associations for established risk-associated SNPs were also found. Among the 250 established genome-wide association study-significant SNPs of PCa or BPH, 49 were significantly associated with the risk of the other disease at p < 0.05, significantly more than expected by chance (N = 12, p < 0.001; χ2 test). Furthermore, significant cross-disease GRS associations were also found; GRSBPH was significantly associated with PCa risk (odds ratio [OR] = 1.26 [1.18-1.36], p < 0.001), and GRSPCa was significantly associated with BPH risk (OR = 1.03 [1.02-1.04], p < 0.001). Moreover, GRSBPH was significantly and inversely associated with lethal PCa risk in a PCa case-case analysis (OR = 0.58 [0.41-0.81], p = 0.002). Only White men were studied.ConclusionsBPH and PCa share common inherited genetics, which suggests that the phenotypic association of these two diseases in observational studies is not entirely caused by the detection bias.Patient summaryFor the first time, we found that benign prostatic hyperplasia and prostate cancer are genetically related. This finding may have implications in disease etiology and risk stratification.

Project description:Early studies suggested macrophages might play roles in inflammation-associated benign prostatic hyperplasia (BPH) development, yet the underlying mechanisms remain unclear. Here we first showed that CD68(+) macrophages were identified in both epithelium and the stromal area of human BPH tissues. We then established an in vitro co-culture model with prostate epithelial and macrophage cell lines to study the potential impacts of infiltrating macrophages in the BPH development and found that co-culturing prostate epithelial cells with macrophages promoted migration of macrophages. In a three-dimensional culture system, the sphere diameter of BPH-1 prostate cells was significantly increased during coculture with THP-1 macrophage cells. Mechanism dissection suggested that expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, Snail, and TGF-β2, were increased, and administration of anti-TGF-β2 neutralizing antibody during co-culture suppressed the EMT and THP-1-mediated growth of BPH-1 cells, suggesting THP-1 might go through EMT to influence the BPH development and progression. Importantly, we found that modulation of androgen receptor (AR) in BPH-1 and mPrE cells significantly increased THP-1 and RAW264.7 cell migration, respectively, and enhanced expression levels of EMT markers, suggesting that AR in prostate epithelial cells might play a role in promoting macrophage-mediated EMT in prostate epithelial cells. Silencing AR function via an AR degradation enhancer, ASC-J9, decreased the macrophage migration to BPH-1 cells and suppressed EMT marker expression. Together, these results provide the first evidence to demonstrate that prostate epithelial AR function is important for macrophage-mediated EMT and proliferation of prostate epithelial cells, which represents a previously unrecognized role of AR in the cross-talk between macrophages and prostate epithelial cells. These results may provide new insights for a new therapeutic approach to battle BPH via targeting AR and AR-mediated inflammatory signaling pathways.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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