Shared Inherited Genetics of Benign Prostatic Hyperplasia and Prostate Cancer

Alexander Glaser; Zhuqing Shi; Jun Wei; Nadia A Lanman; Skylar Ladson-Gary; Renee E Vickman; Omar E Franco; Susan E Crawford; S Lilly Zheng; Simon W Hayward; William B Isaacs; Brian T Helfand; Jianfeng Xu

doi:10.1016/j.euros.2022.07.004

Shared Inherited Genetics of Benign Prostatic Hyperplasia and Prostate Cancer

Eur Urol Open Sci. 2022 Aug 1:43:54-61. doi: 10.1016/j.euros.2022.07.004. eCollection 2022 Sep.

Authors

Alexander Glaser^{1

2}, Zhuqing Shi¹, Jun Wei¹, Nadia A Lanman³, Skylar Ladson-Gary¹, Renee E Vickman¹, Omar E Franco¹, Susan E Crawford¹, S Lilly Zheng¹, Simon W Hayward¹, William B Isaacs⁴, Brian T Helfand^{1

2

5}, Jianfeng Xu^{1

2

5}

Affiliations

¹ Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA.
² Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA.
³ Collaborative Core for Cancer Bioinformatics, Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
⁴ Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Surgery, University of Chicago Pritzker School of Medicine, Chicago, IL, USA.

Abstract

Background: The association between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remains controversial, largely due to a detection bias in traditional observational studies.

Objective: To assess the association between BPH and PCa using inherited single nucleotide polymorphisms (SNPs).

Design setting and participants: The participants were White men from the population-based UK Biobank (UKB).

Outcome measurements and statistical analysis: The 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 limitations: Among 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; GRS_BPH was significantly associated with PCa risk (odds ratio [OR] = 1.26 [1.18-1.36], p < 0.001), and GRS_PCa was significantly associated with BPH risk (OR = 1.03 [1.02-1.04], p < 0.001). Moreover, GRS_BPH 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.

Conclusions: BPH 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 summary: For 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.

Keywords: Benign prostatic hyperplasia; Genetic correlation; Genetic risk score; Heritability; Lethal; Prostate cancer; Single nucleotide polymorphisms.

Abstract

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