Clinical consequences of a genetic predisposition toward higher benign prostate-specific antigen levels

Mingjian Shi; John P Shelley; Kerry R Schaffer; Jeffrey J Tosoian; Minoo Bagheri; John S Witte; Linda Kachuri; Jonathan D Mosley

doi:10.1016/j.ebiom.2023.104838

Clinical consequences of a genetic predisposition toward higher benign prostate-specific antigen levels

EBioMedicine. 2023 Nov:97:104838. doi: 10.1016/j.ebiom.2023.104838. Epub 2023 Oct 20.

Authors

Mingjian Shi¹, John P Shelley¹, Kerry R Schaffer², Jeffrey J Tosoian³, Minoo Bagheri⁴, John S Witte⁵, Linda Kachuri⁶, Jonathan D Mosley⁷

Affiliations

¹ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
² Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵ Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA; Department of Biomedical Data Science and Genetics (by Courtesy), Stanford University, Stanford, CA, USA.
⁶ Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA.
⁷ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: jonathan.d.mosley@vumc.org.

Abstract

Background: Prostate-specific antigen (PSA) levels are influenced by genetic variation unrelated to prostate cancer risk. Whether a genetic predisposition to a higher PSA level predisposes to a diagnostic work-up for prostate cancer is not known.

Methods: Participants were 3110 men of African and European ancestries ages 45-70, without prostate cancer and with a baseline PSA < 4 ng/mL, undergoing routine clinical PSA screening. The exposure was a polygenic score (PGS) comprising 111 single nucleotide polymorphisms associated with PSA level, but not prostate cancer. We tested whether the PGS was associated with a: 1) PSA value > 4 ng/mL, 2) International Classification of Diseases (ICD) code for an elevated PSA, 3) encounter with a urologist, or 4) prostate biopsy. Multivariable Cox proportional hazards models were adjusted for age and genetic principal components. Analyses were stratified by age (45-59 years, and 60-70 years old). Association estimates are per standard deviation change in the PGS.

Findings: The median age was 56.6 years, and 2118 (68%) participants were 45-59 years. The median (IQR) baseline PSA level was 1.0 (0.6-1.7) ng/mL. Among men ages 45-59, the PGS was associated with a PSA > 4 (hazard ratio [HR] = 1.35 [95% CI, 1.17-1.57], p = 4.5 × 10^-5), an ICD code for elevated PSA (HR = 1.30 [1.12-1.52], p = 8.0 × 10^-4), a urological evaluation (HR = 1.34 [1.14-1.57], p = 4.8 × 10^-4), and undergoing a prostate biopsy (HR = 1.35 [1.11-1.64], p = 0.002). Among men ages 60-70, association effect sizes were smaller and not significant.

Interpretation: A predisposition toward higher PSA levels was associated with clinical evaluations of an elevated PSA among men ages 45-59 years.

Funding: National Institutes of Health (NIH).

Keywords: Associations; Cox proportional hazards regression; Polygenic score (PGS); Prostate cancer; Prostate specific antigen (PSA).

MeSH terms

Biopsy
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Proportional Hazards Models
Prostate-Specific Antigen* / genetics
Prostatic Neoplasms* / diagnosis
Prostatic Neoplasms* / genetics

Substances

Prostate-Specific Antigen

Abstract

MeSH terms

Substances

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