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

Abstract

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. Participants were 3110 men of African and European ancestries ages 45-70, without prostate cancer and with a baseline PSA < 4ng/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>4ng/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. 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. A predisposition toward higher PSA levels was associated with clinical evaluations of an elevated PSA among men ages 45-59 years. National Institutes of Health (NIH).