Serum Urate, Genetic Variation, and Prostate Cancer Risk: Atherosclerosis Risk in Communities (ARIC) Study

Evidence is mounting that chronic inflammation influences prostate cancer development (1). Some studies have observed that uric acid is associated with chronic prostatitis, often an inflammatory condition (2). Therefore, urate crystals that deposit in the prostate could be one potential source of prostatic injury and inflammation that may lead to prostate cancer.

Urate crystals from multiple sources may deposit in the prostate. One source is urine reflux (1), which cannot be feasibly studied in a population-based cohort study. Analogous to hyperuricemia, gout, and the joints, another possible source of urate crystal deposition in the prostate is from the circulation; this source can be easily measured by serum urate concentration (3).

Thus, we evaluated the association between serum urate concentration and prostate cancer risk among men in the Atherosclerosis Risk in Communities (ARIC) study. To reflect usual lifetime urate exposure, we evaluated the association of a genetic risk score (GRS) derived from three variants associated with serum urate concentration and gout (4), in combination with serum urate, in relation to prostate cancer risk.

Men ages 45–64 years in 1987–1989 enrolled in ARIC without any cancer history were included. We used calibrated urate concentration previously measured in serum from visits 1 and 2, self-reported gout diagnosis, and urate-influencing medications use at visit 1 (4, 5). We calculated a GRS from rs16890979 at SLC2A9, rs2231142 at ABCG2, and rs1165205 at SLC17A3 by summing the number of alleles associated with higher urate concentration across the three SNPs (unweighted) or by summing the products of the number of alleles and the previously published betas for their association with urate concentration (4) across the three SNPs (weighted). Prostate cancer cases were ascertained through 2012 by cancer registry linkage supplemented with medical records (6).

Cox proportional hazards regression was used to estimate multivariable-adjusted HR of total (N = 813), lethal (first primary with distant metastasis at diagnosis or led to prostate cancer death as the underlying cause; N = 94), and fatal (prostate cancer death as the underlying cause, regardless of whether a first primary; N = 59) prostate cancer in relation to urate quartiles (time-varying); hyperuricemia (≥7 mg/dL; time-varying); gout; GRS quartiles; and joint categories of urate (<5.8, ≥5.8 mg/dL) and GRS (tertiles 1/2, tertile 3) to improve the accuracy of urate classification. In a subanalysis, we excluded (N = 330) men using urate-influencing medications, such as thiazides, allopurinol, and uricosurics. We repeated the analyses stratified by race.

For a two-sided test with alpha = 0.05 and power = 80%, we could detect HRs ≥ 1.37 (black ≥ 1.77, white ≥ 1.45) comparing Q4 versus Q1 of serum urate or higher urate*higher GRS versus lower urate*lower GRS, or comparing hyperuricemia versus normal. For lethal and fatal disease, we could detect large HRs of ≥2.42 and ≥3.11, respectively.

Overall, 6,574 men (mean age = 54 years) were included. Of them, 23.2% (N = 1,523) were black men, who were more likely to have diabetes, and less likely to use aspirin and statins and to have health insurance compared with white men. Urate quartiles and hyperuricemia were not significantly associated with total [P_trend = 0.3; HR, 0.94; 95% confidence interval (CI), 0.79–1.12; Table 1], lethal (P_trend = 0.8; HR, 0.86; 95% CI, 0.50–1.48), or fatal (P_trend = 0.9; HR, 0.77; 95% CI, 0.43–1.39) prostate cancer. These patterns were generally present in black and white men, with one exception: in black men, nonsignificant HRs of fatal disease >1.00 in the top 3 quartiles of serum urate (Q2–Q4 versus Q1: HR, 2.66; 95% CI, 0.90–7.86), although hyperuricemia was not associated (HR, 1.07; 95% CI, 0.47–2.44). Results were similar after excluding urate-influencing medication users (total: P_trend = 0.4, hyperuricemia HR = 0.97, 95% CI, 0.80–1.17; lethal: P_trend = 0.6, HR = 0.98, 95% CI, 0.57–1.68; and fatal: P_trend = 0.9, HR = 0.84, 95% CI, 0.46–1.53). Patterns by race were similar to those when not excluding medication users. A self-reported gout diagnosis was not significantly associated with prostate cancer overall or by race (HRs 0.61–1.10).

Among 4,953 men (75.8%) who provided consent for genetic research and had values in urate-association variants, neither unweighted nor weighted GRS were associated with total, lethal, or fatal prostate cancer overall or by race (per allele increase, HRs 0.85–1.09, all P_trend > 0.1). Joint categories of urate or hyperuricemia and GRS were not associated with risk overall (Table 2) or by race (e.g., hyperuricemia*higher unweighted GRS vs. normal*lower GRS: black, HR = 1.02, 95% CI, 0.64–1.62; white, HR = 1.11, 95% CI, 0.76–1.63). Joint categories were not significantly associated with lethal or fatal disease overall or by race.

In this first study to investigate serum urate in combination with variants in genes predictive of urate concentration in relation to prostate cancer, no association between urate measures and prostate cancer risk was observed overall or in black or white men, although the power to detect a slight difference may be limited after stratification. Our findings are consistent with previous studies investigating serum urate and prostate cancer (7, 8). Taken together with previous evidence, serum urate is unlikely to influence prostate cancer development.

E.A. Platz is the Editor-in-Chief of Cancer Epidemiology, Biomarkers, and Prevention at the American Association for Cancer Research and is a consultant/advisory board member for Kaiser-Permanente Research Division – Cancer. No potential conflicts of interest were disclosed by the other authors.

The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Editor-in-Chief of Cancer Epidemiology, Biomarkers & Prevention is an author on this article. In keeping with AACR editorial policy, a senior member of the Cancer Epidemiology, Biomarkers & Prevention editorial team managed the consideration process for this submission and independently rendered the final decision concerning acceptability.

Conception and design: A.M. De Marzo, E.A. Platz

Development of methodology: J.R. Barber

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J.R. Barber, C.E. Joshu, E.A. Platz

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A. Wang, J.R. Barber, E.A. Platz

Writing, review, and/or revision of the manuscript: A. Wang, A. Tin, A. Kottgen, C.E. Joshu, E.A. Platz

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.E. Joshu

The Atherosclerosis Risk in Communities study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, NIH, Department of Health and Human Services (contract nos. HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HSN268201700005I), R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract no. U01HG004402; and NIH contract no. HHSN268200625226C. Infrastructure was partly supported by grant no. UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Studies on cancer in ARIC are also supported by the NCI (U01 CA164975). E.A. Platz was supported by NCI Cancer Center Support Grant P30 CA006973. C.E. Joshu was supported by the Prostate Cancer Foundation. The authors thank the staff and participants of the ARIC study for their important contributions. Cancer incidence data have been provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Maryland Department of Health, Baltimore, MD. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that helped support the availability of the cancer registry data.

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