Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. ARIC Study Design
2.2. SNP Genotyping
2.3. Statistical Analysis
2.3.1. Genetic Risk Score (GRS)
2.3.2. Sensitivity Analyses
3. Results
3.1. Characteristics of Study Sample
3.2. Univariate Analysis of Cancer-Specific and All-Cause Survival
3.3. Multivariable Analysis of PC-Specific Mortality and All-Cause Mortality for Individual SNPs and a Priori Genetic Risk Score (GRS)
3.3.1. PC-Specific Mortality Associated with Individual SNPs
3.3.2. All-Cause Mortality Associated with Individual SNPs
3.3.3. GRS and PC-Specific and All-Cause Mortality
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | All Men | White Men | Black Men | p-Value 1 |
---|---|---|---|---|
Number of men | 622 | 489 | 133 | |
Mean age at diagnosis (SD), y | 69.7 (6.3) | 69.9 (6.3) | 69.8 (6.3) | <0.12 2 |
Median (range) | 70 (53–86) | 70 (53–86) | 68 (54–84) | |
Stage at diagnosis 3 (%) | 0.14 | |||
1 and 2 combined 3 4 | 82.0 12.2 5.8 | 82.8 12.3 4.9 | 79.2 11.2 9.6 | |
Grade at diagnosis 3 (%) | 0.0005 | |||
1 2 3 Unknown | 20.6 46.1 27.7 5.6 | 21.9 48.9 24.1 5.1 | 15.8 36.1 40.6 7.5 | |
First course of treatment 4 | ||||
Surgery (yes, %) Radiation (yes, %) Hormonal therapy (yes, %) | 51.3 17.6 25.4 | 51.3 20.0 25.0 | 51.1 16.9 26.7 | 0.98 0.45 0.75 |
Co-morbidities at baseline | ||||
Diabetes (yes, %) Cardiovascular disease (yes, %) | 8.1 6.4 | 8.1 7.0 | 8.0 4.0 | 0.96 0.14 |
Co-morbidities before diagnosis | ||||
Diabetes (yes, %) Cardiovascular disease (yes, %) | 14.0 12.1 | 13.7 12.5 | 15.3 10.4 | 0.65 0.15 |
Number of deaths | 350 | 289 | 61 | |
Incidence rate of death from any cause (per 1000 men) | 47.9 | 49.7 | 41.1 | |
Incidence rate of PC-specific death (per 1000 men) | 10.2 | 10.0 | 11.0 | |
Median follow-up time (range, y) | 11.6 (0–29.1) | 11.0 (0.11–29.1) | 10.5 (0–27.7) |
SNP | Gene (Chromosome) Function | Major Allele | Minor Allele | Frequency of Major Allele | Risk Allele 1 | ||
---|---|---|---|---|---|---|---|
All | White Men | Black Men | |||||
rs1047303 (1245C) Missense C–gain of function | HSD3B1 (1) Androgen synthesis and production | A | C | 0.72 | 0.68 | 0.88 | C |
rs1789693 Intron | SLCO2B1(11) Androgen transport and uptake | A | T | 0.59 | 0.66 | 0.34 | A 2 |
rs12422149 Missense | SLCO2B1 (11) Androgen transport and uptake | G | A | 0.90 | 0.90 | 0.90 | G |
rs523349 Missense | SRD5A2 (2) Androgen conversion | C | G | 0.73 | 0.70 | 0.76 | G 2 |
Polymorphisms | Hazard Ratio and 95% Confidence Intervals for PC-Specific Mortality 1 | ||
---|---|---|---|
All | White Men | Black Men | |
No. of men with PC | 622 | 489 | 133 |
No. of PC-specific deaths | 74 | 58 | 16 |
Person-years (per 1000 person-years) | 7273 | 5815 | 1459 |
SNP (risk allele) 2 | |||
rs1047303 (C) | 1.40 (0.96–2.06) p = 0.08 | 1.39 (0.93–2.08) p = 0.11 | 1.89 (0.55–6.48) p = 0.76 |
rs1789693 (A) | 1.46 (0.93–2.27) p = 0.10 | 1.70 (1.01–2.85) p = 0.04 | 0.45 (0.15–1.31) p = 0.14 |
rs12422149 (G) | 1.22 (0.69–2.18) p = 0.49 | 1.15 (0.62–2.12) p = 0.66 | 1.98 (0.28–13.85) p = 0.50 |
rs523349 (G) | 1.05 (0.73–1.51) p = 0.76 | 1.26 (0.83–1.91) p = 0.27 | 0.95 (0.43–2.11) p = 0.88 |
Genetic Risk Score, GRS 3 | |||
Tertiles | |||
0.12–3.76 3.77–4.82 4.83–7.68 | 1 (Reference) 1.39 (0.76–2.55) 1.73 (0.95–3.16) | 1 (Reference) 2.71 (1.15–6.40) 3.21 (1.46–7.07) | 1 (Reference) 0.80 (0.20–3.16) 0.47 (0.06–3.82) |
Continuous (per risk allele) | 1.26 (1.02–1.56) | 1.39 (1.08–1.77) | 0.85 (0.51–1.42) |
P-trend 4 | 0.03 | 0.01 | 0.53 |
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Prizment, A.E.; McSweeney, S.; Pankratz, N.; Joshu, C.E.; Hwang, J.H.; Platz, E.A.; Ryan, C.J. Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study. Cancers 2021, 13, 1958. https://doi.org/10.3390/cancers13081958
Prizment AE, McSweeney S, Pankratz N, Joshu CE, Hwang JH, Platz EA, Ryan CJ. Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study. Cancers. 2021; 13(8):1958. https://doi.org/10.3390/cancers13081958
Chicago/Turabian StylePrizment, Anna E., Sean McSweeney, Nathan Pankratz, Corinne E. Joshu, Justin H. Hwang, Elizabeth A. Platz, and Charles J. Ryan. 2021. "Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study" Cancers 13, no. 8: 1958. https://doi.org/10.3390/cancers13081958