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Analysis of Over 140,000 European Descendants Identifies Genetically Predicted Blood Protein Biomarkers Associated with Prostate Cancer Risk.

ABSTRACT: Several blood protein biomarkers have been associated with prostate cancer risk. However, most studies assessed only a small number of biomarkers and/or included a small sample size. To identify novel protein biomarkers of prostate cancer risk, we studied 79,194 cases and 61,112 controls of European ancestry, included in the PRACTICAL/ELLIPSE consortia, using genetic instruments of protein quantitative trait loci for 1,478 plasma proteins. A total of 31 proteins were associated with prostate cancer risk including proteins encoded by GSTP1, whose methylation level was shown previously to be associated with prostate cancer risk, and MSMB, SPINT2, IGF2R, and CTSS, which were previously implicated as potential target genes of prostate cancer risk variants identified in genome-wide association studies. A total of 18 proteins inversely correlated and 13 positively correlated with prostate cancer risk. For 28 of the identified proteins, gene somatic changes of short indels, splice site, nonsense, or missense mutations were detected in patients with prostate cancer in The Cancer Genome Atlas. Pathway enrichment analysis showed that relevant genes were significantly enriched in cancer-related pathways. In conclusion, this study identifies 31 candidates of protein biomarkers for prostate cancer risk and provides new insights into the biology and genetics of prostate tumorigenesis. SIGNIFICANCE: Integration of genomics and proteomics data identifies biomarkers associated with prostate cancer risk.

SUBMITTER: Wu L

PROVIDER: S-EPMC6744971 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Analysis of Over 140,000 European Descendants Identifies Genetically Predicted Blood Protein Biomarkers Associated with Prostate Cancer Risk.

Wu Lang L Shu Xiang X Bao Jiandong J Guo Xingyi X Kote-Jarai Zsofia Z Haiman Christopher A CA Eeles Rosalind A RA Zheng Wei W

Cancer research 20190723 18

Several blood protein biomarkers have been associated with prostate cancer risk. However, most studies assessed only a small number of biomarkers and/or included a small sample size. To identify novel protein biomarkers of prostate cancer risk, we studied 79,194 cases and 61,112 controls of European ancestry, included in the PRACTICAL/ELLIPSE consortia, using genetic instruments of protein quantitative trait loci for 1,478 plasma proteins. A total of 31 proteins were associated with prostate can ...[more]

PMID: 31337649

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Project description:IntroductionObservational studies have reported a relationship between iron status and the risk of prostate cancer. However, it remains uncertain whether the association is causal or due to confounding or reverse causality. To further clarify the underlying causal relationship, we conducted a Mendelian randomization (MR) analysis.MethodsWe selected three genetic variants (rs1800562, rs1799945, and rs855791) closely correlated with four iron status biomarkers (serum iron, log-transformed ferritin, transferrin saturation, and transferrin) as instrumental variables. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium including 79,148 cases and 61,106 controls of European ancestry. The inverse-variance weighted (IVW) method was conducted primarily to estimate the association of genetically predicted iron status and the risk of prostate cancer, supplemented with simple-median, weighted-median and maximum-likelihood methods as sensitivity analysis. MR-Egger regression was used to detect directional pleiotropy. We also conducted a meta-analysis of observational studies to assess the associations between iron status and the risk of prostate cancer.ResultsGenetically predicted increased iron status was associated with the decreased risk of prostate cancer, with odds ratio of 0.91 [95% confidence interval (CI): 0.84, 0.99; P = 0.035] for serum iron, 0.81 (95% CI: 0.65, 1.00; P = 0.046) for log- transformed ferritin, 0.94 (95% CI: 0.88, 0.99; P = 0.029) for transferrin saturation, and 1.15 (95% CI: 0.98, 1.35; P = 0.084) for transferrin (with higher transferrin levels representing lower systemic iron status), using the inverse-variance weighted method. Sensitivity analyses produced consistent associations, and MR-Egger regression indicated no potential pleiotropy. Our replication analysis based on FinnGen research project showed compatible results with our main analysis. Results from our meta-analysis similarly showed that serum ferritin [standardized mean difference (SMD): -1.25; 95% CI: -2.34, -0.16; P = 0.024] and transferrin saturation (SMD: -1.19; 95% CI: -2.34, -0.05; P = 0.042) were lower in patients with prostate cancer compared with that in controls.DiscussionOur study suggests a protective role of iron in the risk of prostate cancer, further investigations are required to clarify the underlying mechanisms.

Project description:ImportanceHypertension remains the major cardiovascular disease risk factor globally, but variability in measured blood pressure may result in suboptimal management. Whether genetic contributors to elevated blood pressure may complementarily inform cardiovascular disease risk assessment is unknown.ObjectiveTo examine incident cardiovascular disease by blood pressure polygenic risk score independent of measured blood pressures and antihypertensive medication prescriptions.Design, setting, and participantsThe cohort study (UK Biobank) recruited UK residents aged 40 to 69 years between March 2006 and August 2010. Participants without a prior physician diagnosis of cardiovascular disease, including myocardial infarction, stroke, or heart failure, were included. Excluded were individuals with mismatch between self-reported and genotypically inferred sex, sex aneuploidy, missing genotype rates of 1% or greater, and excess genotypic heterozygosity. Data analyses were performed from September 25, 2021, to July 21, 2022.ExposuresMeasured blood pressure and externally derived blood pressure polygenic risk score stratified by hypertension diagnosis and management, which included normal blood pressure (<130/80 mm Hg without antihypertensives), untreated hypertension (systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥80 mm Hg without antihypertensives), and treated hypertension (current antihypertensives prescriptions).Main outcomes and measuresComposite of first incident myocardial infarction, stroke, heart failure, or cardiovascular-related death.ResultsOf the 331 078 study participants included (mean [SD] age at enrollment, 56.9 [8.1] years; 178 824 female [54.0%]), 83 094 (25.1%) had normal blood pressure, 197 597 (59.7%) had untreated hypertension, and 50 387 (15.2%) had treated hypertension. Over a median (IQR) follow-up of 11.1 (10.4-11.8) years, the primary outcome occurred in 15 293 participants. Among those with normal blood pressure, untreated hypertension, and treated hypertension, each SD increase in measured systolic blood pressure was associated with hazard ratios of 1.08 (95% CI, 0.93-1.25), 1.20 (95% CI, 1.16-1.23), and 1.16 (95% CI, 1.11-1.20), respectively, for the primary outcome. Among these same categories, each SD increase in genetically predicted systolic blood pressure was associated with increased hazard ratios of 1.13 (95% CI, 1.05-1.20), 1.04 (95% CI, 1.01-1.07), and 1.06 (95% CI, 1.02-1.10), respectively, for the primary outcome independent of measured blood pressures and other covariates. Findings were similar for measured and genetically predicted diastolic blood pressure.Conclusions and relevanceBlood pressure polygenic risk score may augment identification of individuals at heightened cardiovascular risk, including those with both normal blood pressure and hypertension. Whether it may also guide antihypertensive initiation or intensification requires further study.

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Analysis of Over 140,000 European Descendants Identifies Genetically Predicted Blood Protein Biomarkers Associated with Prostate Cancer Risk.

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Analysis of Over 140,000 European Descendants Identifies Genetically Predicted Blood Protein Biomarkers Associated with Prostate Cancer Risk.

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