Genome‐wide association study identifies novel single nucleotide polymorphisms having age‐specific effect on prostate‐specific antigen levels

Li, Weiqiang; Bicak, Mesude; Sjoberg, Daniel D.; Vertosick, Emily; Dahlin, Anders; Melander, Olle; Ulmert, David; Lilja, Hans; Klein, Robert J.

doi:10.1002/pros.24070

Cited by 3 publications

(3 citation statements)

References 41 publications

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“…Data collected from men with no known prostate cancer or BPH available in the Electronic Medical Records and Genomics (eMERGE) Network study (2015–2020) and for men without prostate cancer recorded in the pre- or early PSA era in the Malmö Diet and Cancer (MDC) study (1991–1996) have recorded median PSA levels and ages of 0.67 ng/ml and 56 y & and 1.12 ng/ml and 62y respectively 23 . The current median PSA levels recorded for NZ-European controls with comparable ages are higher than the eMerge study and lower than the records of MDC study represented by a relatively older group of men.…”

Section: Discussionmentioning

confidence: 99%

“…Literature suggests multiple other factors associated with PSA including BMI 13 , tobacco smoking 14 – 16 , alcohol consumption 17 , ethnicity 16 , and single nucleotide polymorphisms (SNPs) associated with both PSA alone or with PSA and prostate cancer 18 – 22 . Li et al 2020 have recorded SNPs that alter functions of nearby genes leading to age-specific effects on PSA level 23 . Association of genetic polymorphisms in the superfamily of organic anion-transporting polypeptides, encoded by SLCO2B1 and SLCO1B3 genes with a potential to adrenal androgen transport to prostate cells have been shown to regulate PSA levels 24 .…”

Section: Introductionmentioning

confidence: 99%

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Assessment of factors associated with PSA level in prostate cancer cases and controls from three geographical regions

Karunasinghe

Minas

Bao

et al. 2022

Sci Rep

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It is being debated whether prostate-specific antigen (PSA)-based screening effectively reduces prostate cancer mortality. Some of the uncertainty could be related to deficiencies in the age-based PSA cut-off thresholds used in screening. Current study considered 2779 men with prostate cancer and 1606 men without a cancer diagnosis, recruited for various studies in New Zealand, US, and Taiwan. Association of PSA with demographic, lifestyle, clinical characteristics (for cases), and the aldo–keto reductase 1C3 (AKR1C3) rs12529 genetic polymorphisms were analysed using multiple linear regression and univariate modelling. Pooled multivariable analysis of cases showed that PSA was significantly associated with demographic, lifestyle, and clinical data with an interaction between ethnicity and age further modifying the association. Pooled multivariable analysis of controls data also showed that demographic and lifestyle are significantly associated with PSA level. Independent case and control analyses indicated that factors associated with PSA were specific for each cohort. Univariate analyses showed a significant age and PSA correlation among all cases and controls except for the US-European cases while genetic stratification in cases showed variability of correlation. Data suggests that unique PSA cut-off thresholds factorized with demographics, lifestyle and genetics may be more appropriate for prostate cancer screening.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Assessment of factors associated with PSA level in prostate cancer cases and controls from three geographical regions

Karunasinghe

Minas

Bao

et al. 2022

Sci Rep

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“…In terms of genetic influence on the serum PSA level, it is estimated that 40% of the variations between individuals can be explained by inherited factors ( 4 ). In previous genome-wide association studies (GWAS), multiple inherited variants had been demonstrated to influence the serum levels of PSA in European and Asian populations ( 5 – 8 ).…”

Section: Introductionmentioning

confidence: 99%

A Germline Variant at 8q24 Contributes to the Serum p2PSA Level in a Chinese Prostate Biopsy Cohort

Lin

Liu

et al. 2021

Front. Oncol.

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IntroductionThe clinical performance of [–2]proPSA (p2PSA) and its derivatives in predicting the presence and aggressiveness of prostate cancer (PCa) has been well evaluated in prostate biopsy patients. However, no study has been performed to evaluate the common genetic determinants that affect serum level of p2PSA.Materials and MethodsHere, we performed a two-stage genome-wide association study (GWAS) on the p2PSA level in Chinese men who underwent a transperineal ultrasound-guided prostate biopsy at Huashan Hospital, Shanghai Cancer Center, and Ruijin Hospital in Shanghai, China. Germline variants significantly associated with the p2PSA level in the first stage (n = 886) were replicated in the second stage (n = 1,128). Multivariate linear regression was used to assess the independent contribution of confirmed single nucleotide polymorphisms (SNPs) and known covariates, such as age, to the level of p2PSA.ResultsA novel non-synonymous SNP, rs72725879, in region 8q24.21 of the PRNCR1 gene was significantly associated with the serum level of p2PSA in this two-stage GWAS (p = 2.28 × 10−9). Participants with homozygous “T” alleles at rs72725879 had higher p2PSA levels compared to allele “C” carriers. This variant was also nominally associated with PCa risk (p-combined = 3.44 × 10−18). The association with serum level of p2PSA was still significant after adjusting for PCa risk and age (p = 0.017).ConclusionsOur study shows that the genetic variants in the 8q24.21 region are associated with the serum level of p2PSA in a large-scale Chinese population. By taking inherited variations between individuals into account, the findings of these genetic variants may help improve the performance of p2PSA in predicting prostate cancer.

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Meta-regression of genome-wide association studies to estimate age-varying genetic effects

Pagoni,

Higgins,

Lawlor

et al. 2024

Eur J Epidemiol

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Fixed-effect meta-analysis has been used to summarize genetic effects on a phenotype across multiple Genome-Wide Association Studies (GWAS) assuming a common underlying genetic effect. Genetic effects may vary with age (or other characteristics), and not allowing for this in a GWAS might lead to bias. Meta-regression models between study heterogeneity and allows effect modification of the genetic effects to be explored. The aim of this study was to explore the use of meta-analysis and meta-regression for estimating age-varying genetic effects on phenotypes. With simulations we compared the performance of meta-regression to fixed-effect and random -effects meta-analyses in estimating (i) main genetic effects and (ii) age-varying genetic effects (SNP by age interactions) from multiple GWAS studies under a range of scenarios. We applied meta-regression on publicly available summary data to estimate the main and age-varying genetic effects of the FTO SNP rs9939609 on Body Mass Index (BMI). Fixed-effect and random-effects meta-analyses accurately estimated genetic effects when these did not change with age. Meta-regression accurately estimated both main genetic effects and age-varying genetic effects. When the number of studies or the age-diversity between studies was low, meta-regression had limited power. In the applied example, each additional minor allele (A) of rs9939609 was inversely associated with BMI at ages 0 to 3, and positively associated at ages 5.5 to 13. Our findings challenge the assumption that genetic effects are consistent across all ages and provide a method for exploring this. GWAS consortia should be encouraged to use meta-regression to explore age-varying genetic effects.

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Genome‐wide association study identifies novel single nucleotide polymorphisms having age‐specific effect on prostate‐specific antigen levels

Cited by 3 publications

References 41 publications

Assessment of factors associated with PSA level in prostate cancer cases and controls from three geographical regions

Assessment of factors associated with PSA level in prostate cancer cases and controls from three geographical regions

A Germline Variant at 8q24 Contributes to the Serum p2PSA Level in a Chinese Prostate Biopsy Cohort

Meta-regression of genome-wide association studies to estimate age-varying genetic effects

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