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Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200 000 men in UK Biobank.

ABSTRACT: Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF-I, sex hormone-binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable-adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two-sample Mendelian randomisation (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis- and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow-up 6.9 years). Higher circulating IGF-I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05-1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02-1.29). MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment = 1.34, 1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05-1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94-0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.

SUBMITTER: Watts EL

PROVIDER: S-EPMC8048461 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDespite strong evidence of heritability, few studies have attempted to unveil the genetic underpinnings of testosterone levels.ObjectiveTo identify testosterone-associated loci in a large study and assess their biological and clinical implications.Design setting and participantsThe participants were men from the UK Biobank. A two-stage genome-wide association study (GWAS) was first used to identify/validate loci for low testosterone (LowT, <8 nmol/l) in 80% of men (N = 148 902). The cumulative effect of independent LowT risk loci was then evaluated in the remaining 20% of men.Outcome measurements and statistical analysisAssociations of single nucleotide polymorphisms (SNPs) with LowT were tested using an additive model. Analyses of the expression quantitative trait loci (eQTLs) were performed to assess the associations between significant SNPs and expression of nearby genes (within 1 Mbp). A genetic risk score (GRS) was used to assess the cumulative effect of multiple independent SNPs on LowT risk.Results and limitationsThe two-stage GWAS found SNPs in 141 loci of 41 cytobands that were significantly associated with LowT (p < 5 × 10-8), including 94 novel loci from 38 cytobands. An eQTL analysis of these 141 loci revealed significant associations with RNA expression of 155 genes, including previously implicated (SHBG and JMJD1C) and novel (LIN28B, LCMT2, and ZBTB4) genes. Among the 141 loci, 42 were independently associated with LowT after a multivariable analysis. The GRS based on these 42 loci was significantly associated with LowT risk in independent individuals (N = 37 225, p trend = 3.16 × 10-162). The risk ratio for LowT between men in the top and those in the bottom GRS deciles was 4.98-fold. Results are limited in generalizability as only Caucasians were studied.ConclusionsIdentification of the genetic variants associated with LowT may improve our understanding of its etiology and identify high-risk men for LowT screening.Patient summaryWe identified 141 new genetic loci that can be incorporated into a genetic risk score that can potentially identify men with low testosterone.

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Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200 000 men in UK Biobank.

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