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Lung function changes over 8 years and testosterone markers in both sexes: UK Biobank

ABSTRACT: Higher levels of testosterone have been associated with better lung function in cross-sectional population-based studies. The role of testosterone in lung function in women and in lung function decline in men or women is unclear. We studied 5114 men and 5467 women in the UK Biobank with high-quality spirometry at baseline (2006–2010) and 8.4?years later. We studied cross-sectional associations of total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI) and sex hormone-binding globulin (SHBG) with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC using linear regression and associations of baseline markers with lung function decline using linear mixed-effects regression. Men with higher levels of TT had higher FEV1 (27.56?mL per interquartile range increase TT, 95% CI 5.43–49.68) and FVC (48.06?mL, 95% CI 22.07–74.06) at baseline. Higher cFT levels were associated with higher FEV1 and FVC among physically active men only. In women, higher FAI and cFT levels were associated with lower lung function at baseline and higher levels of TT, cFT and FAI were associated with slightly attenuated FEV1 and FVC decline. Higher levels of SHBG were associated with better lung function in both sexes but slightly accelerated decline in men. In this population-based sample, higher levels of TT were associated with better lung function in men and higher levels of cFT with better lung function in physically active men. A small attenuation of lung function decline with higher levels of TT, cFT and FAI was seen in women only. Higher levels of testosterone are associated with better lung function in men, especially if physically active, but not in women. A small attenuation of lung function decline with higher testosterone levels is seen in women only.https://bit.ly/382d0xT

SUBMITTER: Lenoir A

PROVIDER: S-EPMC7520167 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction.DesignTwo sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence.SettingReduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study.Participants3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation.Main outcome measuresThromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death.ResultsOf the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes.ConclusionsEndogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.

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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Lung function changes over 8 years and testosterone markers in both sexes: UK Biobank

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