The role of testosterone in chronic kidney disease and kidney function in men and women: a bi-directional Mendelian randomization study in the UK Biobank

Zhao, Jie; Schooling, C. Mary

doi:10.1186/s12916-020-01594-x

Cited by 53 publications

(42 citation statements)

References 60 publications

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“…Genetic associations with testosterone in this study were adjusted for genotyping chip/release of genetic data, age at baseline, fasting time and ten genetically derived principal components ( Ruth et al, 2020 ). We used all 125 genetic variants given for bioavailable testosterone, hereafter testosterone, in men and all 254 genetic variants given for testosterone in women, as previously ( Zhao and Schooling, 2020 ), because these had little correlation with sex hormone binding globulin (0.05 in men and 0.06 in women) ( Ruth et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation

Schooling

Zhao

Yeung

et al. 2020

eLife

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We examined whether specifically statins, of the major lipid modifiers (statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) have pleiotropic effects on ischemic heart disease (IHD) via testosterone in men or women. As a validation, we similarly assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone. Using previously published genetic instruments we conducted a sex-specific univariable and multivariable Mendelian randomization study in the UK Biobank, including 179918 men with 25410 IHD cases and 212080 women with 12511 IHD cases. Of these three lipid modifiers, only genetically mimicking the effects of statins in men affected testosterone, which partly mediated effects on IHD. Correspondingly, genetically mimicking effects of anakinra on testosterone and IHD presented a reverse pattern to that for statins. These insights may facilitate the development of new interventions for cardiovascular diseases as well as highlighting the importance of sex-specific explanations, investigations, prevention and treatment.

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Section: Methodsmentioning

confidence: 99%

Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation

Schooling

Zhao

Yeung

et al. 2020

eLife

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“…Analyses of the UK biobank provided a great contribution to the prognostic research in CKD. For example, genetically predicted testosterone and fasting insulin, with the latter being an expression of insulin resistance, were found to be associated with CKD and worse kidney function in men, thus highlighting the possible reasons for discrepancy in CKD prevalence and CKD progression among men and women [84,85]. Intriguingly, a genome-wide association study of UK biobank showed that albumin-to-creatinine ratio (ACR) is dependent on multiple pathways and that an ACR genetic risk score may improve the prediction of hypertension and stroke [86].…”

Section: Prognostic Role Of Proteomics Metabolomics and Genomicsmentioning

confidence: 99%

Contribution of Predictive and Prognostic Biomarkers to Clinical Research on Chronic Kidney Disease

Provenzano

Rotundo

Chiodini

et al. 2020

IJMS

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Chronic kidney disease (CKD), defined as the presence of albuminuria and/or reduction in estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, is considered a growing public health problem, with its prevalence and incidence having almost doubled in the past three decades. The implementation of novel biomarkers in clinical practice is crucial, since it could allow earlier diagnosis and lead to an improvement in CKD outcomes. Nevertheless, a clear guidance on how to develop biomarkers in the setting of CKD is not yet available. The aim of this review is to report the framework for implementing biomarkers in observational and intervention studies. Biomarkers are classified as either prognostic or predictive; the first type is used to identify the likelihood of a patient to develop an endpoint regardless of treatment, whereas the second type is used to determine whether the patient is likely to benefit from a specific treatment. Many single assays and complex biomarkers were shown to improve the prediction of cardiovascular and kidney outcomes in CKD patients on top of the traditional risk factors. Biomarkers were also shown to improve clinical trial designs. Understanding the correct ways to validate and implement novel biomarkers in CKD will help to mitigate the global burden of CKD and to improve the individual prognosis of these high-risk patients.

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“…However, an RCT of dual blockade of RAAS with ACE inhibitors and ARB did not exhibit more benefits for kidney function than monotherapy [ 29 ], raising the possibility that other pathways might exist. Notably, CKD has an apparent sex disparity, and testosterone has been recognized as a causal factor explaining, or partly explaining, unfavorable kidney function in men [ 30 , 31 ]. ACE inhibitors and CCB may also play a role by modulating sex hormones.…”

Section: Discussionmentioning

confidence: 99%

Using Mendelian randomization study to assess the renal effects of antihypertensive drugs

Zhao

Schooling

2021

BMC Med

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Background Angiotensin-converting enzyme (ACE) inhibitors and/or in combination with calcium channel blockers (CCBs) are generally recommended as the first-line antihypertensive therapy for people with hypertension and kidney dysfunction. Evidence from large randomized controlled trials comprehensively comparing renal effects of different classes of antihypertensive drugs is lacking. Methods We used a Mendelian randomization study to obtain unconfounded associations of genetic proxies for antihypertensives with kidney function. Specifically, we used published genetic variants in genes regulating target proteins of these drugs and then applied to a meta-analysis of the largest available genome-wide association studies of kidney function (estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and albuminuria). Inverse variance weighting was used as the main analysis and to combine estimates from different sources. Results Genetically predicted ACE inhibition was associated with higher eGFR (effect size 0.06, 95% confidence interval (CI) 0.008, 0.11), while genetic proxies for beta-blockers were associated with lower eGFR (− 0.02, 95% CI − 0.04, − 0.004) when meta-analyzing the UK Biobank and CKDGen. Genetic proxies for CCBs were associated with lower UACR (− 0.15, 95% CI − 0.28, − 0.02) and lower risk of albuminuria (odds ratio 0.58, 95% CI 0.37, 0.90) in CKDGen. The associations were robust to using different analysis methods and different genetic instruments. Conclusions Our findings suggest the reno-protective associations of genetically proxied ACE inhibitors and CCBs, while genetic proxies for beta-blockers may be related to lower eGFR. Understanding the underlying mechanisms would be valuable, with implications for drug development and repositioning of treatments for kidney disease.

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The role of testosterone in chronic kidney disease and kidney function in men and women: a bi-directional Mendelian randomization study in the UK Biobank

Cited by 53 publications

References 60 publications

Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation

Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation

Contribution of Predictive and Prognostic Biomarkers to Clinical Research on Chronic Kidney Disease

Using Mendelian randomization study to assess the renal effects of antihypertensive drugs

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