Effects of testosterone replacement on glucose and lipid metabolism

Utilizing data from the Million Veteran Program (MVP), we investigated the genetic determinants underlying total testosterone levels via a multi-ancestral analysis of 124,593 individuals of European (n=88,385), African (n=25,235) and Hispanic (n=10,973) ancestry. We identified 46 trans-ancestry variants and 17 ancestry-specific variants, of which 14 trans-ancestry variants and 15 ancestry-specific variants are novel associations with testosterone. Results implicate genes regulating testosterone shared across ancestral groups, which include SHBG, JMJD1C, FXR2, SENP3, TNFSF12-TNFSF13 while also implicating genes such as MSN, DMD, VSIG4, CHEK2, TKTL1 that may underlie ancestry-group differences in testosterone regulation. We also linked testosterone variants on the X chromosome with differential risk of chronic kidney disease and hereditary hemolytic anemias in African and Hispanic ancestry groups, respectively. Lastly, we constructed a polygenic score from our 46 trans-ancestry variants and associated it with testicular dysfunction, hyperlipidemia, gout and prostate cancer with stronger prostate cancer associations in Hispanic and African ancestry groups compared to the European ancestry group. These findings provide insight into ancestry-specific androgen regulation and identify novel variants for disease risk stratification in patients.

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“…Variants passing significance threshold (p<5e-08) in meta-analysis were used to construct polygenic scores. 46…”

Section: Testosterone Polygenic Score (Pgs)mentioning

confidence: 99%

“…Since testosterone can influence lab measurements46 , we also ran LabWAS associations with 46 transancestry variants and mean levels of lipid, metabolic and blood lab values. We identified 668 significant associations in the European, 150 in the African and 44 in the Hispanic ancestry groups (FDR<.01).…”

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confidence: 99%

Discovery of Novel Trans-Ancestry and Ancestry-Specific Gene Loci for Total Testosterone in a Multi-Ancestral Analysis of Men in the Million Veteran Program

Pagadala

Jasuja

Palnati

et al. 2022

Preprint

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“…Prior epidemiological studies have also shown that hypotestosteronemia is associated with increased risk of developing metabolic syndrome, diabetes and higher overall mortality rate [8,9]. This mechanism is thought to be due to testosterone's direct effect of increasing insulin sensitivity and regulating enzymes involved in lipolysis [8,10]. Still, the current literature on the relationship between testosterone and cardiovascular disease is unclear.…”

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confidence: 99%

Baseline testosterone level may modulate statin efficacy

Taub²

2021

Coronary Artery Disease

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“…Deficiency of androgens in men and androgen excess in women further modulate cardiometabolic health in men and women. In men, testosterone has multiple protective effects against diabetes, including enhancing insulin sensitivity through cellular androgen receptors, preventing the development of visceral adiposity and maintaining skeletal muscle mass [21,22]. Low testosterone levels, arising, for example, as a consequence of androgen-deprivation therapy or age-related hypogonadism predisposes affected men to type 2 diabetes and cardiovascular disease [23].…”

mentioning

confidence: 99%

Venus and Mars: influence of sex on diabetes and cardiometabolic disease

Krentz¹

2016

Cardiovascular Endocrinology

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The latest estimates for global diabetes prevalence will no doubt concentrate the thoughts of healthcare officials in many countries [1]. Global age-standardized diabetes prevalence increased from 4.3% (95% credible interval 2.4-7.0) in 1980 to 9.0% (7.2-11.1) in 2014 in men, and from 5.0% (2.9-7.9) to 7.9% (6.4-9.7) in women. Thus, over a quarter of a century, the prevalence of diabetes more than doubled in men. The increase seen in women was less pronounced at 60%. These data are consistent with other reports that support a shift from an excess prevalence in women in the earlier part of the 20th century to a consistently higher male prevalence [2,3]. The male predominance in type 2 diabetes has implications for cardiometabolic disease prevention strategies that extend to population screening. For example, in the Rancho Bernardo Study, more women than men had isolated postchallenge (oral glucose tolerance test) hyperglycaemia as the only evidence of diabetes; the incidence of diabetes was higher in men than in women, with higher fasting but lower postchallenge glucose levels compared with women [3]. The prevalence of prediabetes syndromes that is, impaired fasting glucose and impaired glucose tolerancealso differs by sex, with impaired fasting glucose being more prevalent in men and impaired glucose tolerance being more frequent in women [4]. Editorial 352162-688X

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Effects of testosterone replacement on glucose and lipid metabolism

Cited by 5 publications

References 48 publications

Discovery of Novel Trans-Ancestry and Ancestry-Specific Gene Loci for Total Testosterone in a Multi-Ancestral Analysis of Men in the Million Veteran Program

Discovery of Novel Trans-Ancestry and Ancestry-Specific Gene Loci for Total Testosterone in a Multi-Ancestral Analysis of Men in the Million Veteran Program

Baseline testosterone level may modulate statin efficacy

Venus and Mars: influence of sex on diabetes and cardiometabolic disease

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