angel30l482866

angel30l482866

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Sexual dimorphism arises owing to sex differences in gene expression, and steroid hormones are often invoked as a proximate cause of sexual dimorphism. Despite these challenges, in this study we highlight several previously unreported, albeit often expected relationships with genetically determined T levels, human health, and sex differences. Yet we show that the T measures from two distinct visits are highly correlated in both sexes, which together with the robust genetic findings illustrates that the data allows for estimating how variable T levels relate to adult health. This in turn might partly promote the widespread sex differences across multiple traits, and the unique sex-specificity of genetics of T.
We additionally performed SHBG-adjusted PGS associations to all endpoints to control for the effects of SHBG on total and free T associations. Variants in chromosomes 1–22 and chromosome X (imputed with high confidence, imputation INFO ≥ 0.7) were included (total number of variants ranging from 6,535,263 for female total T to 6,536,405 for female SHBG) and we used genotype dosages to incorporate imputation uncertainty. For the genetic correlation analyses in LDSC, pre-computed LD Scores from 1000 Genomes Europeans, excluding the HLA region were used. To construct PGSs we applied the LDpred39 method to the sex-specific GWAS summary statistics from the UK Biobank for total T, SHBG, FAI and free T, using 1000 Genomes Europeans as LD reference and the default LD radius to account for LD. For pathway analysis, to assess whether the genes in the GWAS loci are overrepresented in pre-defined gene sets via hypergeometric tests, we selected manually curated KEGG-pathways36.
Mitochondrial biogenesis needs the expression of numerous genes encoded by both nuclear and mitochondrial genomes . It is worth mentioning that this study was an initial approach to align a large number of testosterone-related SNPs with physiological and functional data in elite athletes. It is unknown how the GRAMD1B rs affects testosterone levels; however, this gene has been shown to be expressed differently between resistance and endurance training—opposite ends of the training-induced muscle adaptation continuum (Vissing and Schjerling 2014). We did not assess the participants' estrogen levels, but a recent study showed that a cluster of testosterone-increasing alleles also increased estradiol levels in men (consistent with the physiological conversion of testosterone to estrogen) (Ruth et al. 2020). The physiological implication of higher testosterone levels in skeletal muscle is the maintenance or increase (hypertrophy) of skeletal muscle mass, and a subsequent indirect increase in muscle strength, which can be advantageous for power athletes.
We then investigated the effects of the PGSs on a wide range of diseases across diverse clinical entities using the FinnGen study. Although demographic phenomena such as assortative mating (mate choice based on similar characteristics in spouse) may affect effect estimates for measures such as educational attainment, based on within-sibship GWAS46 biochemical traits such as T levels seem to less affected by such confounders. Alternatively, older research cohorts, collected prior the start of FinnGen (in August 2017), were collected based on study-specific consents and later transferred to the Finnish biobanks after approval by Valvira, the National Supervisory Authority for Welfare and Health. Although in both the PGS and causality analyses we opted for adjusting for the effects of SHBG, BMI, PCOS and menopause in women—(Supplementary Data 7–12 and Supplementary Fig. 10)42,43,44,45—we remind that related factors may still confound our findings.
Workers in 3M in Cottage Groove of the United States that produced PFOA had higher serum level of PFOA and decreased serum T concentrations 39,40. The serum levels of PFOS, PFOA and PFHxS in the United States in 2006 are about 14.7, 3.4 and 1.5 ng/mL, respectively . The levels of PFOS, PFOA and PFHxS in the blood of human subjects are related to the exposure level and duration. Inhibitors of enzymes for testosterone biosynthesis and metabolic activation. Although some other toxicants (like PCB congeners) that also interfere with steroidogenic machinery, they are not included in this review because none were reported to directly inhibit steroidogenic enzymes. Recently, human SRD5A3 was identified after a genome wide screening of hormone-refractory prostate cancer cDNAs . A mutation of CYP17A1 alters the conversion of progesterone to androstenedione in the male, leading to defective masculinization that can range from partial to complete pseudohermaphroditism and breast enlargement 18,19.
Levels of T, however, appear to be correlated between males and females across species, which creates the potential for conflict over optimal circulating levels – given that traits that are beneficial in males may be detrimental in females . Selection often favors different traits or trait values in males and females, giving rise to sexually antagonistic selection –. Focusing on two brain regions involved in sexually dimorphic behavior and regulation of hormone secretion, we identified 651 genes that differed in expression by sex in medial amygdala and 611 in hypothalamus. Experimental elevation of androgens can modify behavior, physiology, and gene expression, but knowledge of the role of hormones remains incomplete, including how the sexes differ in gene expression in response to hormones.
B Overview of the study design to assess the contribution of T to health and disease using genetic approaches and biobank data. This difference largely results from the testicular T production in males that far exceeds the amount of T produced in the ovaries and the adrenal gland in females, and is known to directly contribute to variation in, for instance, body composition between the sexes1,12. Overall, these findings provide insight into how genetically determined testosterone correlates with several health parameters in both sexes.
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