[Genetic Causation Analysis of Hyperandrogenemia Testing Indicators and Preeclampsia]. / é«˜é›„æ¿€ç´ è¡€ç—‡æ£€æµ‹æŒ‡æ ‡ä¸Žå­ç—«å‰æœŸçš„é—ä¼ å› æžœæ€§ç ”ç©¶.

Objective: Some epidemiological studies have shown that pregnant women who develop preeclampsia (PE) have elevated levels of testosterone in their maternal plasma compared to women with normal blood pressure during pregnancy, revealing a potential association between hyperandrogenism in women and PE. To explore the causal relationship between hyperandrogenism and PE, this study selected total testosterone (TT), bioavailable testosterone (BIOT), and sex hormone binding globulin (SHBG) as exposure factors and PE and chronic hypertension with superimposed PE as disease outcomes. Two-sample Mendelian randomization (MR) analyses were used to genetically dissect the causal relationships between the three exposure factors (TT, BIOT, and SHBG) and the outcomes of PE and chronic hypertension with superimposed PE. Methods: Two independent genome-wide association study (GWAS) databases were used for the two-sample MR analysis. In the GWAS data of female participants from the UK Biobank cohort, single nucleotide polymorphisms (SNPs) associated with TT, BIOT, and SHBG were analyzed, involving 230454, 188507, and 188908 samples, respectively. GWAS data on PE and chronic hypertension with superimposed PE from the Finnish database were used to calculate SNP, involving 3556 PE cases and 114735 controls, as well as 38 cases of chronic hypertension with superimposed PE and 114735 controls. To meet the assumptions of instrumental relevance and independence in MR analysis, SNPs associated with exposure were identified at the genome-wide level (P<5.0×10-8), and those in linkage disequilibrium interference were excluded based on clustering thresholds of R 2<0.001 and an allele distance greater than 10000 kb. Known confounding factors, including previous PE, chronic kidney disease, chronic hypertension, diabetes, systemic lupus erythematosus, or antiphospholipid syndrome, were also identified and the relevant SNPs were removed. Finally, we extracted the outcome data based on the exposure-related SNPs in the outcome GWAS, integrating exposure and outcome data, and removing palindromic sequences. Five genetic causal analysis methods, including inverse variance-weighted method (IVW), MR-Egger regression, weighted median method, simple mode method, and weighted mode method, were used to infer causal relationships. In the IVW, it was assumed that the selected SNPs satisfied the three assumptions and provided the most ideal estimate of the effect. IVW was consequently used as the primary analysis method in this study. Considering the potential heterogeneity among the instrumental variables, random-effects IVW was used for MR analysis. The results were interpreted using odds ratios (OR) and the corresponding 95% confidence interval (CI) to explain the impact of exposure factors on PE and chronic hypertension with superimposed PE. If the CI did not include 1 and had a P value less than 0.05, the difference was considered statistically significant. Sensitivity analysis was conducted to assess heterogeneity and pleiotropy. Heterogeneity was examined using Cochran's Q test, and pleiotropy was assessed using MR-Egger intercept analysis. Additionally, leave-one-out analysis was conducted to examine whether individual SNPs were driving the causal associations. To further validate the findings, MR analyses were performed using the same methods and outcome variables, but with different exposure factors, including waist-to-hip ratio adjusted for BMI (WHRadjBMI) and 25-hydroxyvitamin D levels, with MR results for WHRadjBMI and PE serving as the positive controls and MR results for 25-hydroxyvitamin D levels and PE as the negative controls. Results: According to the criteria for selecting genetic instrumental variables, 186, 127, and 262 SNPs were identified as genetic instrumental variables significantly associated with testosterone indicators TT, BIOT, and SHBG. MR analysis did not find a causal relationship between the TT, BIOT, and SHBG levels and the risk of developing PE and chronic hypertension with superimposed PE. The IVW method predicted that genetically predicted TT (OR [95% CI]=1.018 [0.897-1.156], P=0.78), BIOT (OR [95% CI]=1.11 [0.874-1.408], P=0.392), and SHBG (OR [95% CI]=0.855 [0.659-1.109], P=0.239) were not associated with PE. Similarly, genetically predicted TT (OR [95% CI]=1.222 [0.548-2.722], P=0.624), BIOT (OR [95% CI]=1.066 [0.242-4.695], P=0.933), and SHBG (OR [95% CI]=0.529 [0.119-2.343], P=0.402) were not significantly associated with chronic hypertension with superimposed PE. Additionally, MR analysis using the MR-Egger method, weighted median method, simple mode method, and weighted mode method yielded consistent results, indicating no significant causal relationship between elevated testosterone levels and PE or chronic hypertension with superimposed PE. Heterogeneity was observed for SHBG in the analysis with PE (Cochran's Q test, P=0.01), and pleiotropy was detected for BIOT in the analysis with PE (MR-Egger intercept analysis, P=0.014), suggesting that the instrumental variables did not affect PE through BIOT. Other instrumental variables did not show significant heterogeneity or pleiotropy. Leave-one-out analysis confirmed that the results of the MR analysis were not driven by individual instrumental variables. Consistent with previous MR studies, the results of the control MR analyses using WHRadjBMI and 25-hydroxyvitamin D levels supported the accuracy of the MR analysis approach and the methods used in this study. Conclusion: The MR analysis results suggest that current genetic evidence does not support a causal relationship between TT, BIOT, and SHBG levels and the development of PE and chronic hypertension with superimposed PE. This study suggests that elevated testosterone may be a risk factor for PE but not a direct cause.

Decoding connections in the European population: serum uric acid, sex hormone-binding globulin, total testosterone, estradiol, and female infertility - advanced bidirectional and mediative Mendelian randomization.

Background: Despite observational links between serum uric acid (SUA), sex hormone-related phenotypes, and female infertility, the causality behind these associations remains uncertain. Objective: This study utilizes Bidirectional Two-Sample and Mediation Mendelian Randomization to explore the causal relationships and mediation effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and estradiol on these associations. Methods: We analyzed single-nucleotide polymorphisms (SNPs) associated with SUA and sex hormone levels using data from large-scale GWAS of European populations. Female infertility data were sourced from 6,481 cases and 75,450 controls in the FinnGen Consortium. We employed methods including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger regression to assess causality. Results: We found that elevated SUA levels causally increase the risk of female infertility (IVW OR: 1.13, P=0.047). Elevated SUA levels significantly decrease SHBG levels (ß=-0.261; P=2.177e-04), with SHBG mediating 27.93% of the effect of SUA on infertility (OR=0.854; 95%CI, 0.793-0.920; P=2.853e-05). Additionally, elevated TT levels, which were associated with decreased SUA levels (ß=-0.127), showed an indirect effect on infertility mediated by SUA (ß=-0.0187; 95% CI, -0.041 to -0.003; P=0.046). Conclusion: Our findings demonstrate causal links between high SUA and increased risk of female infertility mediated by hormonal factors such as SHBG and TT. These insights suggest new avenues for infertility treatment and highlight the need for further research into these mechanisms.

Examining the causal relationship between sex hormone-binding globulin (SHBG) and infertility: A Mendelian randomization study.

BACKGROUND: The causal relationship between sex hormone-binding globulin (SHBG) and infertility has remained unclear. Thus, we used Mendelian randomization (MR) to investigate this relationship. METHODS: Risk factors for SHBG were extracted from European individuals within the UK Biobank using single-nucleotide polymorphism (SNP) data. Summary-level data for infertility outcomes were obtained from the FinnGen dataset. The causal relationship between SHBG and infertility was examined using inverse variance weighted, weighted model, weighted median, and MR-Egger regression analyses. Additionally, Cochran's Q test and Egger intercept tests were used to confirm the heterogeneity and pleiotropy of identified instrumental variables (IVs). RESULTS: Our findings revealed a significant negative association between sex hormone-binding globulin (SHBG) levels and infertility, particularly with anovulation, a specific form of female infertility. However, SHBG did not exert a causal impact on male infertility or on female infertility of tubal origin. CONCLUSIONS: SHBG expression offers protection against the development of certain types of female infertility, suggesting it is a potential therapeutic target for infertility.

Genetically predicted high sex hormone binding globulin was associated with decreased risk of polycystic ovary syndrome.

BACKGROUND: Previous observational studies have indicated an inverse correlation between circulating sex hormone binding globulin (SHBG) levels and the incidence of polycystic ovary syndrome (PCOS). Nevertheless, conventional observational studies may be susceptible to bias. Consequently, we conducted a two-sample Mendelian randomization (MR) investigation to delve deeper into the connection between SHBG levels and the risk of PCOS. METHODS: We employed single-nucleotide polymorphisms (SNPs) linked to serum SHBG levels as instrumental variables (IVs). Genetic associations with PCOS were derived from a meta-analysis of GWAS data. Our primary analytical approach relied on the inverse-variance weighted (IVW) method, complemented by alternative MR techniques, including simple-median, weighted-median, MR-Egger regression, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) testing. Additionally, sensitivity analyses were conducted to assess the robustness of the association. RESULTS: We utilized 289 SNPs associated with serum SHBG levels, achieving genome-wide significance, as instrumental variables (IVs). Our MR analyses revealed that genetically predicted elevated circulating SHBG concentrations were linked to a reduced risk of PCOS (odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.39-0.78, P = 8.30 × 10-4) using the IVW method. MR-Egger regression did not detect any directional pleiotropic effects (P intercept = 0.626). Sensitivity analyses, employing alternative MR methods and IV sets, consistently reaffirmed our results, underscoring the robustness of our findings. CONCLUSIONS: Through a genetic epidemiological approach, we have substantiated prior observational literature, indicating a potential causal inverse relationship between serum SHBG concentrations and PCOS risk. Nevertheless, further research is needed to elucidate the underlying mechanism of SHBG in the development of PCOS.

Sex hormone binding globulin (SHBG) modulates mitochondrial dynamics in PPARγ-depleted equine adipose derived stromal cells.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that promotes adipogenesis, lipid uptake and storage, insulin sensitivity, and glucose metabolism. Hence, defects in PPARγ have been associated to the development of metabolic disorders. Sex hormone-binding globulin (SHBG) is a glycoprotein primarily produced in the liver that regulates the bioavailability of sex hormones. Alike PPARγ, low SHBG levels have been correlated with insulin resistance and associated endocrine abnormalities. Therefore, this study aimed to verify whether SHBG may restore depleted PPARγ functions and thus serve as a new candidate for the management of metabolic conditions. A model of equine adipose-derived stromal cells (EqASCs) has been used, in which a PPARγ silencing and SHBG treatment have been achieved to determine the changes in cell viability, premature senescence, oxidative stress, and mitochondrial functions. Obtained data demonstrated that loss in PPARγ triggers cell apoptosis which is not reversed by SHBG application. Moreover, PPARγ knockdown cells exhibited premature senescence, which has been substantially alleviated by SHBG concomitantly to increased BAX/BCL2 ratio, suggesting a possible effect on senescence-induced apoptosis resistance. Interestingly, PPARγ silencing induced a significant alteration in mitochondrial membrane potential as well as the expression of dynamics and metabolism-related markers. SHBG treatment enabled to ameliorate the transmembrane potential, to normalize the expression levels of key dynamics and metabolism mediators, and to restore the protein levels of PINK, which is critically involved in mitochondria recycling machinery. Presented data suggest that SHBG may provide new mechanistic insights into the regulation of PPARγ functions, and thus offers a preliminary picture on a possible SHBG-PPARγ metabolic crosstalk. KEY MESSAGES : PPARγ is a transcription factor that tightly regulates cell metabolism. Low SHBG levels correlate with insulin resistance and associated endocrine abnormalities. PPARγ silencing reduces cell viability, triggers premature senescence and profound mitochondrial failure in equine ASCs. SHBG protein reverses senescent phenotype and apoptosis resistance of PPARγ- ASCs. SHBG improves mitochondrial dynamics and metabolism following PPARγ knockdown. SHBG might serve as a PPARγ potential mimicking agent for the modulation of ASCs metabolic processes.

Hyperglycemia Inhibits Hepatic SHBG Synthesis Through the NGBR-AMPK-HNF4 Pathway in Rats with Polycystic Ovary Syndrome Induced by Letrozole in Combination with a High-Fat Diet.

SCOPE: Polycystic ovary syndrome (PCOS) is closely related to non-alcoholic fatty liver disease (NAFLD), and sex hormone-binding globulin (SHBG) is a glycoprotein produced by the liver. Hepatic lipogenesis inhibits hepatic SHBG synthesis, which leads to hyperandrogenemia and ovarian dysfunction in PCOS. Therefore, this study aims to characterize the mechanism whereby liver lipogenesis inhibits SHBG synthesis. METHODS AND RESULTS: This study establishes a rat model of PCOS complicated by NAFLD using a high-fat diet in combination with letrozole and performs transcriptomic analysis of the liver. Transcriptomic analysis of the liver shows that the expression of neurite growth inhibitor-B receptor (NgBR), hepatocyte nuclear factor 4α (HNF4α), and SHBG is low. Meantime, HepG2 cells are treated with palmitic acid (PA) to model NAFLD in vitro, which causes decreases in the expression of NgBR, HNF4α, and SHBG. However, the expression of HNF4α and SHBG is restored by treatment with the AMP-activated protein kinase (AMPK) agonist AICAR. CONCLUSIONS: NgBR regulates the expression of HNF4α by activating the AMPK signaling pathway, thereby affecting the synthesis of SHBG in the liver. Further mechanistic studies regarding the effect of liver fat on NGBR expression are warranted.

Association of genetically determined chronotype with circulating testosterone: a Mendelian randomization study.

Low testosterone levels in men have been linked to decreased physical and mental function, as well as a reduced quality of life. Previous prospective observational studies have suggested an association between testosterone and sleep traits, but the causality of this relationship remains unclear. We aimed to explore the potential causal link between genetically determined sleep traits and testosterone levels in men using Mendelian randomization (MR) analysis from the UK Biobank dataset. Our exposures were genetic variants associated with sleep traits (chronotype and sleep duration), whereas our outcomes were traits of sex steroid hormones (total testosterone, TT; bioavailable testosterone, BAT; and sex hormone-binding globulin, SHBG). We employed inverse variance weighted (IVW) and weighted median (WM) methods to assess the causal associations. The IVW method offers a robust estimate of causality, whereas the WM method provides reliable results even when some genetic variants are invalid instruments. Our main analysis involving sex steroid hormones and chronotype identified 155 chronotype-related variants. The primary findings from the analysis, which used chronotype as the exposure and sex steroid hormones as the outcomes, showed that a genetically predicted chronotype score was significantly associated with an increased levels of TT (association coefficient ß, 0.08; 95% confidence interval [CI], 0.02-0.14; P = 0.008) and BAT (ß, 0.08; 95% CI, 0.02-0.14; P = 0.007), whereas there was no significant association with SHBG (ß, 0.01; 95% CI, -0.02-0.03; P = 0.64). Meanwhile, MR analysis of sex steroid hormones and sleep duration was performed, and 69 variants associated with sleep duration were extracted. There were no significant association between sleep duration and sex steroid hormones (TT, P = 0.91; BAT, P = 0.82; and SHBG, P = 0.95). Our data support a causal association between chronotype and circulating testosterone levels in men. These findings underscore a potential causal relationship between chronotype and testosterone levels in men, suggesting that lifestyle adjustments are crucial for men's health. Recognizing factors that influence testosterone is essential. One limitation of this study is the use of one-sample MR, which can introduce potential bias due to non-independence of genetic associations for exposure and outcome. In conclusion, our findings indicate that a morning preference is correlated with circulating testosterone levels, emphasizing the potential impact of lifestyle habits on testosterone levels in men.

Blood lipid levels mediating the effects of sex hormone-binding globulin on coronary heart disease: Mendelian randomization and mediation analysis.

Observational studies indicate that serum sex hormone-binding globulin (SHBG) levels are inversely correlated with blood lipid levels and coronary heart disease (CHD) risk. Given that dyslipidemia is an established risk factor for CHD, we aim to employ Mendelian randomization (MR) in conjunction with mediation analysis to confirm the mediating role of blood lipid levels in the association between SHBG and CHD. First, we assessed the causality between serum SHBG levels and five cardiovascular diseases using univariable MR. The results revealed causality between SHBG levels and reduced risk of CHD, myocardial infarction, as well as hypertension. Specifically, the most significant reduction was observed in CHD risk, with an odds ratio of 0.73 (95% CI 0.63-0.86) for each one-standard-deviation increase in SHBG. The summary-level data of serum SHBG levels and CHD are derived from a sex-specific genome-wide association study (GWAS) conducted by UK Biobank (sample size = 368,929) and a large-scale GWAS meta-analysis (60,801 cases and 123,504 controls), respectively. Subsequently, we further investigated the mediating role of blood lipid level in the association between SHBG and CHD. Mediation analysis clarified the mediation proportions for four mediators: high cholesterol (48%), very low-density lipoprotein cholesterol (25.1%), low-density lipoprotein cholesterol (18.5%), and triglycerides (44.3%). Summary-level data for each mediator were sourced from the UK Biobank and publicly available GWAS. The above results confirm negative causality between serum SHBG levels and the risk of CHD, myocardial infarction, and hypertension, with the causal effect on reducing CHD risk largely mediated by the improvement of blood lipid profiles.

Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

Associations between sex hormones, receptors, binding proteins and inflammatory bowel disease: a Mendelian randomization study.

Background: Gender differences existed in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Observational studies have revealed associations between sex hormones and IBD, such as estrogen and testosterone. However, the exact relationship between these sex hormones and IBD is unclear. Method: Based on the genome-wide association studies data of eight sex hormones, two sex hormone receptors, sex hormone-binding globulin (SHBG), total IBD and its two subtypes, we performed a two-sample Mendelian randomization (MR) study to analyze their mutual relationship. For estradiol (E2), progesterone (PROG), bioavailable testosterone (BAT), total testosterone (TT) and SHBG, sex-stratified MR analyses were also performed. Inverse variance weighted method, MR-Egger regression and Weighted median method were used for causal analyses. Sensitivity analyses were conducted to test the stability of causal relationships. Besides, a reverse MR analysis was performed to estimate the reverse causation. Results: E2 (P=0.028) and TT (P=0.034) had protective effects on CD. Sex-stratified analyses revealed protective roles of E2 in males on total IBD (P=0.038) and CD (P=0.020). TT in females had protective effects on total IBD (P=0.025) and CD (P=0.029), and BAT in females decreased the risk of developing CD (P=0.047) and UC (P=0.036). Moreover, SHBG in males was also associated with a decreased risk of CD (P=0.021). The reversed MR analysis showed that CD was negatively correlated with estrogen receptor (P=0.046). UC was negatively correlated with PROG in females (P=0.015) and positively correlated with SHBG levels in males (P=0.046). Conclusion: Findings of this study revealed the mutual causal associations between sex hormones and the risk of developing IBD.

Compensated Hypogonadism Identified in Males with Cluster Headache: A Prospective Case-Controlled Study.

OBJECTIVE: Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear. METHODS: We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations. RESULTS: The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%-47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%-37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified. INTERPRETATION: Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024;95:1149-1161.

Sex hormones and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study.

BACKGROUND: Females are considered to have an increased susceptibility to neuromyelitis optica spectrum disorder (NMOSD) than males, especially aquaporin-4 (AQP4) antibody positive NMOSD, indicating that sex hormones may be involved in the NMOSD pathogenesis. However, the causality between sex hormones and NMOSD still remains unclear. METHODS: Based on the genome-wide association study (GWAS) data of three sex hormones (estradiol (E2), progesterone (PROG) and bioavailable testosterone (BAT)), sex hormone-binding globulin (SHBG), age of menarche, age of menopause, and NMOSD (total, AQP4 + and AQP4 -), we performed a two-sample bidirectional Mendelian randomization (MR) study. Sex-stratified GWAS data of E2, PROG, BAT, and SHBG was obtained for gender-specific MR analysis. Causal inferences were based on the inverse variance weighted method, MR-Egger regression, and weighted median method. The reverse MR analysis was also performed to assess the impact of NMOSD on hormone levels. RESULTS: PROG in females had aggravative effects on NMOSD (P < 0.001), especially AQP4 - NMOSD (P < 0.001). In the reverse MR analysis, total NMOSD was found to decrease the level of BAT (P < 0.001) and increase the level of SHBG (P = 0.001) in females. CONCLUSION: Findings of this MR analysis revealed mutual causal associations between sex hormones and NMOSD, which provided novel perspectives about the gender-related pathogenesis of NMOSD.

Genetically predicted high serum sex hormone-binding globulin levels are associated with lower ischemic stroke risk: A sex-stratified Mendelian randomization study.

OBJECTIVE: Cross-sectional and cohort studies have found insufficient evidence of a causal relationship between sex hormone-binding globulin and ischemic stroke, only associations. Here, we performed a sex-stratified, bidirectional, two-sample Mendelian randomization analysis to evaluate whether a causal relationship exists between sex hormone-binding globulin and ischemic stroke. METHODS: Single-nucleotide polymorphisms associated with sex hormone-binding globulin and ischemic stroke were screened from genome-wide association studies summary data as instrumental variables to enable a bidirectional, two-sample Mendelian randomization study design. Inverse-variance weighted analysis was used as the main method to evaluate potential causality, and additional methods, including the weighted median and MR-Egger tests, were used to validate the Mendelian randomization results. Cochran's Q statistic, MR-Egger intercept test, and Mendelian Randomization-Pleiotropy Residual Sum and Outlier global test were used as sensitivity analysis techniques to assure the reliability of the results. Multivariable analysis was used to show the robustness of the results with key theorized confounders. RESULTS: Inverse-variance weighted analysis showed that genetically predicted higher serum sex hormone-binding globulin levels were associated with significantly decreased risk of ischemic stroke in males (odds radio = 0.934, 95 % confidence interval = 0.885-0.985, P = 0.012) and females (odds radio = 0.924, 95 % confidence interval = 0.868-0.983, P = 0.013). In an analysis of ischemic stroke subtypes, genetically predicted higher serum sex hormone-binding globulin levels were also associated with significantly decreased risk of small-vessel occlusion in both males (odds radio = 0.849, 95 % confidence interval = 0.759-0.949, P = 0.004) and females (odds radio = 0.829, 95 % confidence interval = 0.724-0.949, P = 0.006). The association remained in sensitivity analyses and multivariable analyses. The reverse analysis suggested an association between genetically predicted risk of cardioembolism and increased serum sex hormone-binding globulin in females (Beta = 0.029 nmol/L, Standard Error = 0.010, P = 0.003). CONCLUSION: Our findings provide new insight into the etiology of ischemic stroke and suggest that modulating serum sex hormone-binding globulin may be a therapeutic strategy to protect against ischemic stroke.

Causal relationship between gut microbiome and sex hormone-binding globulin: A bidirectional two-sample Mendelian randomization study.

PROBLEM: Currently, there is a variety of evidence linking the gut microbiota to changes in sex hormones. In contrast, the causal relationship between SHBG, a carrier of sex hormones, and the gut microbiota is unclear. METHOD OF STUDY: Bidirectional two-sample Mendelian randomization (MR) analysis was used to detect the causal effect between SHBG and the gut microbiome. Summary statistics of genome-wide association studies (GWASs) for the gut microbiome and SHBG were obtained from public datasets. Inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger and simple mode methods were used to operate the MR analysis. F-statistics and sensitivity analyses performed to evaluate bias and reliability. RESULTS: When we set gut microbiome as exposure and SHBG as outcome, we identified nine causal relationships. In males, Coprobacter (PIVW = 2.01 × 10-6 ), Ruminococcus2 (PIVW = 3.40 × 10-5 ), Barnesiella (PIVW = 2.79 × 10-2 ), Actinobacteria (PIVW = 3.25 × 10-2 ) and Eubacterium fissicatena groups (PIVW = 3.64 × 10-2 ) were associated with lower SHBG levels; Alphaproteobacteria (PIVW = 1.61 × 10-2 ) is associated with higher SHBG levels. In females, Lachnoclostridium (PIVW = 9.75 × 10-3 ) and Defluviitaleaceae UCG011 (PIVW = 3.67 × 10-2 ) were associated with higher SHBG levels; Victivallaceae (PIVW = 2.23 × 10-2 ) was associated with lower SHBG levels. According to the results of reverse MR analysis, three significant causal effect of SHBG was found on gut microbiota. In males, Dorea (PIVW = 4.17 × 10-2 ) and Clostridiales (PIVW = 4.36 × 10-2 ) were associated with higher SHBG levels. In females, Lachnoclostridium (PIVW = 7.44 × 10-4 ) was associated with higherr SHBG levels. No signifcant heterogeneity of instrumental variables or horizontal pleiotropy was found in bidirectional two-sample MR analysis. CONCLUSIONS: This study may provide new insights into the causal relationship between the gut microbiome and sex hormone-binding protein levels, as well as new treatment and prevention strategies for diseases such as abnormal changes in sex hormones.

Sex-Hormone-Binding Globulin Gene Polymorphisms and Breast Cancer Risk in Caucasian Women of Russia.

In our work, the associations of GWAS (genome-wide associative studies) impact for sex-hormone-binding globulin (SHBG)-level SNPs with the risk of breast cancer (BC) in the cohort of Caucasian women of Russia were assessed. The work was performed on a sample of 1498 women (358 BC patients and 1140 control (non BC) subjects). SHBG correlated in previously GWAS nine polymorphisms such as rs780093 GCKR, rs17496332 PRMT6, rs3779195 BAIAP2L1, rs10454142 PPP1R21, rs7910927 JMJD1C, rs4149056 SLCO1B1, rs440837 ZBTB10, rs12150660 SHBG, and rs8023580 NR2F2 have been genotyped. BC risk effects of allelic and non-allelic SHBG-linked gene SNPs interactions were detected by regression analysis. The risk genetic factor for BC developing is an SHBG-lowering allele variant C rs10454142 PPP1R21 ([additive genetic model] OR = 1.31; 95%CI = 1.08-1.65; pperm = 0.024; power = 85.26%), which determines 0.32% of the cancer variance. Eight of the nine studied SHBG-related SNPs have been involved in cancer susceptibility as part of nine different non-allelic gene interaction models, the greatest contribution to which is made by rs10454142 PPP1R21 (included in all nine models, 100%) and four more SNPs-rs7910927 JMJD1C (five models, 55.56%), rs17496332 PRMT6 (four models, 44.44%), rs780093 GCKR (four models, 44.44%), and rs440837 ZBTB10 (four models, 44.44%). For SHBG-related loci, pronounced functionality in the organism (including breast, liver, fibroblasts, etc.) was predicted in silico, having a direct relationship through many pathways with cancer pathophysiology. In conclusion, our results demonstrated the involvement of SHBG-correlated genes polymorphisms in BC risk in Caucasian women in Russia.

The Association Between SHBG and Osteoporosis: A NHANES Cross-Sectional Study and A Bidirectional Mendelian Randomization.

This study aimed to examine the association between sex hormone-binding globulin (SHBG) and osteoporosis through a cross-sectional study and a two-sample bidirectional Mendelian randomization (MR). We used the National Health and Nutrition Examination Survey (NHANES) 2013-2014 and 2015-2016 data, with exposure as serum SHBG and outcome as osteoporosis and performed multivariate logistic regression to test the correlation between SHBG and osteoporosis. To determine the causal relationship between SHBG and osteoporosis, a two-sample bidirectional MR was employed. The genome-wide association study (GWAS) dataset for SHBG (n = 189,473) was obtained from the IEU database, and the GWAS dataset for osteoporosis (n = 212,778) was obtained from the FinnGen bioBank. The principal MR technique was inverse-variance weighting (IVW). In MR analyses, the MR-Egger intercept and Cochran Q test were used to detect multiple validity and horizontal heterogeneity. 1249 older adult participants (age ≥ 60) were involved in the cross-sectional study, including 113 osteoporosis cases. We identified a significant relationship between circulating SHBG concentration and osteoporosis risk [OR 3.963, 95% CI (2.095-7.495), P < 0.05]. Subgroup analysis indicated that SHBG was closely linked to the risk of osteoporosis in the female population [OR 1.008, 95% CI (1.002-1.013), P = 0.005] but not in males (P = 0.065). In addition, The IVW approach suggested a causal connection between SHBG and increased osteoporosis risk [OR 1.479, 95% CI (1.144-1.912), P = 0.003], and the MR-Egger intercept and the Cochran Q test validated the consistency of the MR results. Finally, the reverse MR analysis declined to identify a causal relation between SHBG and osteoporosis. Our research demonstrates a significant causal connection between circulating SHBG levels and increased osteoporosis risk. These results indicate that high SHBG may be associated with the risk of osteoporosis in postmenopausal women, but more research is needed.

Exploring Causal Relationships between Leukocyte Telomere Length, Sex Hormone-Binding Globulin Levels, and Osteoporosis Using Univariable and Multivariable Mendelian Randomization.

OBJECTIVE: Recent evidence supports that leukocyte telomere length (LTL) may be positively associated with healthy living and inversely correlated with the risk of age-related diseases, including osteoporosis. Furthermore, it is important to note that sex hormone-binding globulin (SHBG) levels play a crucial role in the regulation of osteoporosis by influencing the availability of sex hormones. Hence, this study holds significant importance as it aims to unravel the roles of LTL and SHBG levels and determine which one acts as a predominant intermediary factor in influencing osteoporosis. Using Mendelian randomization (MR), we can gain valuable insights into the intricate relationships between aging, sex hormones, and bone health. METHODS: Univariable and multivariable and MR analyses were employed in this study. First, we used genetic variants associated with both LTL, as determined from a study involving 472,174 European participants by Codd et al., and SHBG levels, as identified in a study conducted by Ruth et al. with 370,125 participants, as instrumental variables (IVs). Then we aimed to establish a causal relationship between LTL and SHBG levels and their potential impact on osteoporosis using univariable MR. Finally, we conducted multivariable MR to provide insights into the independent and combined effects of LTL, SHBG levels on osteoporosis risk. We used various MR methods, with the primary analysis employing the inverse-variance weighted (IVW) model. RESULTS: Univariable MR analysis reveals a potential causal effect of longer LTL on reduced risk of osteoporosis [odds ratio (OR): 0.85; 95% confidence interval (CI): 0.73-0.99; p = 0.03]. Conversely, higher genetically determined SHBG levels affect the risk of osteoporosis positively. (OR: 1.38; 95% CI: 1.09-1.75; p < 0.01). We observed a negative causal effect for LTL on the occurrence of SHBG (OR: 0.96; 95% CI 0.94-0.98, p < 0.01). After adjustment of using multivariable MR, the causal effect of LTL on osteoporosis (OR: 0.92; 95% CI: 0.84-1.03; p = 0.14), and the effect of SHBG on osteoporosis (OR: 1.43; 95% CI: 1.16-1.75; p < 0.01) were observed. CONCLUSION: Longer LTL may confer a protective effect against osteoporosis. Additionally, the levels of SHBG appear to play a crucial role in mediating the relationship between LTL and osteoporosis. By understanding the interplay between these factors, we can gain valuable insights into the mechanisms underlying bone health and aging and potentially identify new avenues for prevention and intervention strategies.

Sex hormone-binding globulin exerts sex-related causal effects on lower extremity varicose veins: evidence from gender-stratified Mendelian randomization.

Background: The association between serum sex hormones and lower extremity varicose veins has been reported in observational studies. However, it is unclear whether the association reflects a causal relationship. Besides, serum sex hormone-binding globulin (SHBG) has been rarely studied in lower extremity varicose veins. Here, we aim to investigate the association between serum levels of SHBG, testosterone, and estradiol and the risk of lower extremity varicose veins using Mendelian randomization (MR). Methods: We obtained genome-wide association study summary statistics for serum SHBG levels with 369,002 European participants, serum testosterone levels with 424,907 European participants, serum estradiol levels with 361,194 European participants, and lower extremity varicose veins with 207,055 European participants. First, a univariable MR was performed to identify the causality from SHBG and sex hormone levels to lower extremity varicose veins with several sensitivity analyses being performed. Then, a multivariable MR (MVMR) was performed to further assess whether the causal effects were independent. Finally, we performed a gender-stratified MR to understand the role of genders on lower extremity varicose veins. Results: Genetically predicted higher serum SHBG levels significantly increased the risk of lower extremity varicose veins in the univariable MR analysis (OR=1.39; 95% CI: 1.13-1.70; P=1.58×10-3). Sensitivity analyses and MVMR (OR=1.50; 95% CI:1.13-1.99; P=5.61×10-3) verified the robustness of the causal relationships. Gender-stratified MR revealed that higher serum SHBG levels were associated with lower extremity varicose veins in both sexes. However, the OR of serum SHBG levels on lower extremity varicose veins risk in females (OR=1.51; 95% CI: 1.23-1.87; P=1.00×10-4) was greater than in males (OR=1.26; 95% CI: 1.04-1.54; P=1.86×10-2). Conclusions: Serum SHBG levels are positively related to lower extremity varicose veins risk in both sexes, especially in females. This may partly explain the higher prevalence of varicose vines among females.

Association of sex hormones and sex hormone-binding globulin with liver fat in men and women: an observational and Mendelian randomization study.

Background: Sex hormones and sex hormone-binding globulin (SHBG) may play a role in fatty liver development. We sought to examine the association of various endogenous sex hormones, including testosterone (T), and SHBG with liver fat using complementary observational and Mendelian randomization (MR) analyses. Methods: The observational analysis included a total of 2,239 participants (mean age 60 years; 35% postmenopausal women) from the population-based KORA study (average follow-up time: 6.5 years). We conducted linear regression analysis to investigate the sex-specific associations of sex hormones and SHBG with liver fat, estimated by fatty liver index (FLI). For MR analyses, we selected genetic variants associated with sex hormones and SHBG and extracted their associations with magnetic resonance imaging measured liver fat from the largest up to date European genome-wide associations studies. Results: In the observational analysis, T, dihydrotestosterone (DHT), progesterone and 17α-hydroxyprogesterone (17-OHP) were inversely associated with FLI in men, with beta estimates ranging from -4.23 to -2.30 [p-value <0.001 to 0.003]. Whereas in women, a positive association of free T with FLI (ß = 4.17, 95%CI: 1.35, 6.98) was observed. SHBG was inversely associated with FLI across sexes [men: -3.45 (-5.13, -1.78); women: -9.23 (-12.19, -6.28)]. No causal association was found between genetically determined sex hormones and liver fat, but higher genetically determined SHBG was associated with lower liver fat in women (ß = -0.36, 95% CI: -0.61, -0.12). Conclusion: Our results provide suggestive evidence for a causal association between SHBG and liver fat in women, implicating the protective role of SHBG against liver fat accumulation.

Beyond apples and pears: sex-specific genetics of body fat percentage.

Introduction: Biological sex influences both overall adiposity and fat distribution. Further, testosterone and sex hormone binding globulin (SHBG) influence adiposity and metabolic function, with differential effects of testosterone in men and women. Here, we aimed to perform sex-stratified genome-wide association studies (GWAS) of body fat percentage (BFPAdj) (adjusting for testosterone and sex hormone binding globulin (SHBG)) to increase statistical power. Methods: GWAS were performed in white British individuals from the UK Biobank (157,937 males and 154,337 females). To avoid collider bias, loci associated with SHBG or testosterone were excluded. We investigated association of BFPAdj loci with high density cholesterol (HDL), triglyceride (TG), type 2 diabetes (T2D), coronary artery disease (CAD), and MRI-derived abdominal subcutaneous adipose tissue (ASAT), visceral adipose tissue (VAT) and gluteofemoral adipose tissue (GFAT) using publicly available data from large GWAS. We also performed 2-sample Mendelian Randomization (MR) using identified BFPAdj variants as instruments to investigate causal effect of BFPAdj on HDL, TG, T2D and CAD in males and females separately. Results: We identified 195 and 174 loci explaining 3.35% and 2.60% of the variation in BFPAdj in males and females, respectively at genome-wide significance (GWS, p<5x10-8). Although the direction of effect at these loci was generally concordant in males and females, only 38 loci were common to both sexes at GWS. Seven loci in males and ten loci in females have not been associated with any adiposity/cardiometabolic traits previously. BFPAdj loci generally did not associate with cardiometabolic traits; several had paradoxically beneficial cardiometabolic effects with favourable fat distribution. MR analyses did not find convincing supportive evidence that increased BFPAdj has deleterious cardiometabolic effects in either sex with highly significant heterogeneity. Conclusions: There was limited genetic overlap between BFPAdj in males and females at GWS. BFPAdj loci generally did not have adverse cardiometabolic effects which may reflect the effects of favourable fat distribution and cardiometabolic risk modulation by testosterone and SHBG.