Dataset Information

Sex Hormones and Risk of Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study.

ABSTRACT:

Background

The risk of aneurysmal subarachnoid hemorrhage (aSAH) is increased in postmenopausal women compared with men of similar age, suggesting a role for sex hormones. We aimed to explore whether sex hormones, and age at menarche/menopause have a causal effect on aSAH risk by conducting a 2-sample MR study (Mendelian randomization).

Methods

We obtained sex-specific genetic instruments for serum estradiol, bioavailable testosterone (BioT), SHBG (sex hormone-binding globulin), and age at menarche/menopause from genome-wide association studies. The associated sex-specific aSAH risk was estimated with inverse-variance weighted MR analyses with various statistical sensitivity analyses. Multivariable and cluster MR analyses were performed for BioT and SHBG to account for a genetic and phenotypic correlation between the 2 exposures. The clusters represented (1) single-nucleotide polymorphisms primarily increasing SHBG, with secondary decreasing effects on BioT, and (2) single-nucleotide polymorphisms affecting BioT without affecting SHBG.

Results

Univariable MR analyses showed an 18% increased aSAH risk among women per 1-SD increase in genetically determined SHBG levels (odds ratio, 1.18 [95% CI, 1.05-1.34]; P=0.007). Suggestive evidence was identified for a 27% decreased risk of aSAH among women per 1-SD increase in BioT (odds ratio, 0.73 [95% CI, 0.55-0.95]; P=0.02). The latter association disappeared in cluster analysis when only using SHBG-independent variants. MR analyses with variants from the cluster with primary SHBG effects and secondary (opposite) BioT-effects yielded a statistically significant association (odds ratio, 1.21 [95% CI, 1.05-1.40]; P=0.008). No other causal associations were identified.

Conclusions

Genetic predisposition to elevated serum levels of SHBG, with secondary lower serum BioT levels, is associated with an increased aSAH risk among women, suggesting that SHBG and BioT causally elevate aSAH risk. Further studies are required to elucidate the underlying mechanisms and their potential as an interventional target to lower aSAH incidence.

SUBMITTER: Molenberg R

PROVIDER: S-EPMC9389934 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Sex Hormones and Risk of Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study.

Molenberg Rob R Thio Chris H L CHL Aalbers Marlien W MW Uyttenboogaart Maarten M Larsson Susanna C SC Bakker Mark K MK Ruigrok Ynte M YM Snieder Harold H van Dijk J Marc C JMC

Stroke 20220602 9

<h4>Background</h4>The risk of aneurysmal subarachnoid hemorrhage (aSAH) is increased in postmenopausal women compared with men of similar age, suggesting a role for sex hormones. We aimed to explore whether sex hormones, and age at menarche/menopause have a causal effect on aSAH risk by conducting a 2-sample MR study (Mendelian randomization).<h4>Methods</h4>We obtained sex-specific genetic instruments for serum estradiol, bioavailable testosterone (BioT), SHBG (sex hormone-binding globulin), a ...[more]

PMID: 35652345

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Project description:IntroductionObservational studies suggest that different classes of antihypertensive drugs may have different effects on the occurrence of intracranial aneurysms (IA) and subarachnoid hemorrhage (SAH). However, the reported results in previous studies are inconsistent, and randomized data are absent. We performed a two-sample Mendelian randomization (MR) analysis to study the causal effects of genetically determined blood pressure (BP) and genetic proxies for antihypertensive drug classes on the risk of IA and SAH.Materials and methodsGenetic instruments and outcome data were obtained from independent genome-wide association studies (GWAS) or published data, which were exclusively restricted to European ancestry. Causal relationships were identified using inverse-variance weighted MR analyses and a series of statistical sensitivity analyses. The FinnGen consortium was used for repeated analysis to verify results obtained from the above GWAS.ResultsTwo-sample MR analysis showed that genetically determined Systolic BP, Dystolic BP, and Pulse Pressure were related to a higher risk of IA and SAH. Based on identified single nucleotide polymorphisms (SNPs) that influence the effect of calcium channel blockers (CCB, 42 SNPs), beta-blockers (BB, 8 SNPs), angiotensin-converting enzyme inhibitors (ACEI, 2 SNPs), angiotensin receptor blockers (ARB, 1 SNPs), and thiazides (5 SNPs), genetically determined effect of CCBs was associated with a higher risk of IA (OR, 1.07 [95% CI, 1.03-1.10], p = 5.02 × 10-5) and SAH (OR, 1.06 [95% CI, 1.03-1.09], p = 1.84 × 10-3). No associations were found between other antihypertensive drugs and the risk of IA or SAH. The effect of CCBs on SAH was confirmed in FinnGenconsortium samples (OR, 1.04 [95% CI, 1.00-1.08], p = 0.042).Discussion and conclusionThis MR analysis supports the role of elevated blood pressure in the occurrence of intracranial aneurysms and subarachnoid hemorrhage. However, genetic proxies for calcium channel blockers were associated with an increased risk of intracranial aneurysms and subarachnoid hemorrhage. Further studies are required to confirm these findings and investigate the underlying mechanisms.

Project description:BackgroundExtracerebral complications in patients with aneurysmal subarachnoid hemorrhage (aSAH) often occur during their stay at the neurocritical care unit (NCCU). Their influence on outcomes is poorly studied. The identification of sex-specific extracerebral complications in patients with aSAH and their impact on outcomes might aid more personalized monitoring and therapy strategies, aiming to improve outcomes.MethodsConsecutive patients with aSAH admitted to the NCCU over a 6-year period were evaluated for the occurrence of extracerebral complications (according to prespecified criteria). Outcomes were assessed with the Glasgow Outcome Scale Extended (GOSE) at 3 months and dichotomized as favorable (GOSE 5-8) and unfavorable (GOSE 1-4). Sex-specific extracerebral complications and their impact on outcomes were investigated. Based on the results of the univariate analysis, a multivariate analysis with unfavorable outcomes or the occurrence of certain complications as dependent variables was performed.ResultsOverall, 343 patients were included. Most of them were women (63.6%), and they were older than men. Demographics, presence of comorbidities, radiological findings, severity of bleeding, and aneurysm-securing strategies were compared among the sexes. More women than men suffered from cardiac complications (p = 0.013) and infection (p = 0.048). Patients with unfavorable outcomes were more likely to suffer from cardiac (p < 0.001), respiratory (p < 0.001), hepatic/gastrointestinal (p = 0.023), and hematological (p = 0.021) complications. In the multivariable analysis, known factors including age, female sex, increasing number of comorbidities, increasing World Federation of Neurosurgical Societies (WFNS), and Fisher grading were expectedly associated with unfavorable outcomes. When adding complications to these models, these factors remained significant. However, when considering the complications, only pulmonary and cardiac complications remained independently associated with unfavorable outcomes.ConclusionExtracerebral complications after aSAH are frequent. Cardiac and pulmonary complications are independent predictors of unfavorable outcomes. Sex-specific extracerebral complications in patients with aSAH exist. Women suffered more frequently from cardiac and infectious complications potentially explaining the worse outcomes.

Project description:BackgroundAneurysmal subarachnoid hemorrhage (aSAH) represents a critical health concern characterized by elevated mortality and morbidity rates. Although both genetic predisposition and lifestyle choices influence aSAH susceptibility, understanding the causative associations between cigarette smoking, alcohol consumption, and aSAH risk remains imperative. Mendelian randomization (MR) offers a robust methodological framework for dissecting these associations, leveraging genetic variants as instrumental variables.ObjectiveIn this study, a two-sample Mendelian randomization (TSMR) approach was employed to elucidate the causal connections between genetically determined cigarette smoking, alcohol consumption, and aSAH risk.MethodsGenetic instruments associated with cigarette smoking and alcohol consumption were sourced from the genome-wide association study (GWAS) and Sequencing Consortium of Alcohol and Nicotine use (GSCAN). Using a genome-wide association study (GWAS) dataset that encompassed aSAH cases and controls of European ancestry, TSMR, which utilized the inverse variance weighting (IVW) method, was employed to estimate the causal effects. Rigorous criteria were applied for selecting instrumental variables to ensure a robust Mendelian randomization analysis.ResultsA significant causal association was found between genetically determined cigarette smoking and an increased risk of aSAH, with a 1-standard deviation (SD) increase in cigarette use genetically linked to a 96% relative risk elevation [OR-IVW = 1.96, 95% confidence interval (CI) = 1.28-3.01, p = 0.0021]. However, genetically determined alcohol consumption did not exhibit a statistically significant association with aSAH risk (OR-IVW = 1.22, 95% CI = 0.61-2.45, p = 0.578).ConclusionThe Mendelian randomization analysis revealed a causal nexus between cigarette smoking and an increased risk of aSAH, advocating for targeted smoking cessation interventions within genetically predisposed cohorts. The results regarding the relationship between alcohol consumption and aSAH were affected by insufficient statistical power. A prudent interpretation of the findings highlights the limitations of Mendelian randomization in elucidating intricate genetic epidemiological relationships. Ongoing research involving larger cohort sizes and advanced methodological approaches is essential for comprehending the genetic underpinnings of aSAH.

Project description:BackgroundBreast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.MethodsGenetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.ResultsWe found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.ConclusionsTT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.

Dataset Information

Sex Hormones and Risk of Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study.

Background

Methods

Results

Conclusions

Publications

Sex Hormones and Risk of Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study.

Similar Datasets

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