Sex differences in risk factor relationships with subarachnoid haemorrhage and intracranial aneurysms: A Mendelian randomization study

Author:

Tschiderer Lena1,Bakker Mark K2ORCID,Gill Dipender3,Burgess Stephen456,Willeit Peter14,Ruigrok Ynte M2ORCID,Peters Sanne AE789ORCID

Affiliation:

1. Institute of Health Economics, Medical University of Innsbruck, Innsbruck, Austria

2. Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, The Netherlands

3. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

4. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

5. Heart and Lung Research Institute, University of Cambridge, Cambridge, UK

6. MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK

7. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

8. The George Institute for Global Health, School of Public Health, Imperial College London, London, UK

9. The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia

Abstract

Background: The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors. Aims: The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA. Methods: We conducted a sex-specific two-sample Mendelian randomization study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e. aSAH and unruptured IA combined) as outcomes. Results: We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men ( p-value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women ( p-value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women ( p-value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men. Conclusions: Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA.

Publisher

SAGE Publications

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