Sex Hormones and Risk of Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study
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...
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| Vydáno v: | Stroke (1970) Ročník 53; číslo 9; s. 101161STROKEAHA121038035 |
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01.09.2022
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| ISSN: | 1524-4628, 1524-4628 |
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| Abstract | 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).
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.
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];
=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];
=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];
=0.008). No other causal associations were identified.
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. |
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| AbstractList | 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).
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.
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];
=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];
=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];
=0.008). No other causal associations were identified.
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. 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).BACKGROUNDThe 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).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.METHODSWe 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.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.RESULTSUnivariable 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.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.CONCLUSIONSGenetic 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. |
| Author | Bakker, Mark K Ruigrok, Ynte M Aalbers, Marlien W Larsson, Susanna C Molenberg, Rob Thio, Chris H L van Dijk, J Marc C Uyttenboogaart, Maarten Snieder, Harold |
| Author_xml | – sequence: 1 givenname: Rob orcidid: 0000-0002-6621-2028 surname: Molenberg fullname: Molenberg, Rob organization: Department of Neurosurgery (R.M., M.W.A., J.M.C.v.D.), University of Groningen, University Medical Center Groningen, the Netherlands – sequence: 2 givenname: Chris H L orcidid: 0000-0003-2623-7172 surname: Thio fullname: Thio, Chris H L organization: Department of Epidemiology (C.H.L.T., H.S.), University of Groningen, University Medical Center Groningen, the Netherlands – sequence: 3 givenname: Marlien W surname: Aalbers fullname: Aalbers, Marlien W organization: Department of Neurosurgery (R.M., M.W.A., J.M.C.v.D.), University of Groningen, University Medical Center Groningen, the Netherlands – sequence: 4 givenname: Maarten orcidid: 0000-0002-6934-4456 surname: Uyttenboogaart fullname: Uyttenboogaart, Maarten organization: Department of Neurology and Medical Imaging Center (M.U.), University of Groningen, University Medical Center Groningen, the Netherlands – sequence: 5 givenname: Susanna C orcidid: 0000-0003-0118-0341 surname: Larsson fullname: Larsson, Susanna C organization: Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Sweden (S.C.L.) – sequence: 6 givenname: Mark K orcidid: 0000-0002-7887-9014 surname: Bakker fullname: Bakker, Mark K organization: Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, University Utrecht, the Netherlands (M.K.B., Y.M.R.) – sequence: 7 givenname: Ynte M orcidid: 0000-0002-5396-2989 surname: Ruigrok fullname: Ruigrok, Ynte M organization: Department of Neurology and Neurosurgery, UMC Utrecht Brain Center, University Medical Center Utrecht, University Utrecht, the Netherlands (M.K.B., Y.M.R.) – sequence: 8 givenname: Harold orcidid: 0000-0003-1949-2298 surname: Snieder fullname: Snieder, Harold organization: Department of Epidemiology (C.H.L.T., H.S.), University of Groningen, University Medical Center Groningen, the Netherlands – sequence: 9 givenname: J Marc C orcidid: 0000-0002-0814-5680 surname: van Dijk fullname: van Dijk, J Marc C organization: Department of Neurosurgery (R.M., M.W.A., J.M.C.v.D.), University of Groningen, University Medical Center Groningen, the Netherlands |
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