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Smoking and family history and risk of aneurysmal subarachnoid hemorrhage

From the University of Cincinnati Department of Neurology (D.W., M.M.H., M.L.F., D.O.K., B.M.K., C.J.M., J.P.B.), Cincinnati Children's Hospital Medical Center–Center for Epidemiology and Biostatistics (J.K.), and University of Cincinnati Department of Environmental Health (P.S., R.D.), OH.

Address correspondence and reprint requests to Dr. Daniel Woo, Department of Neurology, University of Cincinnati College of Medicine, 260 Stetson Street ML 0525, Cincinnati, OH 45267-0525 Daniel.woo{at}uc.edu.

Objective: Smoking and family history of aneurysmal subarachnoid hemorrhage (aSAH) are independent risk factors for aSAH. Using a population-based case-control study of hemorrhagic stroke, we hypothesized that having both a first-degree relative with a brain aneurysm or SAH (+FH) and current smoking interact to increase the risk of aSAH.

Methods: Cases of aneurysmal SAH were prospectively recruited from all 17 hospitals in the five-county region around the University of Cincinnati. Controls were identified by random digit dialing. Controls were matched to cases of aSAH by age (±5 years), race, and sex. Conditional multiple logistic regression was used to identify independent risk factors. For deviation from the additive model, the interaction constant ratio test was used.

Results: A total of 339 cases of aSAH were matched to 1,016 controls. Compared to current nonsmokers with no first-degree relatives with aSAH (–FH), the odds ratio (OR) for aSAH for current nonsmokers with +FH was 2.5 (95% confidence interval [CI] 0.9–6.9); for current smokers with –FH, OR = 3.1 (95% CI 2.2–4.4); and for current smokers with +FH, OR = 6.4 (95% CI 3.1–13. 2). The interaction constant ratio, which measured the deviation from the additive model, was significant: 2.19 (95% CI 0.80–5.99). The lower bound of the 95% CI >0.5 signifies a departure from the additive model.

Conclusion: Evidence of a gene–environment interaction with smoking exists for aneurysmal subarachnoid hemorrhage. This finding is important to counseling family members and for screening of intracranial aneurysm (IA) as well as the design and interpretation of genetic epidemiology of IA studies.

Abbreviations: aSAH = aneurysmal subarachnoid hemorrhage; CI = confidence interval; GERFHS = Genetic and Environmental Risk Factors of Hemorrhagic Stroke; IA = intracranial aneurysm; ICH = intracerebral hemorrhage; ICR = interaction contrast ratio; OR = odds ratio.

Funded by a grant from the NIH (National Institute of Neurological Disorders and Stroke NS36695).

Disclosure: The authors report no disclosures.

Received April 7, 2008. Accepted in final form September 23, 2008.