Causal Link Between Smoking and Subarachnoid Hemorrhage

People who were genetically predisposed to smoking behaviors were at a 63% greater risk for subarachnoid hemorrhage.

Guido J. Falcone, MD, ScD, MPH

Findings from a 1-sample Mendelian randomization (MR) study using data from the UK Biobank revealed a causal link between smoking and the risk of subarachnoid hemorrhage (SAH).1

Senior author Guido J. Falcone, MD, ScD, MPH, assistant professor of neurology, Yale School of Medicine, and colleagues built a polygenic risk score using independent genetic variants known to associate (P <5x10-8) with smoking behavior, as a representative of the genetic susceptibility to smoking initiation.

They found a 21% increased risk of smoking (odds ratio [OR], 1.21; 95% CI, 1.20–1.21; P <.001) and a 10% increased risk of SAH for each additional standard deviation (SD) of the smoking polygenic risk score.

"Previous studies have shown that smoking is associated with higher risks of SAH, yet it has been unclear if smoking or another confounding condition such as high blood pressure was a cause of the stroke,” Falcone said in a statement.2 “A definitive, causal relationship between smoking and the risk of SAH has not been previously established as it has been with other types of stroke.”

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The study evaluated 408,609 participants (mean age, 57 years [SD, 8]; female, 220,937 [54%]), 132,566 (32%) of which smoked regularly, and 904 (0.22%) who had a SAH. SAH cases were ascertained using a combination of self-reported, electronic medical record, and death registry data.

The primary MR analysis, which utilized the ratio method, indicated that genetic susceptibility to smoking was associated with a 63% increase in the risk of SAH (OR, 1.63; 95% CI, 1.15–2.31; P = .006). Secondary analysis, which included the inverse variance weighted (OR, 1.57; 95% CI, 1.13–2.17; P = .007) and weighted median methods (OR, 1.74; 95% CI, 1.06–2.86; P = .03), yielded similar results.

The researchers noted that smoking as a risk factor for aneurysm formation and rupture, leading to SAH, had been previously observed in animal and observational studies. However, it had not been established whether there was a definitive causal relationship between smoking and the risk of SAH.

Falcone and colleagues found the relationship between smoking and SAH risk to be linear, with those who smoked half a pack to 20 packs of cigarettes per year having a 27% increased risk. Additionally, there was a 3-fold risk for SAH in heavier smokers, those who smoked more than 40 packs of cigarettes per year.

"Our results provide justification for future studies to focus on evaluating whether information on genetic variants leading to smoking can be used to better identify people at high risk of having one of these types of brain hemorrhages," Julian N. Acosta, MD, neurologist, postdoctoral research fellow, Yale School of Medicine, and lead study author, said in a statement. "These targeted populations might benefit from aggressive diagnostic interventions that could lead to early identification of the aneurysms that cause this serious type of bleeding stroke."

The dangers of smoking have been documented previously. Data from the Jackson Heart Study published in June 2020 suggested that cigarette smoking was associated with a dose-dependent higher risk of all stroke in black individuals, though past smokers did not have a statistically significant increased risk of all stroke compared with those who never smoked.3

Researchers from that study observed a 2.5 times higher risk for stroke among those who currently smoked compared to non-smokers (hazard ratio [HR], 2.48; 95% CI, 1.60–3.83), while the risk difference between past and never smokers (HR, 1.10; 95% CI, 0.74–1.64) was not significant.

1. Acosta JN, Szejko N, Both CP, et al. Genetically determined smoking behavior and risk of nontraumatic subarachnoid hemorrhage. Stroke. Published January 14, 2021. doi: 10.1161/STROKEAHA.120.031622.
2. Smoking directly linked to a higher risk of subarachnoid hemorrhage. News release. American Heart Association. January 14, 2021. Accessed January 15, 2021.
3. Oshunbade AA, Yimer WK, Valle KA, et al. Cigarette Smoking and Incident Stroke in Blacks of the Jackson Heart Study. J Am Heart Assoc. 2020;9:e014990. doi: 10.1161/JAHA.119.014990
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