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Smoking as a Risk Factor for Cardiovascular Disease in Females and Males: Observational and Mendelian Randomisation

Sophie C de Ruiter1, Lena Tschiderer2, Diederick E Grobbee1

  • 1Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Global Heart
|October 20, 2025
PubMed

Insights

Smoking increases cardiovascular disease (CVD) risk in both sexes. While observational studies suggest stronger risks for females, causal effects of smoking on CVD may be similar between males and females.

Area of Science:

  • Cardiovascular Science
  • Genetics
  • Public Health

Background:

  • Observational studies indicate a stronger association between smoking and cardiovascular disease (CVD) in females compared to males.
  • It remains uncertain if these observed sex differences stem from variations in the causal effects of smoking between sexes.

Purpose of the Study:

  • To investigate sex-specific associations between smoking (initiation, continuation, intensity) and CVD outcomes.
  • To differentiate between observational associations and causal effects using Mendelian randomization (MR).

Main Methods:

  • Sex-stratified observational analyses were conducted using UK Biobank data.
  • Mendelian randomization (MR) analyses were performed to assess causal effects.
  • Key exposures included ever smoking, smoking continuation, and cigarettes smoked per day.

Main Results:

  • Observational analyses revealed a greater excess risk of smoking for CVD in females versus males.
  • Mendelian randomization results were directionally consistent but lacked statistical significance for most CVD outcomes.
  • A stronger causal effect of ever smoking was indicated in females for subarachnoid hemorrhage (SAH).

Conclusions:

  • Both smoking initiation and intensity are linked to increased CVD risk in both sexes.
  • Observed sex differences in smoking-CVD associations align directionally with causal effects.
  • Causal effects of smoking on CVD might be similar in females and males, despite greater uncertainty in MR estimates.
Abstract

Keywords:
Mendelian randomisationSex differencesSmokingcardiovascular disease

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