4.6 Article

Low-Density Lipoprotein Cholesterol Attributable Cardiovascular Disease Risk Is Sex Specific

Journal

JOURNAL OF THE AMERICAN HEART ASSOCIATION
Volume 11, Issue 12, Pages -

Publisher

WILEY
DOI: 10.1161/JAHA.121.024248

Keywords

cardiovascular disease; genetics; risk factor; sex-differences

Funding

  1. Atheros fund
  2. Academic Medical Center Young Talent Fund
  3. Stichting de Drie Lichten
  4. University College London Hospitals National Institute for Health Research Biomedical Research Centre
  5. BigData@Heart Consortium - Innovative Medicines Initiative-2 joint undertaking [116074]
  6. National Institutes of Health [LM010098]
  7. Netherlands Organization for Scientific Research [vidi 016.156.445]
  8. Klinkerpad fonds
  9. European Union
  10. British Heart Foundation [PG/18/5033837]
  11. University College London British Heart Foundation [AA/18/6/34223]
  12. Prince Bernhard Culture fund

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This study found that genetically increased LDL-C has a sex-specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. The observations provide evidence that LDL-C might be a less important determinant of CVD in women compared with men.
Background Epidemiological studies show that women are generally at lower risk for cardiovascular disease than men. Here, we investigated the sex-specific differential effect of genetically increased low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) and other lipid-associated diseases. Methods and Results This is a 2-sample Mendelian randomization study that uses individual participant data from 425 043 participants from the UK Biobank, including 229 279 female participants. An 80-variant LDL-C weighted genetic score was generated. Linear and logistic regression models with interactions were used to identify differences between sex-specific LDL-C effects on lipids, carotid-intima media thickness, and multiple cardiovascular outcomes such as CVD, ischemic heart disease, peripheral artery disease, heart failure, aortic valve disease, type 2 diabetes, atrial fibrillation, and aortic aneurysm and dissection. After correction for multiple testing, we observed that the genetically increased LDL-C effect on CVD events was sex specific: per SD genetically increased LDL-C, female participants had a higher LDL-C increase but an attenuated CVD risk increase compared with male participants (LDL-C: female participants 0.71 mmol/L, 95% CI, 0.70-0.72 and male participants 0.57 mmol/L, 95% CI, 0.56-0.59. P for interaction: 5.03x10(-60); CVD: female participants: odds ratio [OR], 1.32; 95% CI 1.24-1.40 and male participants: OR, 1.52; 95% CI, 1.46-1.58. P for interaction: 9.88x10(-5)). We also observed attenuated risks for ischemic heart disease and (nominally for) heart failure in female participants, and genetically increased LDL-C results in higher risk for aortic valve disease in female participants compared with male participants. Genetically increased LDL-C was also associated with an attenuated carotid-intima media thickness increase in female participants. We did not observe other significant attenuations. Sensitivity analyses with an unweighted genetic score and sex-specific weighted genetic scores showed similar results. Conclusions We found that genetically increased LDL-C has a sex-specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. Our observations provide evidence that LDL-C might be a less important determinant of CVD in women compared with men, suggesting that male patients might benefit more from LDL-C targeted therapies for CVD management than female patients and warranting investigations into the sex-specific relative contribution of risk factors for CVD.

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