CVD risk associated with LDL-c is sex specific

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

Literature - Cupido AJ, Asselbergs FW, Schmidt AF, et al. - J Am Heart Assoc. 2022;11(12):e024248. doi: 10.1161/JAHA.121.024248

Introduction and methods


Observational data have shown that women are at lower risk of CVD than men [1]. Recently, a meta‐analysis of 27 RCTs reported significant heterogeneity between men and women in the effect of statins to prevent a first CVD event compared with placebo [2]. This raises the question of whether there is a sex‐specific differential effect of genetically increased LDL‐c concentration on the risk of CVD and other lipid‐associated diseases.


In this 2‐sample Mendelian randomization study, individual data from 425,043 participants of the UK Biobank cohort, of whom 229,279 (54.3% ) were female, were used to assess the effect of an externally weighted LDL‐c genetic instrument on a range of clinical outcomes (including LDL‐c as a positive control), stratified by sex. With a Mendelian randomization approach, naturally occurring genetic variations can be used to investigate the causal effect of an exposure on an outcome. Participants who self‐identified as being from a White British, White Irish, or other White background were included.

Genetic scores for each UK Biobank participant were calculated by summing the number of LDL‐c increasing alleles a participant had, weighed by the effect that specific allele had on LDL‐c levels based on data from an external genome‐wide association study on LDL‐c conducted by the Global Lipid Genetics Consortium. Subsequently, an 80‐variant LDL‐c–weighted genetic instrument was generated.


The researchers investigated the effects of genetically increased LDL‐c levels on the following individual CVD endpoints: first occurrence of CVD (i.e., a composite outcome of first occurrence of either prevalent or incident event of ischemic heart disease, death due to ischemic heart disease, coronary intervention, and ischemic stroke), all subcomponents of the composite CVD outcome, peripheral artery disease, aortic valve stenosis, AF, HF, aortic aneurysm and dissection, and T2DM.

The effect of the genetic instrument on carotid intima media thickness was also assessed in a subset of up to 41,025 patients who underwent carotid ultrasound.

Main results

  • Female participants showed a higher LDL‐c increase per 1 SD genetically increased LDL‐c (0.71 mmol/L; 95%CI: 0.70–0.72) compared with male participants (0.57 mmol/L; 95%CI: 0.56–0.59; P for interaction=5.03 × 10−60).
  • However, the CVD risk per 1 SD genetically increased LDL‐c was lower for female participants (odds ratio (OR): 1.32; 95%CI: 1.24–1.40) than for their male counterparts (OR: 1.52; 95%CI: 1.46–1.58; P for interaction=9.88 × 10−5).
  • Sex‐specific differential effects were also seen for the association of genetically increased LDL‐c with the first occurrence of ischemic heart disease (OR for females: 1.34; 95%CI: 1.26–1.44 vs. OR for males: 1.60; 95%CI: 1.53–1.68; P for interaction=7.99 × 10−6), aortic valve stenosis (2.09; 95%CI: 1.68–2.61 vs. 1.42; 95%CI: 1.22–1.66; P for interaction=4.48 × 10−3), and—albeit nominally significant—HF (1.08; 95%CI: 0.95–1.22 vs. 1.29; 95%CI: 1.19–1.41; P for interaction=1.54 × 10−2). The sex‐specific differential effect on the association with HF did not reach statistical significance after correction for multiple testing.
  • Genetically increased LDL‐c was associated with a smaller mean increase in pooled carotid‐intima media thickness measurements in female participants (11.8 µm; 95%CI: 7.5–16.0) compared with male participants (22.3 µm; 95%CI: 16.8–27.8; P for interaction=2.90 × 10−3).
  • There were no significant associations between genetically increased LDL‐c and the other outcomes.
  • Sensitivity analyses with an unweighted genetic instrument and male- and female‐specific weighted genetic instruments showed similar results.


In this Mendelian randomization study, the causal effect of LDL-c on CVD risk was stronger in male than in female participants, whereas its causal effect on aortic valve stenosis was stronger in female than in male participants. According to the authors, the results suggest that male patients could benefit more from LDL‐c targeted therapies for CVD management than female patients. In addition, their observations “provide further evidence for causal sex‐specific differences in the pathogenesis of atherosclerosis.”


1. Swiger KJ, Martin SS, Blaha MJ, Toth PP, Nasir K, Michos ED, Gerstenblith G, Blumenthal RS, Jones SR. Narrowing sex differences in lipoprotein cholesterol subclasses following mid‐life: the very large database of lipids (VLDL‐10B). J Am Heart Assoc. 2014;3:e000851.

2. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of LDL‐lowering therapy among men and women: meta‐analysis of individual data from 174 000 participants in 27 randomised trials. The Lancet. 2015;385:1397–1405.

Find this article online at J Am Heart Assoc.

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