Key result
Genetically proxied LDL-C shows ~14% weaker association with ASCVD in females than males.
Why the study?
Are there sex-specific differences in the causal relationships between genetically proxied lipid traits and risk of cardiovascular disease?
Observational (n=337,386)
Yes
Are there sex-specific differences in the causal relationships between genetically proxied lipid traits and risk of cardiovascular disease?
Odds Ratio: 0.86 (95% CI 0.76–0.96)
Absolute Event Rate: 5.9% vs 15.8%
Genetically proxied LDL-C, total cholesterol, and non-HDL-C have a significantly stronger causal association with ASCVD in males compared to females.
Background Elevated lipid levels are among the top risk factors for cardiovascular disease in both females and males. Observational studies have previously suggested potential sex-specific differences in the association between lipid levels and cardiovascular risk. However, whether sex differences translate into differences in causal relationships is not entirely understood. Purpose To investigate potential causal sex-specific relationships between lipid traits and risk of cardiovascular disease using Mendelian randomisation analyses. Methods We studied genetically proxied lipid traits including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol, and non-HDL-C. Sex-specific genetic associations with lipid traits were obtained from the Global Lipids Genetics Consortium. Furthermore, sex-specific genetic associations with atherosclerotic cardiovascular disease (ASCVD) outcomes including major coronary heart disease, ischaemic stroke, and peripheral vascular disease were estimated from individual-level UK Biobank data. We then conducted inverse-variance weighted Mendelian randomisation analyses. Results We included 181,183 females and 156,203 males from the UK Biobank (mean age 57 years [SD 8]), of which 10,612 (5.9%) and 24,710 (15.8%) experienced ASCVD, respectively. Relationships between genetically proxied lipid traits and ASCVD were directionally similar for both females and males. However, the association between genetically proxied LDL-C and ASCVD was significantly stronger in males (OR 1.59 [95% CI 1.45, 1.74] per SD higher value of genetically proxied LDL-C) as compared to females (OR 1.36 [95% CI 1.27, 1.46]) with a females-to-males ratio of odds ratios (ROR) of 0.86 (95% CI 0.76, 0.96). Similar results were found for total cholesterol (females-to-males ROR 0.84 [95% CI 0.75, 0.95]) and non-HDL-C (females-to-males ROR 0.89 [95% CI 0.79, 1.00]). No sex differences were found for genetically proxied HDL-C and triglycerides. Conclusion Our Mendelian randomisation study revealed significant sex differences in the relationships between genetically proxied LDL-C, total cholesterol, and non-HDL-C with ASCVD. No sex differences were found for genetically proxied HDL-C and triglycerides.
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Tschiderer et al. (2026) conducted an observational in Atherosclerotic cardiovascular disease (ASCVD) (n=337,386). Genetically proxied LDL-C vs. Males was evaluated on Atherosclerotic cardiovascular disease (ASCVD) (ROR 0.86, 95% CI 0.76-0.96). Genetically proxied LDL-C had a significantly stronger association with atherosclerotic cardiovascular disease in males than in females (females-to-males ratio of odds ratios 0.86, 95% CI 0.76-0.96).
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