Sex differences in LDL-C genetic architecture and statin efficacy in All of Us

Low-density lipoprotein cholesterol (LDL-C) is a well-established and modifiable risk factor for cardiovascular diseases (CVDs), which has been the leading cause of mortality among women and men in the United States since 1921. Despite research demonstrating sexually dimorphic symptom presentation of CVD, women remain underdiagnosed and undertreated for CVDs relative to men. Using genotype and phenotype data from the All of Us (AoU) Research Program, we examined sex-specific differences in LDL-C measurements, including baseline levels, statin treatment efficacy, age-related patterns, genome-wide association study (GWAS) results, and heritability between women and men. We find that the median LDL-C measurements of women are consistently higher than those of men across all age strata and that this difference is most apparent after 40 years of age. In addition, women are treated with statins at a lower rate than their male counterparts, and statins appear to be less effective in women--particularly Black women, who exhibited the highest median LDL-C levels while prescribed statins. Based on GWAS, genetic variants associated with LDL-C measurements differ between women and men, as do their effect sizes. Finally, heritability differs between sex, age, racial identity, and statin treatment groups. These findings indicate that current clinical intervals of LDL-C and pharmaceutical-based LDL-C modification approaches may not be equally appropriate across subgroups, with significant variation by sex and self-identified race. This highlights the need for sex-specific and population-informed strategies in both the treatment of LDL-C and genetic studies.