Phenotypic and genetic sex differences in LDL-C and statin treatment in All of Us

Abstract

Low-density lipoprotein cholesterol (LDL-C) is a well-established and modifiable risk factor for cardiovascular diseases (CVDs), which have been the leading cause of mortality among individuals in the United States since 1921. Despite known sex differences in CVD presentation and outcomes, women remain underdiagnosed and undertreated relative to men. Using genotype and phenotype data from the All of Us (AoU) Research Program, we assessed sex-specific differences in LDL-C based on measured levels, statin treatment rates and efficacy, age-related patterns, and genetic factors as reflected by GWAS, XWAS, GxSex interaction, and heritability. We find that the median LDL-C measurements of women are consistently higher than those of men across most age strata, regardless of statin treatment, and that this difference is greatest after 40 years of age. In addition, women are treated with statins less often than their male counterparts and appear to respond less effectively to statins. This is particularly true for Black women, who had the highest statin-treated median LDL-C of any race-sex stratum. Our sex-stratified GWAS results recapitulate known sex-differentiated effects at the APOE/APOC1 locus, and our male-stratified XWAS identified an LDL-C associated SNP in the PTCHD1-AS region. While heritability and additive genetic variability of LDL-C do not demonstrate sex differences, residual and phenotypic variability do. This suggests that environmental factors may drive variation in LDL-C levels and statin treatment rates across sex and self-identified race groups. These findings highlight the need for sex- and population-specific strategies in genetic studies and LDL-C treatment.