Introduction: Familial hypercholesterolemia (FH), characterized by severely elevated levels of low-density lipoprotein cholesterol (LDL-C) and consequently premature coronary heart disease (CHD), is caused by many rare variants in a few genes, including LDLR,APOB and PCSK9. Hundreds of FH variants have been documented, but the impact of these variants at the population level is poorly studied due to their low frequencies.
Hypothesis: Carrying FH variants is associated with higher prevalence of cardiovascular disease.
Methods: Using genotypes from 331,107 ethnically diverse participants of the Million Veteran Program (MVP), we identified the subset of FH variants labelled as “pathogenic” or “likely pathogenic” (P/LP) by ClinVar. We then determined the collective impact of these variants on the prevalence of CHD, peripheral artery disease (PAD), and other clinical outcomes by leveraging data from 61.7 million clinical encounters over a cumulative of 3 million patient-years of health data.
Results: We identified 1,616 veterans carrying at least one of the 58 P/LP SNPs archived in ClinVar and genotyped in the MVP. Compared to non-carriers, carriers of FH variants had a higher maximum recorded LDL-C (maxLDL, +20.4 mg/dL), a higher prevalence of clinical diagnoses related to hypercholesterolemia, and a higher prevalence of CHD related diagnoses (Figure). Adjusted for age, sex, population structure and maxLDL, FH variants remained collectively associated with higher prevalence of CHD (odds ratio of 1.38, p=1.23х10-8) but not PAD (odds ratio of 1.05, p=0.65).
Conclusion: In the largest US-based clinical study of FH variants, we observed robust association between FH variants and CHD. The residual association with CHD after adjusting for maxLDL supports the presence of an elevated risk of carrying FH variants that is independent of a single measure of LDL-C. Early screening, diagnosis and treatment of FH would further prevent disease outcomes at the population level.