Increased prevalence of clinical and subclinical atherosclerosis in patients with damaging mutations in ABCA1 or APOA1.

BACKGROUND:A low level of high-density lipoprotein cholesterol (HDL-C) is a common clinical scenario and poses challenges for management. Many patients with low HDL-C harbor a damaging mutation in ABCA1 or APOA1, but the clinical implications of genetic testing for these mutations are unclear. OBJECTIVE:The purpose of this study was to investigate the prevalence of clinical or subclinical atherosclerosis among patients with low HDL-C due to a mutation in ABCA1 or APOA1, compared with patients with low HDL-C without such a mutation. METHODS:We performed targeted next-generation sequencing to identify mutations in ABCA1 and APOA1 in 72 patients with HDL-C levels below the 10th percentile. We examined the prevalence of clinical atherosclerosis and subclinical atherosclerosis in these patients. We also measured cholesterol efflux capacity (CEC) in plasma. RESULTS:We identified a known disease-causing or likely pathogenic variant in the ABCA1 or APOA1 genes in 22% of patients with low HDL-C. Eighty-three percent of patients with a damaging mutation in ABCA1 or APOA1 had evidence of atherosclerosis compared with 38.6% with low HDL-C without such a mutation (P = .04). Patients with damaging mutations in ABCA1 or APOA1 had lower CEC compared with patients without a mutation (25.9% vs 30.1%). CONCLUSION:The presence of a damaging mutation in ABCA1 or APOA1 confers an increased risk of atherosclerosis relative to patients without such a mutation at a comparable level of HDL cholesterol, possibly because of a reduction in CEC.