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 10 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.