Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease

Journal article

BACKGROUND:Familial hypobetalipoproteinemia (FHBL) is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding apolipoprotein B ( APOB), the major protein component of low-density and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating low-density lipoprotein cholesterol (LDL-C), triglycerides, and risk for CHD. METHODS:We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families as well as 57,973 individuals derived from 12 CHD case-control studies - 18,442 with early-onset CHD and 39,531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. RESULTS:Among 29 FHBL families, 8 families harbored APOB PTVs. Carrying one APOB PTV was associated with 55 mg/dL lower LDL-C (p = 3x10-5) and 53% lower triglyceride level (p = 2x10-4). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C (p=2x10-7), a 30% decrease in triglycerides (p=5x10-4), and a 72% lower risk for CHD (odds ratio=0.28, 95%CI: 0.12-0.64; p=0.002). CONCLUSIONS:Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD.

Authors: Peloso, G; Nomura, A; Khera, A; Chaffin, M; Won, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wolters Kluwer Health
• Journal: Circulation: Genomic and Precision Medicine
• Volume: 12
• Issue: 5
• Article number: e002376
• Publication date: 2019-04-02
• Acceptance date: 2019-03-22
• DOI: 10.1161/circgen.118.002376
• EISSN: 2574-8300
• Pmid: 30939045
• Language: English
• Keywords: FFR