Rare Protein-Truncating Variants in APOB, Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease

Gina M. Peloso, Akihiro Nomura, Amit V. Khera, Mark Chaffin, Hong Hee Won, Diego Ardissino, John Danesh, Heribert Schunkert, James G. Wilson, Nilesh Samani, Jeanette Erdmann, Ruth McPherson, Hugh Watkins, Danish Saleheen, Shane McCarthy, Tanya M. Teslovich, Joseph B. Leader, H. Lester Kirchner, Jaume Marrugat, Atsushi NoharaMasa Aki Kawashiri, Hayato Tada, Frederick E. Dewey, David J. Carey, Aris Baras, Sekar Kathiresan

11 Citations (Scopus)


Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) 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 LDL-C (LDL cholesterol), 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 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10-5) and 53% lower triglyceride level ( P=2×10-4). 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=2×10-7), a 30% decrease in triglycerides ( P=5×10-4), 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.

Original languageEnglish
JournalCirculation. Genomic and precision medicine
Issue number5
Pages (from-to)e002376
Publication statusPublished - 01.05.2019

Research Areas and Centers

  • Research Area: Medical Genetics


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