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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) and 53% lower triglyceride level (p = 2x10). 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), a 30% decrease in triglycerides (p=5x10), 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.