Rare Protein-truncating Variants in APOB, Lower LDL-C, and Protection Against Coronary Heart Disease.
Peloso GM., Nomura A., Khera AV., Chaffin M., Won H-H., Ardissino D., Danesh J., Schunkert H., Wilson JG., Samani N., Erdmann J., McPherson R., Watkins H., Saleheen D., McCarthy S., Teslovich TM., Leader JB., Kirchner HL., Marrugat J., Nohara A., Kawashiri M., Tada H., Dewey FE., Carey DJ., Baras A., Kathiresan S.
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.