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

<jats:sec> <jats:title>Background</jats:title> <jats:p> Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding <jats:italic>APOB</jats:italic> (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous <jats:italic>APOB</jats:italic> 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 <jats:italic>APOB</jats:italic> with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p> We sequenced the <jats:italic>APOB</jats:italic> 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 <jats:italic>APOB</jats:italic> PTV carrier status with blood lipid levels and CHD. </jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> Among 29 familial hypobetalipoproteinemia families, 8 families harbored <jats:italic>APOB</jats:italic> PTVs. Carrying 1 <jats:italic>APOB</jats:italic> PTV was associated with 55 mg/dL lower LDL-C ( <jats:italic>P</jats:italic> =3×10 <jats:sup>-5</jats:sup> ) and 53% lower triglyceride level ( <jats:italic>P</jats:italic> =2×10 <jats:sup>-4</jats:sup> ). Among 12 case-control studies, an <jats:italic>APOB</jats:italic> PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. <jats:italic>APOB</jats:italic> PTV carrier status was associated with a 43 mg/dL lower LDL-C ( <jats:italic>P</jats:italic> =2×10 <jats:sup>-7</jats:sup> ), a 30% decrease in triglycerides ( <jats:italic>P</jats:italic> =5×10 <jats:sup>-4</jats:sup> ), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12–0.64; <jats:italic>P</jats:italic> =0.002). </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p> Rare PTV mutations in <jats:italic>APOB</jats:italic> which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD. </jats:p> </jats:sec>