e4 Arterioscler Thromb Vasc Biol February 2015 robustly associated with lower TG and decreased incidence of CAD. 41, 42 One of these studies, a large collaboration of the Exome Sequencing Project of the National Heart, Lung, and Blood Institute, sequenced the exomes of 3734 subjects and tested the association of identified mutations, either individually or in aggregate within a gene, that were associated with plasma TG. 41 They identified 7 coding variants in APOC3 in a total of 33 individuals. Of these variants, all were rare in frequency, with 3 missense, 1 nonsense, and 3 splice-site variants identified. When tested in aggregate, the APOC3 variants were robustly associated with lower TG (by 39 mg/dL) relative to noncarriers. Four of the 7 variants were found in heterozygosity at an aggregate frequency of 1 in 150 in individuals of European descent. These variants were associated with approximately half of the circulating apoC-III concentrations of noncarriers, supporting the notion that these variants conferred the loss of apoC-III function. The authors tested the association of these 4 variants with the presence of CAD in> 110 000 subjects and found 40% lower CAD risk in mutation carriers. Notably, 1 of the 4 variants studied by Crosby et al, 41 a nonsense mutation R19X (rs76353203) was previously shown in an Amish population to reduce TG and improve the clearance of dietary fat in an oral fat challenge and was associated with reduced coronary artery calcium scores, a surrogate measurement of atherosclerosis. 43 Working independently in Denmark, Jørgensen et al42 tested the association of plasma TG with the presence of ischemic vascular disease (CAD or cerebrovascular disease) in 2 prospective cohorts comprising 75 725 subjects. 21 They found that the subjects with TG< 90 mg/dL had significantly lower risk of ischemic vascular disease compared with the subjects with TG> 350 mg/dL. Initial deep medical resequencing of the exons of APOC3 and subsequent genotyping in the larger cohort identified 260 heterozygous carriers for 1 of 3 APOC3 mutations, which were associated with lower fasting TG. The 3 variants identified by this approach were among the 4 SNPs that drove the association of APOC3 variants with TG described by the Exome Sequencing Project of National Heart, Lung, and Blood Institute. Of the 75 725 subjects studied, 10 797 subjects developed ischemic vascular disease, of which 7557 had ischemic heart disease. When separated by APOC3 genotype, they noted a 41% reduction in risk of vascular disease among mutation carriers. The association of the variants with lower incidence of vascular disease was attenuated when comparisons were adjusted for nonfasting TG levels in the participants, implying that the effect of apoC-III on TG levels is at least partially responsible for the protection from disease conferred by the variants. These 2 recent studies present the argument that apoC-III’s influence on plasma TG is responsible for the relationship of apoC-III with CAD risk. However, given apoC-III’s pleiotropic influence on lipoprotein metabolism and additional contributions to vascular risk, others have suggested that this interpretation may be incomplete. Cohen et al44 recently commented on the possibility that the reduced LDL-C levels in APOC3 mutation carriers may account for the observed protection from vascular disease. ApoC-III on intermediatedensity lipoproteins and LDLs is thought to delay hepatic clearance of these particles by lipoprotein receptors, and LDL-containing apoC-III was shown to be positively associated with development of coronary heart disease. 34, 35, 45 In addition, LDL-bound apoC-III was …