Coding Variation inANGPTL4,LPL,andSVEP1and the Risk of Coronary Disease

Abstract

BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2×10−10) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0×10−8), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0×10−4) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447⋆; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5×10−7). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.)

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

“…In line with these findings, ANGPTL4 variants have been identified in European subjects 14, 15, 16, 17. For instance, E40K carriers, who have loss‐of‐function mutation of ANGPTL4, display higher HDL‐c with reduced risk of coronary heart disease when compared with noncarriers 14, 15, 16, 17. Recently, plasma levels of ANGPTL4 have been found to be increased in patients with type‐2 diabetes mellitus (T2DM) and subjects with metabolic syndromes; both of them are featured as having reduced HDL‐c 8.…”

“…The inverse correlation between ANGPTL4 and high‐density lipoprotein‐cholesterol HDL‐c (high‐density lipoprotein‐cholesterol) has been reported in European and American populations 12, 13. In line with these findings, ANGPTL4 variants have been identified in European subjects 14, 15, 16, 17. For instance, E40K carriers, who have loss‐of‐function mutation of ANGPTL4, display higher HDL‐c with reduced risk of coronary heart disease when compared with noncarriers 14, 15, 16, 17.…”

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

“…In accordance, loss‐of‐function variants were associated with a lower risk for CAD. This becomes even more apparent since we also detected a missense variant in the LPL gene, which led to a 20% reduction in LPL activity, to be associated with increased risk for CAD (Stitziel et al , 2016). The findings for LPL and ANGPTL4 confirm recent results for two other regulators of LPL activity, APOA5 and APOC3, in that rare APOA5 mutations increase both plasma triglyceride levels and risk of CAD (Do et al , 2015), whereas rare loss‐of‐function mutations in the APOC3 gene have opposite effects (The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, 2014).…”

“…The results of the first exome‐wide association study on CAD have been just published (Stitziel et al , 2016). The authors included more than 72,000 cases and more than 120,000 controls, respectively.…”

“…They confirmed signals in the LPA and PCSK9 genes but also identified novel variants in genes thus far not associated with CAD: a missense variant in the ANGPTL4 gene and a missense variant in the sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 gene ( SVEP1 ). SVEP1 was not associated with lipid levels, but with both systolic and diastolic blood pressure leading to an increase of 0.94 and 0.57 mmHg, respectively, in those carrying the risk allele (Stitziel et al , 2016). Moreover, SVEP1 has been investigated in septic shock and endotoxaemia (Nakada et al , 2015).…”