Through DNA genotyping using the Exome-Array, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with CAD and 120,770 controls who did not have CAD. Furthermore, through DNA sequencing, we studied the effects of loss-of-function mutations in selected
Here, we confirmed previously observed significant associations between CAD and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between CAD 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.
In a next step, through sequencing of ANGPTL4, we identified 9 loss-of-function mutation carriers among 6924 patients with myocardial infarction, as compared with 19 loss-of-function mutation carriers among 6834 controls (odds ratio, 0.47; P = 0.04).
Interestingly, 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).
Functionally, Angiopoietin-like 4 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 CAD (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 CAD (p.S447*; minor-allele frequency, 9.9%; odds ratio,
0.94; P = 2.5×10−7).
This highly collaborative study – involving 129 scientists from 15 countries – was published online on March 2nd, 2016 in the New England Journal of Medicine.