A. The positions of all nonsynonymous and synonymous variants identified by resequencing APOA1 in the Copenhagen City Heart Study (CCHS, n = 10,330) have been superimposed on the secondary structure of apoA-I. B. Evolutionary sequence conservation and predicted functional effects of nonsynonymous genetic variants in APOA1. Variants are divided into four groups, depending on whether they were identified exclusively in the lowest 20 percentile, the highest 20 percentile, or in both the lowest and highest 20 percentiles of the apoA-I distribution, using the extreme phenotype approach. The fourth group includes variants exclusively identified using the population-based resequencing approach. The truncation, APOA1 V11X, is not included in the figure. The alignment includes human (H. sapiens), chimpanzee (P. troglodytes), dog (C. lupus familiaris), cow (B. taurus), mouse (M. musculus), chicken (G. gallus), and zebrafish (D. Rerio). Alignment by HomoloGene (www.ncbi.nlm.nih.gov/homologene/). anot possible to model. PANTHER: + = P-deleterious>0.5; − = P-deleterious<0.5 (www.pantherdb.org/). SIFT: + = affect protein function; − = tolerated (http://sift.jcvi.org/). PolyPhen: + = probably or possibly damaging; − = benign (http://genetics.bwh.harvard.edu/pph2/). PMut: + = pathological; − = neutral (http://mmb2.pcb.ub.es:8080/PMut/). Figure 7A was adapted from [6].