Neuropeptide Y and Early-Onset Atherosclerosis Figure 2. NPY structure, genotyped SNPs, and LD between SNPs. NPY gene structure is displayed diagrammatically (top), with exons symbolized as cylinders, and sites of translation initiation (ATG) and termination (TGA) indicated. Genotyped SNPs are noted with arrows and color- coded: coding-nonsynonymous (red); coding-synonymous (green); intronic (blue); mRNA-untranslated region (lavender); 59 and 39 gene-flanking region (black). The bottom panel constitutes a LD graphic with R2 values (n6102) between SNPs; darker squares signify higher degrees of LD. SNPs genotyped as part of this study are highlighted in yellow. doi:10.1371/journal.pgen.1000318.g002 Because we observed increased linkage and association between NPY SNPs and CAD in the very youngest age-of-onset cases, NPY may make a particularly appealing therapeutic target for CAD prevention in families with early-onset disease. Together with our mouse data, our results support the following scenario by which NPY variants promote atherosclerosis: presence of the rs16147 risk Table 3. Association of NPY SNPs with early-onset CAD in CATHGEN, adjusted for race and sex. 5 p 0.15 0.05 0.03 0.02 0.01 0.02 SNP RS16147 RS9785023 RS5574 RS16474 RS16120 RS16119 CATHGEN Cases Genotype OR (95% CI) 1.25 (0.97–1.62) 1.27 (0.99–1.63) 1.29 (1.01–1.66) 1.32 (1.03–1.70) 1.34 (1.05–1.73) 1.32 (1.02–1.70) p 0.08 0.06 0.04 0.03 0.02 0.03 Allele OR (95% CI) 1.33 (0.91–1.94) 1.46 (1.00–2.12) 1.48 (1.04–2.12) 1.57 (1.08–2.29) 1.65 (1.13–2.40) 1.57 (1.07–2.31) CATHGEN Very-young AOO Cases Genotype OR (95% CI) 1.55 (1.01–2.38) 1.59 (1.04–2.43) 1.51 (0.99–2.30) 1.62 (1.06–2.47) 1.57 (1.03–2.40) 1.59 (1.07–2.35) p 0.05 0.03 0.06 0.03 0.04 0.02 Allele OR (95% CI) 1.84 (0.91–3.72) 1.98 (0.99–3.99) 2.01 (1.03–3.92) 1.93 (0.96–3.89) 2.07 (1.01–4.23) 2.20 (1.43–3.38) p 0.09 0.06 0.04 0.07 0.05 0.0004 AOO: age of onset; OR: Odds Ratio; 95% CI: 95% Confidence Interval; p: p-value. All case groups compared with CATHGEN controls. doi:10.1371/journal.pgen.1000318.t003 PLoS Genetics | www.plosgenetics.org January 2009 | Volume 5 | Issue 1 | e1000318