A recent meta-analysis of Genome-Wide Association Studies (GWAS) of coronary artery disease (CAD) involving over 86,000 individuals identified PPAP2B (encodes lipid phosphate phosphatase-3; LPP3) as a new loci (SNP rs17114036; P= 3.81 X 10−19) that independently predicts CAD. LPP3 is an integral membrane enzyme that dephosphorylates lysophosphatidic acid, sphingosine-1-phosphate and related bioactive lipids. Strikingly, we found that targeted inactivation of LPP3 in endothelial cells results in early embryonic lethality, in part to due to vascular patterning defects. In addition, we found that constitutive inactivation of LPP3 in the myocardium results in cardiac dysfunction, indicating that dysregulation of LPP3-dependent cardiomyocyte cell function. Heart rate was significantly higher in conditional Ppap2bΔ mice (P<0.001), which may indicate a role for LPP3 in regulating heart rate and/or function. Further, we found that myocardial LPP3 levels are altered following myocardial infarction in mice and these results are in accord with our myocardial infarct data from patient that had down-regulated myocardial LPP3 levels. The major rs17114036A allele was associated with a 1.17 odds ratio for CAD. This SNP is located in the final intron of the six exon PPAP2B gene. At least seven SNPs are in robust linkage disequilbrium (r2>0.9) with rs17114036. The sequence surrounding the SNP rs17114036 matches a U1 spliceosome recognition sequence, and the variant base is located at the final position of a sequence with high homology to a U1 spliceosome 5’ spice site recognition motif. Binding of the U1 spliceosome may alter mRNA stability or processing, perhaps by masking cryptic splice sites, thus enabling efficient splicing or promoting polyadenylation of the mature message. To address the polymorphism, we transfected MDA MB 453 cells, which are homozygous for the “T’ allele of rs17114036 SNP, with a short synthetic 2’-O-methyl phosphorothioate RNA. We found a dramatic decrease in both LPP3 protein expression and LPP3 mRNA levels. These results imply that the region containing the rs17114036 SNP may be important for proper processing and/or stability of the LPP3 transcript thereby functionally validating the GWAS study.