Comprehensive genetic analysis of the platelet activating factor acetylhydrolase ( PLA2G7 ) gene and cardiovascular disease in casecontrol and family datasets

Author: Sutton Beth S.   Crosslin David R.   Shah Svati H.   Nelson Sarah C.   Bassil Anthony   Hale A. Brent   Haynes Carol   Goldschmidt-Clermont Pascal J.   Vance Jeffery M.   Seo David   Kraus William E.   Gregory Simon G.   Hauser Elizabeth R.  

Publisher: Oxford University Press

ISSN: 1460-2083

Source: Human Molecular Genetics, Vol.17, Iss.9, 2008-05, pp. : 1318-1328

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Abstract

Platelet-activating factor acetylhydrolase (PLA2G7) is a potent pro- and anti-inflammatory molecule that has been implicated in multiple inflammatory disease processes, including cardiovascular disease. The goal of this study was to investigate the genetic effects of PLA2G7 on coronary artery disease (CAD) risk in two large, independent datasets with CAD. Using a haplotype tagging (ht) approach, 19 ht single nucleotide polymorphisms (SNPs) were genotyped in CATHGEN casecontrol samples (cases 806 and controls 267) and in the GENECARD Family Study (n 1101 families, 2954 individuals). Single SNP analysis using logistic regression revealed nine SNPs with significant association in all CATHGEN subjects (P 0.00040.02). CATHGEN cases were further stratified into subgroups based on age of CAD onset (AOO) and severity of disease; 599 young affecteds (YA, AOO <56) and="" 207="" old="" affected="" (oa,="" aoo="">56). Significant genetic effects were observed in both OA and YA (P 0.00010.02). The GENECARD probands demonstrated results similar to those seen in the YA CATHGEN cases (P 0.0020.05). Of the 19 SNPs genotyped, 3 SNPs result in nonsynonymous coding changes (I198T, A379V and R92H). Two of the coding SNPs, R92H and A379V, constitute two of the most significantly associated SNPs, even after Bonferroni correction and appear to represent independent associations (r 2 0.09). Multiple additional polymorphisms in low linkage disequilibrium with these coding SNPs were also strongly associated. In summary, PLA2G7 represents an important, potentially functional candidate in the pathophysiology of CAD based on replicated associations using two independent datasets and multiple statistical approaches. Further functional studies involving a combination of risk alleles are warranted.

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