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Human Molecular Genetics Advance Access published online on January 18, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn020
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Comprehensive Genetic Analysis of the Platelet Activating Factor Acetylhydrolase (PLA2G7) Gene and Cardiovascular Disease in Case/Control and Family Datasets

Beth S. Sutton1, David R. Crosslin1, Svati H. Shah1,2, Sarah C. Nelson1, Anthony Bassil1, A. Brent Hale1, Carol Haynes1, Pascal J. Goldschmidt-Clermont3, Jeffery M. Vance4, William E. Kraus2, Simon G. Gregory1 and Elizabeth R. Hauser1,*

Duke University Medical Center, Durham, NC 27710 1 Center for Human Genetics 2 Division of Cardiovascular Medicine University of Miami, Miami, FL 33136 3 Miller School of Medicine 4 Institute of Human Genomics

* Address Correspondence to: Elizabeth R. Hauser, PhD Center for Human Genetics Duke University Medical Center Center for Human Genetics 595 LaSalle Street Durham, NC 27710 USA Telephone: 919-684-0603 Fax: 919-684-0913 Email: bhauser{at}chg.duhs.duke.edu

Received November 14, 2007; Revised December 20, 2007; Accepted January 15, 2008

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 CAD risk in two large, independent datasets with coronary artery disease (CAD). Using a haplotype tagging (ht) approach, 19 htSNPs were genotyped in CATHGEN case/control samples (cases=806 and controls=267) and in the GENECARD Family Study (n= 1,101 families, 2,954 individuals). Single SNP analysis using logistic regression revealed nine SNPs with significant association in all CATHGEN subjects (P-values ranged 0.0004-0.02). 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-value ranged 0.0001-0.02). The GENECARD probands demonstrated results similar to those seen in the YA CATHGEN cases (P-values ranged 0.002-0.05). Of the 19 SNPs genotyped, three 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 (r2 =0.09). Multiple additional polymorphisms in low LD 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 data sets and multiple statistical approaches. Further functional studies involving a combination of risk alleles are warranted.


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