A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

PS Wild, T Zeller, A Schillert, S Szymczak, CR Sinning, A Deiseroth, RB Schnabel, E Lubos, T Keller, MS Eleftheriadis, C Bickel, HJ Rupprecht, S Wilde, H Rossmann, P Diemert, LA Cupples, C Perret, J Erdmann, K Stark, ME KleberSE Epstein, BF Voight, K Kuulasmaa, MY Li, AS Schafer, N Klopp, PS Braund, H Sager, S Demissie, C Proust, IR Konig, HE Wichmann, W Reinhard, MM Hoffmann, J Virtamo, MS Burnett, D Siscovick, PG Wiklund, LM Qu, NE El Mokthari, JR Thompson, A Peters, AV Smith, E Yon, J Baumert, C Hengstenberg, W Marz, P Amouyel, J Devaney, S Schwartz, O Saarela, NN Mehta, D Rubin, K Silander, AS Hall, J Ferriers, TB Harris, O Melander, F Kee, H Hakonarson, J Schrezenmeir, V Gudnason, R Elosua, D Arveiler, A Evans, DJ Rader, T Illig, S Schreiber, JC Bis, D Altshuler, Maryam Kavousi, JCM Witteman, André Uitterlinden, Bert Hofman, AR Folsom, M Barbalic, E Boerwinkle, S Kathiresan, MP Reilly, CJ O'Donnell, NJ Samani, H Schunkert, F Cambien, KJ Lackner, L Tiret, V Salomaa, T Munzel, A Ziegler, S Blankenberg

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Abstract

Background-eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results-In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7 x 10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3 x 10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4 x 10(-3)). Conclusions-The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD. (Circ Cardiovasc Genet. 2011;4:403-412.)
Original languageUndefined/Unknown
Pages (from-to)403-U203
JournalCirculation-cardiovascular genetics
Volume4
Issue number4
Publication statusPublished - 2011

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