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

Wild, Philipp S.; Zeller, Tanja; Schillert, Arne; Szymczak, Silke; Sinning, Christoph R.; Deiseroth, Arne; Schnabel, Renate B.; Lubos, Edith; Keller, Till and Eleftheriadis, Medea S., et al. (2011) In Circulation: Cardiovascular Genetics 4(4). p.203-403
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;... (More)
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.) (Less)
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keywords
coronary artery disease, genome-wide association studies, gene, expression, genetic variation, genomics, eQTL, eSNP, LIPA
in
Circulation: Cardiovascular Genetics
volume
4
issue
4
pages
203 - 403
publisher
American Heart Association
external identifiers
  • wos:000293901300014
  • scopus:80052733701
ISSN
1942-325X
DOI
10.1161/CIRCGENETICS.110.958728
language
English
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yes
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86ac4894-f029-4fcc-adae-61499537b83b (old id 2187159)
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2011-11-01 07:55:06
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2017-10-22 03:30:16
@article{86ac4894-f029-4fcc-adae-61499537b83b,
  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&lt;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.)},
  author       = {Wild, Philipp S. and Zeller, Tanja and Schillert, Arne and Szymczak, Silke and Sinning, Christoph R. and Deiseroth, Arne and Schnabel, Renate B. and Lubos, Edith and Keller, Till and Eleftheriadis, Medea S. and Bickel, Christoph and Rupprecht, Hans J. and Wilde, Sandra and Rossmann, Heidi and Diemert, Patrick and Cupples, L. Adrienne and Perret, Claire and Erdmann, Jeanette and Stark, Klaus and Kleber, Marcus E. and Epstein, Stephen E. and Voight, Benjamin F. and Kuulasmaa, Kari and Li, Mingyao and Schaefer, Arne S. and Klopp, Norman and Braund, Peter S. and Sager, Hendrik and Demissie, Serkalem and Proust, Carole and Koenig, Inke R. and Wichmann, Heinz-Erich and Reinhard, Wibke and Hoffmann, Michael M. and Virtamo, Jarmo and Burnett, Mary Susan and Siscovick, David and Wiklund, Per Gunnar and Qu, Liming and El Mokthari, Nour Eddine and Thompson, John R. and Peters, Annette and Smith, Albert V. and Yon, Emmanuelle and Baumert, Jens and Hengstenberg, Christian and Maerz, Winfried and Amouyel, Philippe and Devaney, Joseph and Schwartz, Stephen and Saarela, Olli and Mehta, Nehal N. and Rubin, Diana and Silander, Kaisa and Hall, Alistair S. and Ferriers, Jean and Harris, Tamara B. and Melander, Olle and Kee, Frank and Hakonarson, Hakon and Schrezenmeir, Juergen and Gudnason, Vilmundur and Elosua, Roberto and Arveiler, Dominique and Evans, Alun and Rader, Daniel J. and Illig, Thomas and Schreiber, Stefan and Bis, Joshua C. and Altshuler, David and Kavousi, Maryam and Witteman, Jaqueline C. M. and Uitterlinden, Andre G. and Hofman, Albert and Folsom, Aaron R. and Barbalic, Maja and Boerwinkle, Eric and Kathiresan, Sekar and Reilly, Muredach P. and O'Donnell, Christopher J. and Samani, Nilesh J. and Schunkert, Heribert and Cambien, Francois and Lackner, Karl J. and Tiret, Laurence and Salomaa, Veikko and Munzel, Thomas and Ziegler, Andreas and Blankenberg, Stefan},
  issn         = {1942-325X},
  keyword      = {coronary artery disease,genome-wide association studies,gene,expression,genetic variation,genomics,eQTL,eSNP,LIPA},
  language     = {eng},
  number       = {4},
  pages        = {203--403},
  publisher    = {American Heart Association},
  series       = {Circulation: Cardiovascular Genetics},
  title        = {A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease},
  url          = {http://dx.doi.org/10.1161/CIRCGENETICS.110.958728},
  volume       = {4},
  year         = {2011},
}