A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease
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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; Eleftheriadis, Medea S; Bickel, Christoph; Rupprecht, Hans J; Wilde, Sandra; Rossmann, Heidi; Diemert, Patrick; Cupples, L Adrienne; Perret, Claire; Erdmann, Jeanette; Stark, Klaus; Kleber, Marcus E; Epstein, Stephen E; Voight, Benjamin F; Kuulasmaa, Kari; Li, Mingyao; Schäfer, Arne S; Klopp, Norman; Braund, Peter S; Sager, Hendrik B; Demissie, Serkalem; Proust, Carole; König, Inke R; Wichmann, Heinz-Erich; Reinhard, Wibke; Hoffmann, Michael M; Virtamo, Jarmo; Burnett, Mary Susan; Siscovick, David; Wiklund, Per Gunnar; Qu, Liming; El Mokthari, Nour Eddine; Thompson, John R; Peters, Annette; Smith, Albert V; Yon, Emmanuelle; Baumert, Jens; Hengstenberg, Christian; März, Winfried; Amouyel, Philippe; Devaney, Joseph; Schwartz, Stephen M; Saarela, Olli; Mehta, Nehal N; Rubin, Diana; Silander, Kaisa; Hall, Alistair S; Ferrieres, Jean; Harris, Tamara B; Melander, Olle; Kee, Frank; Hakonarson, Hakon; Schrezenmeir, Juergen; Gudnason, Vilmundur; Elosua, Roberto; Arveiler, Dominique; Evans, Alun; Rader, Daniel J; Illig, Thomas; Schreiber, Stefan; Bis, Joshua C; Altshuler, David; Kavousi, Maryam; Witteman, Jaqueline C M; Uitterlinden, Andre G; Hofman, Albert; Folsom, Aaron R; Barbalic, Maja; Boerwinkle, Eric; Kathiresan, Sekar; Reilly, Muredach P; O'Donnell, Christopher J; Samani, Nilesh J; Schunkert, Heribert; Cambien, Francois; Lackner, Karl J; Tiret, Laurence; Salomaa, Veikko; Munzel, Thomas; Ziegler, Andreas; Blankenberg, Stefan.
in: CIRC-CARDIOVASC GENE, Jahrgang 4, Nr. 4, 01.08.2011, S. 403-12.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease
AU - Wild, Philipp S
AU - Zeller, Tanja
AU - Schillert, Arne
AU - Szymczak, Silke
AU - Sinning, Christoph R
AU - Deiseroth, Arne
AU - Schnabel, Renate B
AU - Lubos, Edith
AU - Keller, Till
AU - Eleftheriadis, Medea S
AU - Bickel, Christoph
AU - Rupprecht, Hans J
AU - Wilde, Sandra
AU - Rossmann, Heidi
AU - Diemert, Patrick
AU - Cupples, L Adrienne
AU - Perret, Claire
AU - Erdmann, Jeanette
AU - Stark, Klaus
AU - Kleber, Marcus E
AU - Epstein, Stephen E
AU - Voight, Benjamin F
AU - Kuulasmaa, Kari
AU - Li, Mingyao
AU - Schäfer, Arne S
AU - Klopp, Norman
AU - Braund, Peter S
AU - Sager, Hendrik B
AU - Demissie, Serkalem
AU - Proust, Carole
AU - König, Inke R
AU - Wichmann, Heinz-Erich
AU - Reinhard, Wibke
AU - Hoffmann, Michael M
AU - Virtamo, Jarmo
AU - Burnett, Mary Susan
AU - Siscovick, David
AU - Wiklund, Per Gunnar
AU - Qu, Liming
AU - El Mokthari, Nour Eddine
AU - Thompson, John R
AU - Peters, Annette
AU - Smith, Albert V
AU - Yon, Emmanuelle
AU - Baumert, Jens
AU - Hengstenberg, Christian
AU - März, Winfried
AU - Amouyel, Philippe
AU - Devaney, Joseph
AU - Schwartz, Stephen M
AU - Saarela, Olli
AU - Mehta, Nehal N
AU - Rubin, Diana
AU - Silander, Kaisa
AU - Hall, Alistair S
AU - Ferrieres, Jean
AU - Harris, Tamara B
AU - Melander, Olle
AU - Kee, Frank
AU - Hakonarson, Hakon
AU - Schrezenmeir, Juergen
AU - Gudnason, Vilmundur
AU - Elosua, Roberto
AU - Arveiler, Dominique
AU - Evans, Alun
AU - Rader, Daniel J
AU - Illig, Thomas
AU - Schreiber, Stefan
AU - Bis, Joshua C
AU - Altshuler, David
AU - Kavousi, Maryam
AU - Witteman, Jaqueline C M
AU - Uitterlinden, Andre G
AU - Hofman, Albert
AU - Folsom, Aaron R
AU - Barbalic, Maja
AU - Boerwinkle, Eric
AU - Kathiresan, Sekar
AU - Reilly, Muredach P
AU - O'Donnell, Christopher J
AU - Samani, Nilesh J
AU - Schunkert, Heribert
AU - Cambien, Francois
AU - Lackner, Karl J
AU - Tiret, Laurence
AU - Salomaa, Veikko
AU - Munzel, Thomas
AU - Ziegler, Andreas
AU - Blankenberg, Stefan
PY - 2011/8/1
Y1 - 2011/8/1
N2 - 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=3.7×10(-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=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-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.
AB - 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=3.7×10(-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=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-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.
KW - Case-Control Studies
KW - Chromosomes, Human, Pair 10
KW - Coronary Artery Disease
KW - Endothelium, Vascular
KW - Gene Expression Profiling
KW - Genetic Predisposition to Disease
KW - Genetic Variation
KW - Genome-Wide Association Study
KW - Humans
KW - Monocytes
KW - Polymorphism, Single Nucleotide
KW - RNA, Messenger
KW - Sterol Esterase
U2 - 10.1161/CIRCGENETICS.110.958728
DO - 10.1161/CIRCGENETICS.110.958728
M3 - SCORING: Journal article
C2 - 21606135
VL - 4
SP - 403
EP - 412
JO - CIRC-CARDIOVASC GENE
JF - CIRC-CARDIOVASC GENE
SN - 1942-325X
IS - 4
ER -