A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease

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 -