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

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  • Additional Information
    • Source:
      Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 101489144 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1942-3268 (Electronic) Linking ISSN: 19423268 NLM ISO Abbreviation: Circ Cardiovasc Genet Subsets: MEDLINE
    • Publication Information:
      Original Publication: Hagerstown, MD : Lippincott Williams & Wilkins
    • Subject Terms:
      Genome-Wide Association Study*; Coronary Artery Disease/*genetics ; Sterol Esterase/*genetics; Case-Control Studies ; Chromosomes, Human, Pair 10 ; Coronary Artery Disease/etiology ; Endothelium, Vascular/physiopathology ; Gene Expression Profiling ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Monocytes/metabolism ; Polymorphism, Single Nucleotide ; RNA, Messenger/analysis
    • 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=3.7×10(-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.
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    • Grant Information:
      N01 AG012100 United States AG NIA NIH HHS; N01 HC025195 United States HC NHLBI NIH HHS; R01 HL087676 United States HL NHLBI NIH HHS; R01 HL087676-01 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (RNA, Messenger)
      EC 3.1.1.13 (LIPA protein, human)
      EC 3.1.1.13 (Sterol Esterase)
    • Publication Date:
      Date Created: 20110525 Date Completed: 20120217 Latest Revision: 20220317
    • Publication Date:
      20231215
    • Accession Number:
      PMC3157552
    • Accession Number:
      10.1161/CIRCGENETICS.110.958728
    • Accession Number:
      21606135