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Common variants in CASQ2, GPD1L, and NOS1AP are significantly associated with risk of sudden death in patients with coronary artery disease.

ABSTRACT: Recent evidence suggests a genetic component for sudden cardiac death (SCD) in subjects with coronary artery disease (CAD). We conducted a systematic candidate-gene approach using haplotype-tagging single nucleotide polymorphisms (htSNPs) to identify genes associated with SCD risk in the context of CAD.We investigated 1424 htSNPs representing 18 genes with mutations described in patients with ventricular arrhythmias in 291 subjects from the Oregon Sudden Unexpected Death Study (Ore-SUDS). The Ore-SUDS is an ongoing prospective investigation of SCD in the Portland, OR, metropolitan area (population, 1 000 000). SCD cases were ascertained from multiple sources and medical records were reviewed to determine the presence of CAD. A total of 36 SNPs were associated with risk of SCD (uncorrected probability values <0.01) in the initial study sample. These SNPs were subsequently tested for replication in an independent case-control study sample from the Ore-SUDS (n=688). The association analysis in the replication stage revealed 6 SNPs associated with SCD: CASQ2 region (rs17500488, P=0.04; rs3010396, P=0.007; rs7366407; P=0.04), NOS1AP (rs12084280, P=0.04; rs10918859, P=0.02), and 1 SNP located ?26 kb upstream of GPD1L (rs9862154, P=0.04).Common variations in or near CASQ2, GPD1L, and NOS1AP are associated with increased risk of SCD in patients with CAD. These findings provide further evidence for overlap between the genetic architecture of rare and common forms of SCD, and replication in additional populations is warranted.

SUBMITTER: Westaway SK

PROVIDER: S-EPMC3160237 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Common variants in CASQ2, GPD1L, and NOS1AP are significantly associated with risk of sudden death in patients with coronary artery disease.

Westaway Shawn K SK Reinier Kyndaron K Huertas-Vazquez Adriana A Evanado Audrey A Teodorescu Carmen C Navarro Jo J Sinner Moritz F MF Gunson Karen K Jui Jonathan J Spooner Peter P Kaab Stefan S Chugh Sumeet S SS

Circulation. Cardiovascular genetics 20110617 4

<h4>Background</h4>Recent evidence suggests a genetic component for sudden cardiac death (SCD) in subjects with coronary artery disease (CAD). We conducted a systematic candidate-gene approach using haplotype-tagging single nucleotide polymorphisms (htSNPs) to identify genes associated with SCD risk in the context of CAD.<h4>Methods and results</h4>We investigated 1424 htSNPs representing 18 genes with mutations described in patients with ventricular arrhythmias in 291 subjects from the Oregon S ...[more]

PMID: 21685173

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Project description:Coronary artery spasm (CAS) plays an important role in the pathogeneses of various ischemic heart diseases and has gradually become a common cause of life-threatening arrhythmia. The specific molecular mechanism of CAS has not been fully elucidated, nor are there any specific diagnostic markers for the condition. Therefore, this study aimed to examine the specific molecular mechanism underlying CAS, and screen for potential diagnostic markers. To this end, we successfully constructed a rat CAS model and achieved in vitro culture of a human coronary-artery smooth-muscle cell (hCASMC) contraction model. Possible molecular mechanisms by which protein kinase C (PKC) regulated CAS through the C kinase-potentiated protein phosphatase 1 inhibitor of 17 kDa (CPI-17)/myosin II regulatory light chain (MLC2) pathway were studied in vivo and in vitro to screen for potential molecular markers of CAS. We performed hematoxylin and eosin staining, myocardial zymogram, and transmission electron microscopy to determine myocardial and coronary artery injury in CAS rats. Then, using immunohistochemical staining, immunofluorescence staining, and Western blotting, we further demonstrated a potential molecular mechanism by which PKC regulated CAS via the CPI-17/MLC2 pathway. The results showed that membrane translocation of PKCα occurred in the coronary arteries of CAS rats. CPI-17/MLC2 signaling was observably activated in coronary arteries undergoing CAS. In addition, in vitro treatment of hCASMCs with angiotensin II (Ang II) increased PKCα membrane translocation while consistently activating CPI-17/MLC2 signaling. Conversely, GF-109203X and calphostin C, specific inhibitors of PKC, inactivated CPI-17/MLC2 signaling. We also collected the coronary artery tissues from deceased subjects suspected to have died of CAS and measured their levels of phosphorylated CPI-17 (p-CPI-17) and MLC2 (p-MLC2). Immunohistochemical staining was positive for p-CPI-17 and p-MLC2 in the tissues of these subjects. These findings suggest that PKCα induced CAS through the CPI-17/MLC2 pathway; therefore, p-CPI-17 and p-MLC2 could be used as potential markers for CAS. Our data provide novel evidence that therapeutic strategies against PKC or CPI-17/MLC2 signaling might be promising in the treatment of CAS.

Project description:BackgroundLate gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) offers the potential to noninvasively characterize the phenotypic substrate for sudden cardiac death (SCD).ObjectivesThe authors assessed the utility of infarct characterization by CMR, including scar microstructure analysis, to predict SCD in patients with coronary artery disease (CAD).MethodsPatients with stable CAD were prospectively recruited into a CMR registry. LGE quantification of core infarction and the peri-infarct zone (PIZ) was performed alongside computational image analysis to extract morphologic and texture scar microstructure features. The primary outcome was SCD or aborted SCD.ResultsOf 437 patients (mean age: 64 years; mean left ventricular ejection fraction [LVEF]: 47%) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. On multivariable analysis, PIZ mass and core infarct mass were independently associated with the primary outcome (per gram: HR: 1.07 [95% CI: 1.02-1.12]; P = 0.002 and HR: 1.03 [95% CI: 1.01-1.05]; P = 0.01, respectively), and the addition of both parameters improved discrimination of the model (Harrell's C-statistic: 0.64-0.79). PIZ mass, however, did not provide incremental prognostic value over core infarct mass based on Harrell's C-statistic or risk reclassification analysis. Severely reduced LVEF did not predict the primary endpoint after adjustment for scar mass. On scar microstructure analysis, the number of LGE islands in addition to scar transmurality, radiality, interface area, and entropy were all associated with the primary outcome after adjustment for severely reduced LVEF and New York Heart Association functional class of >1. No scar microstructure feature remained associated with the primary endpoint when PIZ mass and core infarct mass were added to the regression models.ConclusionsComprehensive LGE characterization independently predicted SCD risk beyond conventional predictors used in implantable cardioverter-defibrillator (ICD) insertion guidelines. These results signify the potential for a more personalized approach to determining ICD candidacy in CAD.

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Common variants in CASQ2, GPD1L, and NOS1AP are significantly associated with risk of sudden death in patients with coronary artery disease.

Publications

Common variants in CASQ2, GPD1L, and NOS1AP are significantly associated with risk of sudden death in patients with coronary artery disease.

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