CARDIoGRAM study to expand knowledge on the role of genetic variation in CAD
Preuss M. Circ Cardiovasc Genet. 2010;doi:10.1161/CIRCGENETICS.109.899443.
A documented increase in risk for MI of more than 25% in three single nucleotide polymorphisms is leading researchers to conduct CARDIoGRAM, the largest published individual coronary artery disease genome-wide association study, according to a recent proof-of-principal analysis published online by Circulation: Cardiovascular Genetics.
The Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) study is a genome-wide association meta-analysis of individuals with European ancestry, involving more than 22,000 cases with CAD and/or MI and 60,000 controls. All genotyping was performed on Affymetrix or Illumina platforms followed by imputation of genotypes in most studies.
According to data presented in their analysis, there was a strong association between CAD and the single nucleotide polymorphisms rs1333049 (OR=1.29; 95% CI, 1.22-1.36), rs2383206 (OR=1.28; 95% CI, 1.22-1.35), rs10757278 (OR=1.28; 95% CI, 1.21-1.35), but no association with rs10811661 (OR=1.02; 95% CI, 0.98-1.05).
Collectively, the consortium will enhance the statistical power to association by increasing the sample size by a factor of 10 for cases and 20 for controls, the researchers commented in their analysis.
“These larger samples are likely to substantially enhance the detection of true associations for CAD risk. Furthermore, we have prepared for a substantial replication phase and defined hierarchical levels of evidence a priori to help attach an appropriate level of confidence to our various findings as they emerge,” they added.
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Distinct characteristics of myocytes reported in patients with type 1 long-QT syndrome
Moretti A. N Engl J Med. 2010;363:1397-1409.
Myocytes of patients with type 1 long-QT syndrome exhibit prolongation of the action potential, altered IKs activation and deactivation properties, and an abnormal response to catecholamine stimulation with a protective effect of beta-blockade, study data have shown.
“Even though the incidence of the long-QT syndrome is only one case per 2,500 live births, [type 1 long-QT syndrome] provides a platform for showing the suitability of induced pluripotent stem-cell technology as a means of exploring disease mechanisms in human genetic cardiac disorders,” researchers wrote.
In the study, researchers screened a family affected by type 1 long-QT syndrome, which included an 8-year-old boy and his 42-year-old father, 39-year-old aunt and 70-year-old grandfather. They identified an autosomal dominant missense mutation (R190Q) in the KCNQ1 gene and collected dermal fibroblasts from two family members and two healthy controls. The fibroblasts were then infected with retroviral vectors encoding the human transcription factors OCT3/4, SOX2, KLF4 and c-MYC to generate pluripotent stem cells.
According to researchers, induced pluripotent stem cells maintained the disease genotype of long-QT syndrome type 1 and generated functional myocytes. Expression of cell type-specific markers and recordings of the action potentials in single cells indicated a “ventricular,” “atrial” or “nodal” phenotype of individual cells.
Additional characterization of the role of the R190Q-KCNQ1 mutation in the syndrome’s pathogenesis suggested a dominant negative trafficking defect, which was associated with a 70% to 80% reduction in IKs current and altered channel activation and deactivation properties. Furthermore, myocytes derived from patients with long-QT syndrome type 1 had a heightened susceptibility to catecholamine-induced tachyarrhythmia, which was attenuated by beta-blockade.
“Larger sets of long-QT syndrome cell lines harboring different channel mutations will be needed to further validate the disease phenotype and compare pathogenetic mechanisms in diverse forms of the disease,” the researchers concluded. “Clinically, the severity of manifestations of the long-QT syndrome varies among family members, and incomplete penetrance exists. However, we did not observe any phenotypic differences in the prolongation of the action potential between the myocytes from our two patients, a finding that is probably due to the similarity of the clinical phenotype in these cases.”
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