Leaving out control groups: an internal contrast analysis of gene expression profiles in atrial fibrillation patients--a systems biology approach to clinical categorization.

Atrial fibrillation (AF) is a frequent chronic dysrythmia with an incidence that increases with age (>40). Because of its medical and socio-economic impacts it is expected to become an increasing burden on most health care systems. AF is a multi-factorial disease for which the identification of subtypes is warranted. Novel approaches based on the broad concepts of systems biology may overcome the blurred notion of normal and pathological phenotype, which is inherent to high throughput molecular arrays analysis. Here we apply an internal contrast algorithm on AF patient data with an analytical focus on potential entry pathways into the disease. We used a RMA (Robust Multichip Average) normalized Affymetrix micro-array data set from 10 AF patients (geo_accession #GSE2240). Four series of probes were selected based on physiopathogenic links with AF entryways: apoptosis (remodeling), MAP kinase (cell remodeling), OXPHOS (ability to sustain hemodynamic workload) and glycolysis (ischemia). Annotated probe lists were polled with Bioconductor packages in R (version 2.7.1). Genetic profile contrasts were analysed with hierarchical clustering and principal component analysis. The analysis revealed distinct patient groups for all probe sets. A substantial part (54% till 67%) of the variance is explained in the first 2 principal components. Genes in PC1/2 with high discriminatory value were selected and analyzed in detail. We aim for reliable molecular stratification of AF. We show that stratification is possible based on physiologically relevant gene sets. Genes with high contrast value are likely to give pathophysiological insight into permanent AF subtypes.

Same genotype and different phenotypes in a family with PRKAG2 gene mutation / 中华心血管病杂志

<p><b>OBJECTIVE</b>The gamma(2) subunit of AMP-activated protein kinase (PRKAG2) located in chromosome 7 plays an important role in regulating metabolic pathways, and patients with PRKAG2 mutations are associated with familial ventricular pre-excitation, hypertrophic cardiomyopathy and AV block. We observed the difference on the phenotypes in a large family with same PRKAG2 mutation.</p><p><b>METHOD</b>Direct DNA sequence was performed to screen the exons and exon-intron boundaries of PRKAG2 gene in a large family with 13 affected persons detected by electrocardiography (ECG).</p><p><b>RESULTS</b>Sinus bradycardia, short PR interval, right bundle bunch block (RBBB), complete AV block, atrial flutter, atrial fibrillation and sudden cardiac death were identified in this family. Hypertrophic cardiomyopathy was found in one family member. Genetic analysis revealed a missense mutation (Arg302Glu) in all affected family members. This mutation was previous described in patients with Wolff-Parkinson-White (WPW) syndrome and hypertrophic cardiomyopathy.</p><p><b>CONCLUSIONS</b>Besides WPW syndrome and hypertrophic cardiomyopathy, PRKAG2 mutations are responsible also for a diverse phenotypes. PRKAG2 gene mutation should be suspected with familial occurrence of RBBB, sinus bradycardia, and short PR interval.</p>