Left ventricular global transcriptional profiling in human end-stage dilated cardiomyopathy

AbstractWe employed ABI high-density oligonucleotide microarrays containing 31,700 sixty-mer probes (representing 27,868 annotated human genes) to determine differential gene expression in idiopathic dilated cardiomyopathy (DCM). We identified 626 up-regulated and 636 down-regulated genes in DCM compared to controls. Most significant changes occurred in the tricarboxylic acid cycle, angiogenesis, and apoptotic signaling pathways, among which 32 apoptosis- and 13 MAPK activity-related genes were altered. Inorganic cation transporter, catalytic activities, energy metabolism and electron transport-related processes were among the most critically influenced pathways. Among the up-regulated genes were HTRA1 (6.9-fold), PDCD8(AIFM1) (5.2) and PRDX2 (4.4) and the down-regulated genes were NR4A2 (4.8), MX1 (4.3), LGALS9 (4), IFNA13 (4), UNC5D (3.6) and HDAC2 (3) (p<0.05), all of which have no clearly defined cardiac-related function yet. Gene ontology and enrichment analysis also revealed significant alterations in mitochondrial oxidative phosphorylation, metabolism and Alzheimer's disease pathways. Concordance was also confirmed for a significant number of genes and pathways in an independent validation microarray dataset. Furthermore, verification by real-time RT-PCR showed a high degree of consistency with the microarray results. Our data demonstrate an association of DCM with alterations in various cellular events and multiple yet undeciphered genes that may contribute to heart muscle disease pathways

Association of the angiotensinogen gene polymorphism with atherosclerosis and its risk traits in the Saudi population

BACKGROUND: Angiotensinogen (AGT) constitutes a central component of the renin-angiotensin system that controls the systemic blood pressure and several other cardiovascular functions and may play an important role in atherosclerosis pathways. In this study, we employed TaqMan genotyping assays to evaluate the role of 8 AGT variants in primary hypertension (HTN), type 2 diabetes mellitus (T2DM), and obesity as a possible trigger of coronary artery disease (CAD) in a population of 4615 angiographed native Saudi individuals. METHODS: Linkage analysis was done by using the Affymetrix Gene Chip array, sequencing by using the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry using the Applied Biosystem real-time Prism 7900HT Sequence Detection System. RESULTS: Six variants, rs2067853 GG [Odds ratio(95% Confidence Interval) = 1.44(1.17-1.78); p = 0.001], rs7079 [1.49(1.20-1.85); p < 0.0001], rs699 G [1.19(1.08-1.13); p < 0.0001], rs3789679 A [1.51(1.14-1.99); p = 0.004], rs2148582 GG [1.31(1.11-1.55); p = 0.002] and rs5051 TC + CC [1.32(1.13-1.60); p = 0.001] conferred risk for HTN (3521 cases versus 1094 controls). The rs2067853 (p = 0.042), rs699G (p = 0.007) and rs5051 (p = 0.051) also conferred risk for myocardial infarction (MI; 2982 vs 1633), while rs3789679 A (p < 0.0001) and GA + AA (p < 0.0001) as well as rs4762G (p = 0.019) were associated with obesity (1576 vs 2458). However, while these variants appeared to be also associated with CAD (2323 vs 2292), only the rs7079G (p = 0.035) retained its significant relationship. Interestingly, among the haplotypes constructed from these SNPs, the baseline 8-mer haplotype, GGTGGGGT (χ(2) = 7.02; p = 0.0081) and another GGCGGAGT (χ(2) = 5.10; p = 0.024), together with several of their derivatives were associated with HTN. T2DM was associated with two 8-mer haplotypes, GGTAGGAC (χ(2) = 5.66; p = 0.017) and ATTGAGAC (χ(2) = 5.93; p = 0.015), obesity with GGCGGAGT (χ(2) = 9.49; p = 0.0021) and MI was linked to ATTGGGAC (χ(2) = 6.68; p = 0.010) and GGTGGGAT (χ(2) = 4.25; p = 0.039). Furthermore, several causative haplotypes were also shared among the risk traits as well as with CAD. CONCLUSION: These results point to AGT as independently conferring risk for various cardiovascular traits, and possibly interacting with these traits in events leading to atherosclerosis

Behavior of the density current in a semi-closed water body and tidal river

研究科: 千葉大学大学院自然科学研究科博士(学術)報告番号:甲第学287

The Affymetrix DMET Plus Platform Reveals Unique Distribution of ADME-Related Variants in Ethnic Arabs

Background. The Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus Premier Pack has been designed to genotype 1936 gene variants thought to be essential for screening patients in personalized drug therapy. These variants include the cytochrome P450s (CYP450s), the key metabolizing enzymes, many other enzymes involved in phase I and phase II pharmacokinetic reactions, and signaling mediators associated with variability in clinical response to numerous drugs not only among individuals, but also between ethnic populations. Materials and Methods. We genotyped 600 Saudi individuals for 1936 variants on the DMET platform to evaluate their clinical potential in personalized medicine in ethnic Arabs. Results. Approximately 49% each of the 437 CYP450 variants, 56% of the 581 transporters, 56% of 419 transferases, 48% of the 104 dehydrogenases, and 58% of the remaining 390 variants were detected. Several variants, such as rs3740071, rs6193, rs258751, rs6199, rs11568421, and rs8187797, exhibited significantly either higher or lower minor allele frequencies (MAFs) than those in other ethnic groups. Discussion. The present study revealed some unique distribution trends for several variants in Arabs, which displayed partly inverse allelic prevalence compared to other ethnic populations. The results point therefore to the need to verify and ascertain the prevalence of a variant as a prerequisite for engaging it in clinical routine screening in personalized medicine in any given population

Data on common variants associated with coronary artery disease/myocardial infarction in ethnic Arabs

The data shows results acquired in a large cohort of 5668 ethnic Arabs involved in a common variants association study for coronary artery disease (CAD) and myocardial infarction (MI) using the Affymetrix Axiom Genotyping platform (“A genome-wide association study reveals susceptibility loci for myocardial infarction/coronary artery disease in Saudi Arabs” Wakil et al. (2015) [1] ). Several loci were described that conferred risk for CAD or MI, some of which were validated in an independent set of samples. Principal Component (PCA) analysis suggested that the Saudi Cohort was close to the CEU and TSI populations, thus pointing to similarity with European populations

Integrated Left Ventricular Global Transcriptome and Proteome Profiling in Human End-Stage Dilated Cardiomyopathy - Fig 7

<p>Venn diagrams representing overlap of (A) predicted upstream regulators, (B) enriched GO biological processes, and (C) KEGG pathways between differentially expressed genes and proteins.</p

A New Susceptibility Locus for Myocardial Infarction, Hypertension, Type 2 Diabetes Mellitus, and Dyslipidemia on Chromosome 12q24

We examined the role of hepatic nuclear factor-1 alpha (HNF1a) gene polymorphism on coronary artery disease (CAD) traits in 4631 Saudi angiographed individuals (2419 CAD versus 2212 controls) using TaqMan assay on ABI Prism 7900HT sequence detection system. Following adjustment for confounders, the rs2259820_CC (1.19 (1.01–1.42); P=0.041), rs2464196_TT (1.19 (1.00–1.40); P=0.045), and rs2259816_T (1.13 (1.01–1.26); P=0.031) were associated with MI. The rs2259820_T (1.14 (1.03–1.26); P=0.011) and rs2464196_C (1.12 (1.02–1.24); P=0.024) were associated with type 2 diabetes mellitus (T2DM), while the rs2393791_T (1.14 (1.01–1.28); P=0.032), rs7310409_G (1.16 (1.03–1.30); P=0.013), and rs2464196_AG+GG (1.25 (1.05–1.49); P=0.012) were implicated in hypertension. Hypertriglyceridemia was linked to the rs2393791_T (1.14 (1.02–1.27); P=0.018), rs7310409_G (1.12 (1.01–1.25); P=0.031), rs1169310_G (1.15 (1.04–1.28); P=0.010), and rs1169313_CT+TT (1.24 (1.06–1.45); P=0.008) and high low density lipoprotein-cholesterol levels were associated with rs2259820_T (1.23 (1.07–1.41); P=0.004), rs2464196_T (1.22 (1.06–1.39); P=0.004), and rs2259816_T (1.18 (1.02–1.36); P=0.023). A 7-mer haplotype CATATAC (χ2=7.50; P=0.0062), constructed from the studied SNPs, was associated with MI, and CATATA implicated in T2DM (χ2=3.94; P=0.047). Hypertriglyceridemia was linked to TGCGGG (χ2=4.26; P=0.039), and obesity to ACGGGT (χ2=5.04; P=0.025). Our results suggest that the HNF1a is a common susceptibility gene for MI, T2DM, hypertension, and dyslipidemia

Overlapping KEGG pathways for mRNA and proteomics in in dilated cardiomyopathy.

<p>Overlapping KEGG pathways for mRNA and proteomics in in dilated cardiomyopathy.</p

Functional interaction network of 16 genes.

<p>Genes were clustered according to their associated pathways, which are shaded with a different color. Green nodes indicate down-regulated, red, up-regulated, and linker genes (non-colored nodes). The edges represent interactions between genes, with arrows indicating directed interactions and dotted lines indicating predicted relationships.</p

GO Biological Process and pathway analyses of differentially expressed genes (DEGs) and proteins (DEPs) using the PANTHER classification system.

<p>(A-B) Pie charts displaying significantly enriched biological processes respectively, and (C-D) signaling pathways associated with DEGs and DEPs.</p