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Mar 2017 DOI 10.14302/issn.2326-0793.jpgr-17-1447
D. Howard TimothyCorresponding author
Center for Genomics & Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
Factors that contribute to the onset of atherosclerosis may be elucidated by bioinformatic techniques applied to multiple sources of genomic and proteomic data. The results of genome wide association studies, such as the CardioGramPlusC4D study, expression data, such as that available from expression quantitative trait loci (eQTL) databases, along with protein interaction and pathway data available in Ingenuity Pathway Analysis (IPA), constitute a substantial set of data amenable to bioinformatics analysis. This study used bioinformatic analyses of recent genome wide association data to identify a seed set of genes likely associated with atherosclerosis. The set was expanded to include protein interaction candidates to create a network of proteins possibly influencing the onset and progression of atherosclerosis. Local average connectivity (LAC), eigenvector centrality, and betweenness metrics were calculated for the interaction network to identify top gene and protein candidates for a better understanding of the atherosclerotic disease process. The top ranking genes included some known to be involved with cardiovascular disease (APOA1, APOA5, APOB, APOC1, APOC2, APOE, CDKN1A, CXCL12, SCARB1, SMARCA4 and TERT), and others that are less obvious and require further investigation (TP53, MYC, PPARG, YWHAQ, RB1, AR, ESR1, EGFR, UBC and YWHAZ). Collectively these data help define a more focused set of genes that likely play a pivotal role in the pathogenesis of atherosclerosis and are therefore natural targets for novel therapeutic interventions.
Jul 2020 DOI 10.14302/issn.2576-6694.jbbs-20-3450
M. Mahmoud MagdyCorresponding author
Faculty of Science, Ain Shams University, Cairo Egypt.
Background Hyperphenylalaninemia (HPA) combined with neurological signs due to impaired catecholamine, dopamine and serotonin synthesis. Symptoms may appears in first week of life but most seen in age of 4 months. Atypical PKU disease caused mainly by deficiency in 6-pyruvoyltetrahydropterin synthase (PTPS) involved in synthesis of BH4. Clinical symptoms may include poor sucking, impaired tone, ataxia, and seizures. The purpose of this study was to analyze the genotype-phenotype relation among BH4 deficient patients because of PTPS mutations in different state of Egypt. Methods Suspected PKU patients loaded with phenylalanine/Kuvan, and the level of phe and phe/tyrosine ratio determined using tandem mass spectrometry by dried blood spots. Blood samples of 13 unrelated Egyptian patients were collected for total RNA extraction, amplification of PTPS gene by PCR followed with sequencing by Sanger method and finally mutations were recorded for genetic analysis. Results The mean value of phe in 13 patients decreased after loaded of phenylalanine from 482.5μmol/L to 270.63 μmol/L as well as phe/tyrosine ratio was decreased from 13.4 to 6.36 after 24hour of treatment with Kuvan. Sanger sequencing of PTPS gene of those patient showed 21 SNPs and Indels mutations. The most repeated mutation is a novel 23 base pair homozygous deletion in 12/13; c.200C>T in four patients, a novel c.86A>T in two patients and three different mutations located once in three different patients (novel c.22C>T; novel c.273G>A and 405T>C) among patients. On amino acid predicted sequences 4 different types of mutations on protein level were presented, 1 deletion mutation in seven amino acid and 3 different missense mutations in addition to 2 silent mutations among 13 patients. Conclusion Patients were the first case of clinical diagnosis as hyperphenylalaninemia (HPA) undergoing genetic diagnosis for PTPS deficiency in Egypt. The sever HPA patients with severe nervous system damage mainly accompanied with deletion mutations and should pay more attention to the BH4 deficiency. While mild HPA is associated with base substitution mutations with mainly transition mutations (7/9; 78%). Next-generation sequencing technique can increase the mutation detection rate when the hereditary diseases are highly suspected in clinic.
Jun 2017 DOI 10.14302/issn.2576-9359.jot-17-1603
Caprara CarlottaCorresponding author
Department of Nephrology, Dialysis and Transplantation; International Renal Research Institute Vicenza (IRRIV); San Bortolo Hospital; Vicenza.
Single-nucleotide polymorphisms (SNPs) in genes involved in immune responses and in the pharmacokinetics/pharmacodynamics of immunosuppressive drugs influence transplant outcomes of patients receiving the same immunosuppressive therapy. The aim of our preliminary study was to determine the SNPs profiles of ABCB1/MDR-1, UGT1A9, IMPDH2, IL-10 and TNF-α genes associated with acute rejection (AR) events in renal allograft recipients. DNA was extracted from whole blood samples of 220 individuals in 3 experimental groups; Case: 41 kidney transplant patients with AR event(s), Control I: 109 kidney transplant patients without AR event, Control II: 70 healthy blood donors. Acute rejection defined as rapid, unexplained rise in serum creatinine was biopsy-proven. 19 SNPs were analyzed by Sanger Sequencing. Analysis of allele and genotype frequencies and gene-disease association tests were performed. Allele frequencies of healthy persons are in line with ones reported from Europe indicating that the studied population is representative. Statistically significant differences only by the comparison of kidney transplant patients with AR event(s) and healthy individuals are found for rs2032582 and rs1045642 SNPs of ABCB1/MDR1, the latter is also not in Hardy-Weinberg equilibrium in our population. Patients with specific alleles for these SPNs are more prone to have acute rejection events. Certain allele variants of ABCB1/MDR1 by modifying the effectiveness of the drugs may compromise the success of the immunosuppressive therapy and put patients at higher risk to reject the new organ. Therefore screening for these polymorphisms before transplantation would help clinicians to more accurately personalize medications.
Feb 2016 DOI 10.14302/issn.2374-9431.jbd-15-890
E. Buroker NormanCorresponding author
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Purpose Signal Transducer and Activator of Transcription 4 (STAT4) is important for signaling by interleukins (IL-12 and IL-23) and type 1 interferons and has been found to have several simple nucleotide polymorphisms (SNPs) associated with human disease. STAT4 SNPs were computationally examined with respect to changes in potential transcriptional factor binding sites (TFBS) and these changes were discussed in relation to human disease. Methods The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in locating all theTFBS in theSTAT4 gene from 4 kb upstream of the transcriptional start site to 8.3 kb past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results The STAT4 SNPs in the 70 kb intron between exon 2 and 3 are in linkage disequilibrium and have previously been found to be significantly associated with several vasculitis diseases as well as diabetes. The SNP alleles were found to alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS and thereby, alter which transcriptional factors potentially regulate the STAT4 gene. These STAT4 SNPs should be considered as regulatory (r) SNPs. Conclusion The alleles of each rSNP were found to generate unique TFBS resulting in potential changes in TF STAT4 regulation. These regulatory changes were discussed with respect to changes in human health that result in disease.
Feb 2016 DOI 10.14302/issn.2326-0793.jpgr-15-889
E. Buroker NormanCorresponding author
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Purpose The endothetal Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) gene which encodes hypoxia-inducible-factor-2 alpha (HIF2a) is a transcription factor that is involved in the response to hypoxia. EPAS1 has been found to have four (rs56721780, rs6756667, rs7589621, rs1868092) simple nucleotide polymorphisms (SNPs) associated with human disease.These SNPs were computationally examined with respect to changes in potential transcriptional factor binding sites (TFBS) and these changes were discussed in relation to disease and alterations in high altitude adaptation in humans. Methods The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in locating all theTFBS in theEPAS1 gene from 1.6 kb upstream of the transcriptional start site to 539 bps past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results The EPAS1 SNPs in the promoter, intron two and the 3’UTR regions have previously been found to be significantly associated with disease and different levels of high-altitude hypoxia among native Tibetans. The SNP alleles were found to alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS and thereby, alter which transcriptional factors potentially regulate the EPAS1 genesuch as for the glucocorticoid and mineralocorticoid nuclear receptor binding sites created by the rs7589621 rSNP EPAS1-G allele. These receptors regulate carbohydrate, protein and fat metabolism. Also the minor rs7589621 rSNP EPAS1-A creates a punitive TFBS for the FOXC TF which is an important regulator of cell viability and resistance to oxidative stress. These EPAS1 SNPs should be considered as regulatory (r) SNPs. Conclusion The alleles of each rSNP were found to generate unique TFBS resulting in potential changes in TF EPAS1 regulation. The punitive changes in TFBS created by the four rSNPs could very well influence the significant cline in allele frequencies seen in Tibetans with increasing altitude or the haplotype association with high altitude polycythemia in male Han Chinese. These regulatory changes were discussed with respect to changes in human health that result in disease and sickness.
May 2013 DOI 10.14302/issn.2324-7339.jcrhap-12-140
Dold LeonaCorresponding author
Department of Internal Medicine, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany
Analyzing SNPs linked to fatty liver disease, this study finds no association with HAART‑related hepatic steatosis in HIV patients. The work underscores the multifactorial nature of antiretroviral toxicity and points to metabolic and pharmacologic contributors beyond common variants.