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Dina El-Dahshan Doaa Bahy Ahmed Wahid Amr E. Ahmed Amro Hanora 《Arab Journal Of Gastroenterology》2018,19(3):106-115
Background and study aims
The double-stranded RNA dependent protein kinase (PKR) plays a vital role in the immune system. During HCV infection, PKR has antiviral effect by inhibition of protein synthesis of the HCV. The functional single nucleotide polymorphisms (SNPs) in PKR promoter region might have a relation to HCV disease outcome and response to treatment. The objective of the present work was threefold. First, it proposed an optimized protocol for PCR amplification of PKR promoter. Second, it screened the promoter region of PKR gene in HCV Egyptian patients to detect the possible SNPs’ function. Third, to study the association between the detected SNPs and the response to treatment.Patients and methods
The functional SNPs in PKR promoter region were detected using DNA sequencing in 40 HCV infected patients; 20 sustained virologic response (SVR) patients and 20 nonresponse (NR) patients after combined interferon/ribavirin therapy. Twenty healthy subjects were included as a control.Results
Two functional SNPs were detected: rs62133148T>G and rs12992188C>T within our target PKR promoter region. In rs62133148 polymorphism, there is a significant difference between patients and control subjects for TT and TG genotypes (p?<?0.0001). In addition, the G allele is more predominant in HCV patients. In rs12992188 polymorphism, the CC genotype is significantly different between patients and healthy control subjects (OR/95% CI: 0.033/0.006–0.172, p?<?0.0001). The presence of C allele was significantly associated with the NR patients (OR/95%CI: 0.25/0.097–0.643, p?=?0.006). The TT genotype is significantly different between SVR and NR (OR/95%CI: 8.5/1.54–46.871, p?=?0.014).Conclusion
This study is a pioneer clinical study on these two functional SNPs (rs62133148T>G and rs12992188 C>T). The rs62133148 polymorphism does not show any association with response to treatment. The TT genotype in rs12992188 polymorphism shows association with response to treatment. Therefore, patients with TT genotypes were more likely to achieve SVR. 相似文献14.
目的分析前列腺亮氨酸拉链(PrLZ)基因3′非编码区(3′-UTR)可能的微小RNA(miRNA)调控位点,构建PrLZ基因3′-UTR荧光素酶报告载体,为研究PrLZ基因转录后的miRNA调控提供有效的工具。方法使用PCR方法从PrLZ阳性的C4-2细胞中扩增含PrLZ基因3′-UTR区序列,插入到T-Vector载体上,提高PCR产物的连接、克隆效率,通过Xbal和BamHI限制性内切酶双酶切后将其连入经相同内切酶双酶切后的荧光素酶报告基因载体pLUC中,构建pLUC-PrLZ 3′-UTR载体,使用生物信息学方法预测PrLZ基因3′-UTR可能是miR-34a的作用靶点,使用慢病毒载体构建对照载体(质粒名称-NC)和过表达miR-34a(质粒名称-miR-34a),包装成病毒颗粒后分别感染293-T细胞,然后通过X-tremeGENE HP DNA Transfection Reagent转染试剂将pLUC空质粒和pLUC-PrLZ 3′-UTR重组质粒分别转染293-T细胞,Promega试剂盒测定荧光素酶的活性。结果得到含PrLZ基因3′-UTR序列的荧光素酶报告重组质粒,并用凝胶电泳和基因测序的方法验证了其序列的正确性。在miR-34a高表达组的293-T细胞中,重组质粒组荧光素酶活性比空质粒组低40%,差异具有统计学意义(P0.05)。结论成功构建PrLZ基因3′-UTR荧光素酶报告载体,miR-34a可以显著降低荧光素酶的活性,PrLZ基因3′-UTR上可能有miR-34a的调控作用靶点。 相似文献
15.
Natalia Castaño-Rodríguez Nadeem O. Kaakoush Aryce L. Pardo Khean-Lee Goh Kwong Ming Fock Hazel M. Mitchell 《Human immunology》2014
Background
Gastric cancer (GC) is a progressive process initiated by Helicobacter pylori-induced inflammation. Initial recognition of H. pylori involves Toll-like receptors (TLRs), central molecules in the host inflammatory response. Here, we investigated the association between novel polymorphisms in genes involved in the TLR signalling pathway, including TLR2, TLR4, LBP, MD-2, CD14 and TIRAP, and risk of H. pylori infection and related GC.Methods
A case-control study comprising 310 ethnic Chinese individuals (87 non-cardia GC cases and 223 controls with functional dyspepsia) was conducted. Twenty-five polymorphisms were detected by MALDI-TOF mass spectrometry, PCR, PCR–RFLP and real-time PCR.Results
Seven polymorphisms showed significant associations with GC (TLR4 rs11536889, TLR4 rs10759931, TLR4 rs1927911, TLR4 rs10116253, TLR4 rs10759932, TLR4 rs2149356 and CD14 −260 C/T). In multivariate analyses, TLR4 rs11536889 remained a risk factor for GC (OR: 3.58, 95% CI: 1.20–10.65). TLR4 rs10759932 decreased the risk of H. pylori infection (OR: 0.59, 95% CI: 0.41–0.86). Statistical analyses assessing the joint effect of H. pylori infection and the selected polymorphisms revealed strong associations with GC (TLR2, TLR4, MD-2, LBP and TIRAP polymorphisms).Conclusions
Novel polymorphisms in TLR2, TLR4, MD-2, LBP, CD14 and TIRAP, genes encoding important molecules of the TLR signalling pathway, showed clear associations with H. pylori-related GC in Chinese. 相似文献16.
Reduced expression of human leukocyte antigen-G (HLA-G) has been linked to onset of preeclampsia. Associations have also been reported between preeclampsia and single nucleotide polymorphisms (SNP) in the 3′-untranslated region (UTR) of the HLA-G gene. However, there are conflicting results between studies. This studied examined whether a SNP, by itself or in combination with other SNPs, in the 3′UTR of the HLA-G gene is associated with an increased risk of preeclampsia. Placenta samples were obtained from 47 preeclamptic and 68 control cases. DNA was extracted, and the 3′UTR was sequenced and analyzed for nine polymorphisms using different genetic models of inheritance. Four of these polymorphisms have never been analyzed for an association with preeclampsia. Disputing existing reports, preeclamptic cases were suggestively associated with a G/G-genotype at SNP +3187 (p < 0.05). Several SNP combinations were more prevalent in preeclampsia cases. Following corrections for multiple testing, one SNP combination (+3027C/C and +3187G/G) was significantly more prevalent in preeclampsia cases using co-dominant, additive, and dominant models (p < 0.001). Taken together with the current literature, the data suggests that HLA-G 3′UTR SNP-pair associations, and not individual SNPs, could be useful in a predictive test for the susceptibility to preeclampsia. 相似文献
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18.
Daniel P. Potaczek Sebastian D. Unger Nan Zhang Styliani Taka Sven Michel Nesibe Akdağ Feng Lan Markus Helfer Christoph Hudemann Markus Eickmann Chrysanthi Skevaki Spyridon Megremis Anne Sadewasser Bilal Alashkar Alhamwe Fahd Alhamdan Mübeccel Akdis Michael R. Edwards Sebastian L. Johnston Harald Renz 《The Journal of allergy and clinical immunology》2019,143(4):1403-1415
19.
Jajati K. Mohapatra Abhipsa Sahu Sushanta K. Barik Aniket Sanyal Bramhadev Pattnaik 《Virus genes》2009,39(1):81-89
India is endemic for foot-and-mouth disease (FMD) and in recent years a unique group within serotype A, carrying a codon deletion
at an antigenically critical site in capsid protein VP3 has emerged (VP359-deletion group). This tempted us to analyze the noncoding region, which is an under represented area, though critically associated
with virus biology and pathogenesis. Analysis of the large fragment of 5′ untranslated region (LF-5′ UTR) of type A FMD virus
revealed discrepancy in the overall tree topology between LF-5′ UTR and 1D region possibly due to independent evolution of
coding and noncoding regions. The VP359-deletion group maintained its phylogenetic distinctness even at the LF-5′ UTR. Eighteen lineage specific signatures detected
here support independent evolutionary paths for the lineages. Extensive deletions of 45 and 89 nucleotides corresponding to
the pseudoknot region were noticed. Conservation pattern in the ‘A253AACA’ motif in the cre/bus stem-loop indicates the importance of first three ‘A’ residues in VPg uridylylation. Of the three polypyrimidine tract binding
protein (PTB) binding sites mapped on the internal ribosome entry site (IRES), the pyrimidine tract (Py tract) in the loop
of domain 2 was found to be maximally conserved and it might be the major PTB binding site. Strikingly, a deletion group lineage
specific transversion was noticed in the Py tract at the 3′ end of IRES without significantly affecting its in vitro infectious
titer. Hence, we presume that for efficient cap-independent viral translation, either a minimum number of pyrimidine residues
rather than a complete Py tract or a Py tract tolerating transversions only at specific locations and a core motif ‘CUUU’
within the Py tract is essential. 相似文献
20.
Cynthia J. Schoen Sarah B. Emery Marc C. Thorne Hima R. Ammana El?bieta ?liwerska Jameson Arnett Michael Hortsch Frances Hannan Margit Burmeister Marci M. Lesperance 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(30):13396-13401
Auditory neuropathy is a rare form of deafness characterized by an absent or abnormal auditory brainstem response with preservation of outer hair cell function. We have identified Diaphanous homolog 3 (DIAPH3) as the gene responsible for autosomal dominant nonsyndromic auditory neuropathy (AUNA1), which we previously mapped to chromosome 13q21-q24. Genotyping of additional family members narrowed the interval to an 11-Mb, 3.28-cM gene-poor region containing only four genes, including DIAPH3. DNA sequencing of DIAPH3 revealed a c.-172G > A, g. 48G > A mutation in a highly conserved region of the 5′ UTR. The c.-172G > A mutation occurs within a GC box sequence element and was not found in 379 controls. Using genome-wide expression arrays and quantitative RT-PCR, we demonstrate a 2- to 3-fold overexpression of DIAPH3 mRNA in lymphoblastoid cell lines from affected individuals. Likewise, a significant increase (≈1.5-fold) in DIAPH3 protein was found by quantitative immunoblotting of lysates from lymphoblastoid cell lines derived from affected individuals in comparison with controls. In addition, the c.-172G > A mutation is sufficient to drive overexpression of a luciferase reporter. Finally, the expression of a constitutively active form of diaphanous protein in the auditory organ of Drosophila melanogaster recapitulates the phenotype of impaired response to sound. To date, only two genes, the otoferlin gene OTOF and the pejvakin gene PJVK, are known to underlie nonsyndromic auditory neuropathy. Genetic testing for DIAPH3 may be useful for individuals with recessive as well as dominant inheritance of nonsyndromic auditory neuropathy. 相似文献