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Wu Y, Song J, Liu M, Ma H, Zhang J. Integrating GWAS and proteome data to identify novel drug targets for MU. Sci Rep 2023; 13:10437. [PMID: 37369724 DOI: 10.1038/s41598-023-37177-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 06/17/2023] [Indexed: 06/29/2023] Open
Abstract
Mouth ulcers have been associated with numerous loci in genome wide association studies (GWAS). Nonetheless, it remains unclear what mechanisms are involved in the pathogenesis of mouth ulcers at these loci, as well as what the most effective ulcer drugs are. Thus, we aimed to screen hub genes responsible for mouth ulcer pathogenesis. We conducted an imputed/in-silico proteome-wide association study to discover candidate genes that impact the development of mouth ulcers and affect the expression and concentration of associated proteins in the bloodstream. The integrative analysis revealed that 35 genes play a significant role in the development of mouth ulcers, both in terms of their protein and transcriptional levels. Following this analysis, the researchers identified 6 key genes, namely BTN3A3, IL12B, BPI, FAM213A, PLXNB2, and IL22RA2, which were related to the onset of mouth ulcers. By combining with multidimensional data, six genes were found to correlate with mouth ulcer pathogenesis, which can be useful for further biological and therapeutic research.
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Affiliation(s)
- Yadong Wu
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang, China
| | - Jukun Song
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang, China.
| | - Manyi Liu
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
| | - Hong Ma
- Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang, China.
| | - Junmei Zhang
- Department of Orthodontics, The Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang, 550002, China.
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Forgerini M, Lucchetta RC, Urbano G, de Nadai TR, de Carvalho Mastroianni P. Genetic polymorphisms associated with upper gastrointestinal bleeding: a systematic review. THE PHARMACOGENOMICS JOURNAL 2021; 21:20-36. [PMID: 32948830 DOI: 10.1038/s41397-020-00185-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 08/17/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023]
Abstract
Non-variceal upper gastrointestinal bleeding (non-variceal UGIB) is a frequent and severe adverse drug reaction. Idiosyncratic responses due to genetic susceptibility to non-variceal UGIB has been suggested. A systematic review was conducted to assess the association between genetic polymorphisms and non-variceal UGIB. Twenty-one publications and 7134 participants were included. Thirteen studies evaluated genetic polymorphism in patients exposed to non-steroidal anti-inflammatory drugs, low-dose aspirin, and warfarin. Eight studies present at least one methodological problem. Only six studies clearly defined that the outcome evaluated was non-variceal UGIB. Genetic polymorphisms involved in platelet activation and aggregation, angiogenesis, inflammatory process, and drug metabolism were associated with risk of non-variceal UGIB (NOS3, COX-1; COX-2; PLA2G7; GP1BA; GRS; IL1RN; F13A1; CDKN2B-AS1; DPP6; TBXA2R; TNF-alpha; VKORC1; CYP2C9; and AGT). Further well-designed studies are needed (e.g., clear restriction to non-variceal UGIB; proper selection of participants; and adjustment of confounding factors) to provide strong evidence for pharmacogenetic and personalized medicine.
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Affiliation(s)
- Marcela Forgerini
- Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil
| | - Rosa Camila Lucchetta
- Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil
| | - Gustavo Urbano
- Department of Surgery, School of Medicine, University of São Paulo (USP), Ribeirão Preto, Brazil
| | - Tales Rubens de Nadai
- Department of Public Health, Bauru School of Dentistry, University of São Paulo (USP), Bauru, Brazil
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Sayed KS, El-Komy MHM, Shehata H, ElShazly SH, El Desouky ED, Amr KS, ElAraby NM, AlOrbani AM. JAK1 rs310241 and JAK3 rs3008 Genotypes May Increase Susceptibility to Psoriasis: A Case Control Study. Skin Pharmacol Physiol 2020; 33:207-212. [PMID: 32877908 DOI: 10.1159/000509880] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/17/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Janus kinases (JAKs) are a family of non-receptor protein tyrosine kinases that are expressed in a variety of tissues. Several JAK-controlled cytokine receptor pathways are incriminated in the initiation and progression of psoriasis. Genetic polymorphisms influencing JAK expression would be anticipated to have a great impact on disease activity. OBJECTIVE The aim of the study was to evaluate the association between JAK1 rs310241 and JAK3 rs3008 polymorphisms and the risk of developing psoriasis. METHODS Blood samples of 150 patients and 120 controls were screened for nucleotide polymorphisms in JAK1 rs310241 and JAK3 rs3008 genes by using polymerase chain reaction (PCR)-restriction fragment length polymorphism technique. RESULTS The GG genotype of the JAK1 rs310241 and JAK3 rs3008 genes was significantly associated with an increase in psoriasis risk (p = 0.000, OR = 7.7, 95% CI = 2.8-21.5; p = 0.003, OR = 3.3, 95% CI = 1.5-6.9, respectively). The G allele of both genes was also associated with psoriasis susceptibility (p = 0.000, OR = 2.0, 95% CI = 1.4-2.8; p = 0.002, OR = 1.7, 95% CI = 1.2-2.4, respectively). CONCLUSION The results indicate a possible association between JAK1 rs310241 and JAK3 rs3008 gene polymorphisms and susceptibility to psoriasis. These findings validate the importance of these molecules in psoriasis and may enable the identification of the individuals most susceptible to the disease.
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Affiliation(s)
- Khadiga S Sayed
- Dermatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.,Kasr AL-Ainy's Psoriasis Unit (KAPU), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed H M El-Komy
- Dermatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.,Kasr AL-Ainy's Psoriasis Unit (KAPU), Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hany Shehata
- Department of Dermatology and Venereology, National Research Centre, Giza, Egypt
| | - Sarah H ElShazly
- Dermatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Eman D El Desouky
- Department of Epidemiology and Biostatistics, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Khalda Sayed Amr
- Medical Molecular Genetics Department, National Research Centre, Giza, Egypt
| | - Nesma M ElAraby
- Medical Molecular Genetics Department, National Research Centre, Giza, Egypt
| | - Aya M AlOrbani
- Dermatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt, .,Kasr AL-Ainy's Psoriasis Unit (KAPU), Faculty of Medicine, Cairo University, Cairo, Egypt,
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Figueiredo CA, Marques CR, Costa RDS, Silva HBFD, Alcantara-Neves NM. Cytokines, cytokine gene polymorphisms and Helicobacter pylori infection: Friend or foe? World J Gastroenterol 2014; 20:5235-5243. [PMID: 24833853 PMCID: PMC4017038 DOI: 10.3748/wjg.v20.i18.5235] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 12/11/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is a flagellated, spiral-shaped, microaerophilic Gram-negative bacillus that colonises the gastric mucosa of more than 50% of the human population. Infection is a risk factor for gastritis, ulcer disease and stomach cancer. Immunity against H. pylori is mainly related to Th1/Th17 skewing, and the activation of regulatory T cells is the main strategy used to limit inflammatory responses, which can result in the pathogen persistence and can lead to chronic gastrointestinal diseases, including cancer. Furthermore, host genetic factors that affect cytokines may determine differences in the susceptibility to many diseases. In this review, we present the cytokine profiles and the main cytokine gene polymorphisms associated with resistance/susceptibility to H. pylori and discuss how such polymorphisms may influence infection/disease outcomes.
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Youssef SS, Mostafa A, Nasr AS, el Zanaty T, Seif SM. Interleukin-12B Gene Polymorphism Frequencies in Egyptians and Sex-Related Susceptibility to Hepatitis C Infection. J Interferon Cytokine Res 2013; 33:415-9. [DOI: 10.1089/jir.2012.0161] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
| | - Asmaa Mostafa
- Microbial Biotechnology Department, National Research Center, Cairo, Egypt
| | | | - Taher el Zanaty
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Sameh Mohamed Seif
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
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Cytokine Polymorphisms, Their Influence and Levels in Brazilian Patients with Pulmonary Tuberculosis during Antituberculosis Treatment. Tuberc Res Treat 2013; 2013:285094. [PMID: 23634300 PMCID: PMC3619634 DOI: 10.1155/2013/285094] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 02/19/2013] [Accepted: 02/26/2013] [Indexed: 12/04/2022] Open
Abstract
Cytokines play an essential role during active tuberculosis disease and cytokine genes have been described in association with altered cytokine levels. Therefore, the aim of this study was to verify if IFNG, IL12B, TNF, IL17A, IL10, and TGFB1 gene polymorphisms influence the immune response of Brazilian patients with pulmonary tuberculosis (PTB) at different time points of antituberculosis treatment (T1, T2, and T3). Our results showed the following associations: IFNG +874 T allele and IFNG +2109 A allele with higher IFN-γ levels; IL12B +1188 C allele with higher IL-12 levels; TNF −308 A allele with higher TNF-α plasma levels in controls and mRNA levels in PTB patients at T1; IL17A A allele at rs7747909 with higher IL-17 levels; IL10 −819 T allele with higher IL-10 levels; and TGFB1 +29 CC genotype higher TGF-β plasma levels in PTB patients at T2. The present study suggests that IFNG +874T/A, IFNG +2109A/G, IL12B +1188A/C, IL10 −819C/T, and TGFB1 +21C/T are associated with differential cytokine levels in pulmonary tuberculosis patients and may play a role in the initiation and maintenance of acquired cellular immunity to tuberculosis and in the outcome of the active disease while on antituberculosis treatment.
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Eskandari-Nasab E, Sepanjnia A, Moghadampour M, Hadadi-Fishani M, Rezaeifar A, Asadi-Saghandi A, Sadeghi-Kalani B, Manshadi MD, Pourrajab F, Pourmasoumi H. Circulating levels of interleukin (IL)-12 and IL-13 in Helicobacter pylori-infected patients, and their associations with bacterial CagA and VacA virulence factors. ACTA ACUST UNITED AC 2012; 45:342-9. [PMID: 23163894 DOI: 10.3109/00365548.2012.737930] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The aim of this study was to determine the association of the Helicobacter pylori virulence factors, cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) antibodies, with serum levels of interleukin (IL)-12 and IL-13 in H. pylori-infected duodenal ulcer (DU) patients and H. pylori-infected asymptomatic (AS) carriers in order to elucidate any correlation between them. METHODS A total of 67 DU patients, 48 AS individuals, and 26 healthy H. pylori-negative subjects were enrolled in this study. Serum concentrations of IL-12 and IL-13 were determined by enzyme-linked immunosorbent assay (ELISA) method. Patient sera were tested by Western blot method to determine the presence of serum antibodies to bacterial virulence antigens p120 (CagA) and p95 (VacA). Serum concentrations of IL-12 and IL-13 were compared in 9 groups, including 4 AS phenotypes (CagA⁺VacA⁺, CagA⁺VacA⁻, CagA⁻VacA⁺, CagA⁻VacA⁻), 4 DU phenotypes (CagA⁺VacA⁺, CagA⁺VacA⁻, CagA⁻VacA⁺, CagA⁻VacA⁻), and 1 control group. RESULTS The results revealed that DU patients positive for CagA, independent of the anti-VacA antibody status, showed drastically elevated levels of IL-12 (251 ± 43 pg/ml) when compared with the other groups (p = 0.0001). No significant difference was found between groups regarding levels of IL-13 (p > 0.05). CONCLUSIONS Our findings indicate that in the DU group, the serum concentrations of IL-12 but not of IL-13 were influenced by bacterial CagA, independent of the VacA status, suggesting that high IL-12 levels may contribute to susceptibility to DU in CagA-positive individuals. These findings could possibly be considered to improve the predictive or prognostic values of inflammatory cytokines for DU, and also to design possible novel therapeutic approaches.
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Affiliation(s)
- Ebrahim Eskandari-Nasab
- Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
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Miteva L, Stanilov N, Deliysky T, Mintchev N, Stanilova S. Association of Polymorphisms in Regulatory Regions of Interleukin-12p40 Gene and Cytokine Serum Level with Colorectal Cancer. Cancer Invest 2009; 27:924-31. [DOI: 10.3109/07357900902918486] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Suneetha PV, Goyal A, Hissar SS, Sarin SK. Studies on TAQ1 polymorphism in the 3'untranslated region of IL-12P40 gene in HCV patients infected predominantly with genotype 3. J Med Virol 2006; 78:1055-60. [PMID: 16789008 DOI: 10.1002/jmv.20662] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Host immunity plays an important role in viral persistence and progression of liver disease in HCV infected patients. IL-12 induces production of IFN-gamma, a potent antiviral agent. IL-12 comprises two subunits; IL-p35 and IL-12p40, which are encoded by two different genes located on chromosome 3 and 5, respectively. Single nucleotide polymorphism at A1188C in the 3'UTR of IL-12p40 gene is associated with immune mediated diseases. Association of IL-12p40 A1188C polymorphism with the outcome of HCV infection was investigated in this study. Two hundred and fifty three histologically proven chronic hepatitis C patients (43 +/- 13 years, male:female: 185:68) and 380 matched controls were included. Genotyping was performed by RFLP and confirmed by direct sequencing. To assess correlation of immune gene polymorphism with severity of HCV-related liver disease, patients were divided into those with fibrosis score of < or = 2 (mild) or > 2 (severe), and histological activity index (HAI) of = 5 (mild) or > 5 (severe). The distribution of A/A, A/C or C/C alleles in the controls was comparable to the patients. The distribution of C/C allele was significantly more common in patients with mild as compared to severe fibrosis (23.7% vs. 6.25%, P = 0.004). No significant difference was observed for any of the genetic markers with HAI or with normal or raised alanine aminotransferase (ALT). These results show that the C/C allele of IL-12p40 gene could render genetic protection against development of severe liver disease in patients infected with HCV.
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Affiliation(s)
- P V Suneetha
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
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Current World Literature. Curr Opin Allergy Clin Immunol 2006; 6:67-9. [PMID: 16505615 DOI: 10.1097/01.all.0000202355.95779.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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