1
|
Ab Rajab NS, Yasin MAM, Ghazali WSW, Talib NA, Taib WRW, Sulong S. Schizophrenia and Rheumatoid Arthritis Genetic Scenery: Potential Non-HLA Genes Involved in Both Diseases Relationship. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2024; 97:281-295. [PMID: 39351328 PMCID: PMC11426293 DOI: 10.59249/fbot5313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
Background: The link between rheumatoid arthritis (RA) and schizophrenia (SZ) has long been a hot topic of deliberation among scientists from various fields. Especially when it comes to genetics, the connection between RA and SZ is still up for discussion, as can be observed in this study. The HLA genes are the most disputed in identifying a connection between the two diseases, but a more thorough investigation of other genes that may be ignored could yield something even more interesting. Thus, finding the genes responsible for this long-sought relationship will necessitate looking for them. Materials and Methods: Shared and overlapped associated genes involved between SZ and RA were extracted from four databases. The overlapping genes were examined using Database for Annotation, Visualization and Integrated Discovery (DAVID) and InnateDB to search the pertinent genes that concatenate between these two disorders. Results: A total of 91 overlapped genes were discovered, and that 13 genes, divided into two clusters, showed a similarity in function, suggesting that they may serve as an important meeting point. FCGR2A, IL18R, BTNL2, AGER, and CTLA4 are five non-HLA genes related to the immune system, which could lead to new discoveries about the connection between these two disorders. Conclusion: An in-depth investigation of these functionally comparable non-HLA genes that overlap could reveal new interesting information in both diseases. Understanding the molecular and immune-related aspects of RA and SZ may shed light on their etiology and inform future research on targeted treatment strategies.
Collapse
Affiliation(s)
- Nur Shafawati Ab Rajab
- Human Genome Centre, School of Medical Sciences,
Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Mohd Azhar Mohd Yasin
- Department of Psychiatry, School of Medical Sciences,
Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Wan Syamimee Wan Ghazali
- Department of Internal Medicine, School of Medical
Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Norlelawati Abdul Talib
- Department of Pathology and Laboratory Medicine,
Kuliyyah of Medicine, International Islamic University Malaysia, Kuantan,
Pahang, Malaysia
| | - Wan Rohani Wan Taib
- Faculty of Medicine and Health Sciences, Universiti
Sultan Zainal Abidin, Kampung Gong Badak, Terengganu, Malaysia
| | - Sarina Sulong
- Human Genome Centre, School of Medical Sciences,
Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| |
Collapse
|
2
|
Jahid M, Khan KU, Rehan-Ul-Haq, Ahmed RS. Overview of Rheumatoid Arthritis and Scientific Understanding of the Disease. Mediterr J Rheumatol 2023; 34:284-291. [PMID: 37941854 PMCID: PMC10628871 DOI: 10.31138/mjr.20230801.oo] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/08/2023] [Accepted: 02/13/2023] [Indexed: 11/10/2023] Open
Abstract
Rheumatoid arthritis (RA), a chronic inflammatory autoimmune disorder, is characterised by persistent synovial inflammation, erosion of bones and cartilage, leading to joint destruction. Clinical manifestations are morning stiffness, pain in shoulder, neck and pelvic girdle, loss of mobility with fever, fatigue, malaise, loss of body weight, and development of rheumatoid nodules. Environmental and genetic factors are important contributors in its susceptibility. Association between RA and diet, cigarette smoking, hormones, alcohol, microbiota, infection, and coffee have also been reported. To diagnose patients with RA, American college of rheumatology (ACR, 2010) criteria, developed by European league against rheumatism (EULAR). Inflammation produced in RA patients is due to cell-mediated immune response. The rheumatoid synovium consists of a large number of CD4+ T cells suggesting pathogenic nature of T cells in this disorder. B-cells may also participate in the pathogenesis by several means such as autoantibodies, by instigation of T-cells through expression of co-stimulatory molecules, by generating pro-inflammatory and anti-inflammatory cytokines and by organisation of other inflammatory cells. The conventional management of RA usually focuses over reducing pain and limiting the disability by medical therapies which include a number of classes of agents such as non-steroidal anti-inflammatory drugs (NSAIDs), non-biological and biological agents, disease-modifying anti rheumatic drugs (DMARDs), immunosuppressants, and corticosteroids. However, only proper rehabilitation can promote the objective to achieve the joint functionality and ease of motion which improves independence as well as quality of life in patient suffering from Rheumatoid Arthritis.
Collapse
Affiliation(s)
- Mohd Jahid
- Department of Biochemistry, University College of Medical Sciences and GTB Hospital (University of Delhi), Dilshad Garden, Delhi, India
| | - Karim Ullah Khan
- Department of Orthopaedics, University College of Medical Sciences and GTB Hospital (University of Delhi), Dilshad Garden, Delhi, India
| | - Rehan-Ul-Haq
- Department of Orthopaedics, All India Institute of Medical Sciences (AIIMS) Bhopal, India
| | - Rafat Sultana Ahmed
- Department of Biochemistry, University College of Medical Sciences and GTB Hospital (University of Delhi), Dilshad Garden, Delhi, India
| |
Collapse
|
3
|
Ataş PK. A novel hybrid model to predict concomitant diseases for Hashimoto's thyroiditis. BMC Bioinformatics 2023; 24:319. [PMID: 37620755 PMCID: PMC10464155 DOI: 10.1186/s12859-023-05443-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023] Open
Abstract
Hashimoto's thyroiditis is an autoimmune disorder characterized by the destruction of thyroid cells through immune-mediated mechanisms involving cells and antibodies. The condition can trigger disturbances in metabolism, leading to the development of other autoimmune diseases, known as concomitant diseases. Multiple concomitant diseases may coexist in a single individual, making it challenging to diagnose and manage them effectively. This study aims to propose a novel hybrid algorithm that classifies concomitant diseases associated with Hashimoto's thyroiditis based on sequences. The approach involves building distinct prediction models for each class and using the output of one model as input for the subsequent one, resulting in a dynamic decision-making process. Genes associated with concomitant diseases were collected alongside those related to Hashimoto's thyroiditis, and their sequences were obtained from the NCBI site in fasta format. The hybrid algorithm was evaluated against common machine learning algorithms and their various combinations. The experimental results demonstrate that the proposed hybrid model outperforms existing classification methods in terms of performance metrics. The significance of this study lies in its two distinctive aspects. Firstly, it presents a new benchmarking dataset that has not been previously developed in this field, using diverse methods. Secondly, it proposes a more effective and efficient solution that accounts for the dynamic nature of the dataset. The hybrid approach holds promise in investigating the genetic heterogeneity of complex diseases such as Hashimoto's thyroiditis and identifying new autoimmune disease genes. Additionally, the results of this study may aid in the development of genetic screening tools and laboratory experiments targeting Hashimoto's thyroiditis genetic risk factors. New software, models, and techniques for computing, including systems biology, machine learning, and artificial intelligence, are used in our study.
Collapse
Affiliation(s)
- Pınar Karadayı Ataş
- Department of Computer Engineering, Istanbul Arel University, 34537, Buyukcekmece, Istanbul, Turkey.
| |
Collapse
|
4
|
Curtis JR, Yun H, Chen L, Ford SS, van Hoogstraten H, Fiore S, Ford K, Praestgaard A, Rehberg M, Choy E. Real-World Sarilumab Use and Rule Testing to Predict Treatment Response in Patients with Rheumatoid Arthritis: Findings from the RISE Registry. Rheumatol Ther 2023; 10:1055-1072. [PMID: 37349636 PMCID: PMC10326227 DOI: 10.1007/s40744-023-00568-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 05/30/2023] [Indexed: 06/24/2023] Open
Abstract
INTRODUCTION Clinical trial findings may not be generalizable to routine practice. This study evaluated sarilumab effectiveness in patients with rheumatoid arthritis (RA) and tested the real-world applicability of a response prediction rule, derived from trial data using machine learning (based on C-reactive protein [CRP] > 12.3 mg/l and seropositivity [anticyclic citrullinated peptide antibodies, ACPA +]). METHODS Sarilumab initiators from the ACR-RISE Registry, with ≥ 1 prescription on/after its FDA approval (2017-2020), were divided into three cohorts based on progressively restrictive criteria: Cohort A (had active disease), Cohort B (met eligibility criteria of a phase 3 trial in RA patients with inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi]), and Cohort C (characteristics matched to the phase 3 trial baseline). Mean changes in Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) were evaluated at 6 and 12 months. In a separate cohort, predictive rule was tested based on CRP levels and seropositive status (ACPA and/or rheumatoid factor); patients were categorized into rule-positive (seropositive with CRP > 12.3 mg/l) and rule-negative groups to compare the odds of achieving CDAI low disease activity (LDA)/remission and minimal clinically important difference (MCID) over 24 weeks. RESULTS Among sarilumab initiators (N = 2949), treatment effectiveness was noted across cohorts, with greater improvement noted for Cohort C at 6 and 12 months. Among the predictive rule cohort (N = 205), rule-positive (vs. rule-negative) patients were more likely to reach LDA (odds ratio: 1.5 [0.7, 3.2]) and MCID (1.1 [0.5, 2.4]). Sensitivity analyses (CRP > 5 mg/l) showed better response to sarilumab in rule-positive patients. CONCLUSIONS In real-world setting, sarilumab demonstrated treatment effectiveness, with greater improvements in the most selective population, mirroring phase 3 TNFi-refractory and rule-positive RA patients. Seropositivity appeared a stronger driver for treatment response than CRP, although optimization of the rule in routine practice requires further data.
Collapse
Affiliation(s)
- Jeffrey R Curtis
- University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
| | - Huifeng Yun
- University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Lang Chen
- University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | | | | | | | | | | | | | - Ernest Choy
- CREATE Centre, Cardiff University, Cardiff, UK
| |
Collapse
|
5
|
Daghestani M, Othman N, Omair MA, Alenzi F, Omair MA, Alqurtas E, Amin S, Warsy A. Single Nucleotide Polymorphisms Associated with Rheumatoid Arthritis in Saudi Patients. J Clin Med 2023; 12:4944. [PMID: 37568346 PMCID: PMC10419658 DOI: 10.3390/jcm12154944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/22/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Rheumatoid arthritis (RA) is a complex, multifactorial disorder with an autoimmune etiology. RA is highly heritable and is associated with both human leucocyte antigen (HLA) and non-HLA genes. We investigated the associations of 33 single nucleotide polymorphisms (SNPs) with RA in the Saudi population. METHODS This study included 105 patients with RA and an equal number of age- and sex-matched controls. The patients with RA attended outpatient clinics at King Khalid University Hospital in Riyadh, Saudi Arabia. Blood samples were collected, and DNA was extracted using Qiagen kits. Primers were designed for the 33 selected SNPs using the MassEXTEND primers program, and samples were genotyped on the Sequenom MassARRAY iPLEX platform. The allele frequencies and genotypes were determined for each SNP, and the results obtained for the patients were compared to those for the controls. RESULTS The allele and genotype frequencies of six SNPs were significantly associated with RA: rs1188934, rs10919563, rs3087243, rs1980422, rs10499194, and rs629326. The minor alleles of rs1188934, rs10919563, rs10499194, and rs629326 were protective, with odds ratios of 0.542, 0.597, 0.589, and 0.625, and p-values of 0.002, 0.023, 0.013 and 0.036, respectively. In addition, the heterozygote frequencies of two SNPs (rs6859219 and rs11586238) were significantly higher in the controls than in the patients. CONCLUSIONS There is considerable heterogeneity in the genetics of RA in different populations, and the SNPs that are associated with RA in some populations are not in others. We studied 33 SNPs and only eight were associated with RA. The remaining SNPs showed no allelic or genotypic associations with RA.
Collapse
Affiliation(s)
- Maha Daghestani
- Department of Zoology, College of Science, Center for Science and Medical Studies for Girls, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Nashwa Othman
- Central Laboratory, Center for Science and Medical Studies for Girls, King Saud University, Riyadh 11451, Saudi Arabia; (N.O.); (S.A.); (A.W.)
| | - Mohammed A. Omair
- Rheumatology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia; (M.A.O.); (E.A.)
| | - Fahidah Alenzi
- Department of Clinical Science, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Maha A. Omair
- Department of Statistics and Operations Research, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Eman Alqurtas
- Rheumatology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia; (M.A.O.); (E.A.)
| | - Shireen Amin
- Central Laboratory, Center for Science and Medical Studies for Girls, King Saud University, Riyadh 11451, Saudi Arabia; (N.O.); (S.A.); (A.W.)
| | - Arjumand Warsy
- Central Laboratory, Center for Science and Medical Studies for Girls, King Saud University, Riyadh 11451, Saudi Arabia; (N.O.); (S.A.); (A.W.)
| |
Collapse
|
6
|
Shri Preethi M, Asha Devi S. An attempt to unravel the association of TAGAP gene SNPs with rheumatoid arthritis in the Indian population using high-resolution melting analysis. Gene 2022; 834:146584. [PMID: 35597527 DOI: 10.1016/j.gene.2022.146584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 11/29/2022]
Abstract
Rheumatoid arthritis (RA) is an inflammatory disease that causes inflammation of the synovium, cartilage, and deformity of the bones. Single nucleotide polymorphism (SNPs) at 5'UTR rs1738074 (A/G) and a novel candidate non-synonymous single nucleotide polymorphism (nsSNP) rs759674898 (G/A) of TAGAP gene were studied for its association with RA in the Indian population. Real-time PCR coupled with High Resolution Melting analysis technique was employed to detect SNPs. The resulting outcomes were confirmed using the "traditional" Sanger's sequencing method. From this study, we identified that rs1738074 SNP was associated with RA. The odds ratio (OR) obtained for the AG genotype was 3.3379 (Confidence Interval (C.I) 1.7881 to 6.2350); for AA genotype 0.5510 (C.I 0.3043 to 0.9979) and GG genotype 0.5609 (CI 0.3062 to 1.0275). The study also confirmed that AG heterozygous condition had more significant association with RA than AA and GG genotypes. The obtained relative risk (RR) for the AA genotype was 0.676; for AG genotype (RR = 2.253) and GG genotype (RR = 0.6741). The novel candidate nsSNP rs759674898 had only the G allele, and the A allele was not detected in the population studied. In conclusion, this study emphasizes that the rs1738074 SNP in the TAGAP gene's 5'UTR is substantially linked to RA in the Indian population.
Collapse
Affiliation(s)
- M Shri Preethi
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore 632014, TN, India
| | - S Asha Devi
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore 632014, TN, India.
| |
Collapse
|
7
|
Aloke C, Ohanenye IC, Aja PM, Ejike CECC. Phytochemicals from medicinal plants from African forests with potentials in rheumatoid arthritis management. J Pharm Pharmacol 2022; 74:1205-1219. [PMID: 35788356 DOI: 10.1093/jpp/rgac043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 06/04/2022] [Indexed: 11/13/2022]
Abstract
OBJECTIVES Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation, pain, and cartilage and bone damage. There is currently no cure for RA. It is however managed using nonsteroidal anti-inflammatory drugs, corticosteroids and disease-modifying anti-rheumatic drugs, often with severe side effects. Hidden within Africa's lush vegetation are plants with diverse medicinal properties including anti-RA potentials. This paper reviews the scientific literature for medicinal plants, growing in Africa, with reported anti-RA activities and identifies the most abundant phytochemicals deserving research attention. A search of relevant published scientific literature, using the major search engines, such as Pubmed/Medline, Scopus, Google Scholar, etc. was conducted to identify medicinal plants, growing in Africa, with anti-RA potentials. KEY FINDINGS Twenty plants belonging to 17 families were identified. The plants are rich in phytochemicals, predominantly quercetin, rutin, catechin, kaempferol, etc., known to affect some pathways relevant in RA initiation and progression, and therefore useful in its management. SUMMARY Targeted research is needed to unlock the potentials of medicinal plants by developing easy-to-use technologies for preparing medicines from them. Research attention should focus on how best to exploit the major phytochemicals identified in this review for the development of anti-RA 'green pharmaceuticals'.
Collapse
Affiliation(s)
- Chinyere Aloke
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ebonyi State, Nigeria.,Protein Structure-Function and Research Unit, School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, Braamfontein 2050, Johannesburg, South Africa
| | - Ikenna C Ohanenye
- School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa Ontario Canada
| | - Patrick M Aja
- Department of Biochemistry, Faculty of Science, Ebonyi State University Abakaliki, Ebonyi State, Nigeria
| | - Chukwunonso E C C Ejike
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ebonyi State, Nigeria
| |
Collapse
|
8
|
Sakyi SA, Boateng AO, Fondjo LA, Mensah KY, Opoku S, Senu E, Buckman TA, Sampson JE. Polymorphism of protein tyrosine phosphatase non-receptor type 22 and protein arginine deiminase 4 gene among Ghanaian rheumatoid arthritis patients: A case-control study. Int J Rheum Dis 2022; 25:781-786. [PMID: 35607828 DOI: 10.1111/1756-185x.14348] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/10/2022] [Accepted: 05/10/2022] [Indexed: 11/26/2022]
Abstract
AIM Rheumatoid arthritis (RA) is an autoimmune disease which affects millions of lives globally characterized by chronic inflammation in the joints of the body. There is no known cause for RA; however, genetic predisposition has been associated with its occurrence. The association between genetic predisposition and RA has been reported largely among Caucasians and Asians. However, few studies with limited data have reported genome-wide association studies of RA in Africa, especially in Ghana. In addition, there is genetic heterogeneity that exists geographically among different populations. This study therefore investigated the association of protein arginine deiminase type 4 (PAD4) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) single nucleotide polymorphisms with susceptibility of RA among Ghanaians. METHODS This case-control study included 75 RA patients and 75 healthy controls from the Komfo Anokye Teaching Hospital in Ghana. Validated questionnaires were used to obtain demographic data, and blood samples were collected and processed for DNA and polymerase chain reaction analysis. Statistical analysis was done using SPSS version 25.0. RESULTS PTPN22 demonstrated a 100% minor allele frequency (GG) in both cases and healthy controls; however, an association could not be made for PTPN22 polymorphism with susceptibility of RA when comparing cases to controls. The homozygous minor allele (GG) of PAD4 was absent in the population. CONCLUSION PAD4 polymorphism was absent, while PTPN22 was present in the Ghanaian population. The association between PTPN22 (rs2476601) and PAD4 (rs2240340) with RA susceptibility could not be established, thus may not contribute as risk factors for RA in the Ghanaian population.
Collapse
Affiliation(s)
- Samuel Asamoah Sakyi
- Department of Molecular Medicine, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Andy Opoku Boateng
- Department of Molecular Medicine, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Linda Ahenkorah Fondjo
- Department of Molecular Medicine, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Kwame Yeboah Mensah
- Department of Internal Medicine, Komfo Anokye Teaching Hospital, Kumasi, Ghana
| | - Stephen Opoku
- Department of Molecular Medicine, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Ebenezer Senu
- Department of Molecular Medicine, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Tonnies Abeku Buckman
- Department of Molecular Medicine, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Joseph Entwi Sampson
- Department of Molecular Medicine, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| |
Collapse
|
9
|
Mikhaylenko DS, Kuznetsova EB, Musatova VV, Bure IV, Deryagina TA, Alekseeva EA, Tarasov VV, Zamyatnin AA, Nemtsova MV. Genetic and Clinical Factors Associated with Olokizumab Treatment in Russian Patients with Rheumatoid Arthritis. J Pers Med 2022; 12:jpm12040641. [PMID: 35455757 PMCID: PMC9024465 DOI: 10.3390/jpm12040641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 11/16/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease and its treatment is an urgent problem of rheumatology. Olokizumab (OKZ) is a new humanized monoclonal antibody targeting IL-6 and is one of the few promising drugs for RA therapy. One-hundred-and-twenty-five DNA samples from Russian patients with RA, treated with olokizumab, were genotyped with an NGS panel containing 60 single nucleotide polymorphisms (SNPs) and the whole coding sequences of IL6, IL6R, TNFRSF1A, CTLA4, IL10, IL23R, and PADI4; and by RT-PCR for HLA-DRB1 and HLA-B. Associations of polymorphic variants with olokizumab efficacy according to the scores ACR20, ACR50, and DAS28-CRP were determined. We analyzed the obtained data by using logistic regression, ROC curves, and multivariate ANOVA. A high predictive value of the response to olokizumab therapy at 24 weeks was found for the combination of HLA-DRB1*04 and HLA-B*27 alleles with SNPs located in non-HLA genes (IL1B, IL17A, PADI4, DHODH, GLCCI1, IL23R, and TNFAIP3), and clinical characteristics (age, RA duration, and intensity) according to ACR20. Thus, the comprehensive assessment of polymorphic variants of HLA and non-HLA genes considering population characteristics in combination with clinical parameters allows for the elaboration of an RA prognostic panel.
Collapse
Affiliation(s)
- Dmitry S. Mikhaylenko
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (D.S.M.); (E.B.K.); (I.V.B.); (E.A.A.); (M.V.N.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia; (V.V.M.); (T.A.D.)
| | - Ekaterina B. Kuznetsova
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (D.S.M.); (E.B.K.); (I.V.B.); (E.A.A.); (M.V.N.)
| | - Viktoria V. Musatova
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia; (V.V.M.); (T.A.D.)
| | - Irina V. Bure
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (D.S.M.); (E.B.K.); (I.V.B.); (E.A.A.); (M.V.N.)
| | - Tatiana A. Deryagina
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia; (V.V.M.); (T.A.D.)
| | - Ekaterina A. Alekseeva
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (D.S.M.); (E.B.K.); (I.V.B.); (E.A.A.); (M.V.N.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia; (V.V.M.); (T.A.D.)
| | - Vadim V. Tarasov
- Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
| | - Andrey A. Zamyatnin
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (D.S.M.); (E.B.K.); (I.V.B.); (E.A.A.); (M.V.N.)
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- Department of Biotechnology, Sirius University of Science and Technology, 1 Olympic Ave, 354340 Sochi, Russia
- Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7X, UK
- Correspondence: ; Tel.: +7-9261180220
| | - Marina V. Nemtsova
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (D.S.M.); (E.B.K.); (I.V.B.); (E.A.A.); (M.V.N.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia; (V.V.M.); (T.A.D.)
| |
Collapse
|
10
|
Rahimizadeh P, Rezaieyazdi Z, Behzadi F, Hajizade A, Lim SI. Nanotechnology as a promising platform for rheumatoid arthritis management: Diagnosis, treatment, and treatment monitoring. Int J Pharm 2021; 609:121137. [PMID: 34592396 DOI: 10.1016/j.ijpharm.2021.121137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 09/16/2021] [Accepted: 09/23/2021] [Indexed: 12/18/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that develops in about 5 per 1000 people. Over the past years, substantial progresses in knowledge of the disease's pathophysiology, effective diagnosis methods, early detection, and efficient treatment strategies have been made. Notably, nanotechnology has emerged as a game-changer in the efficacious management of many diseases, especially for RA. Joint replacement, photothermal therapy (PTT), photodynamic therapy (PDT), RA diagnosis, and treatment monitoring are nano-based avenues in RA management. Here, we present a brief overview of the pathogenesis of RA, risk factors, conventional diagnostic methods and treatment approaches, and then discuss the role of nanomedicine in RA diagnosis, treatment, and treatment monitoring with an emphasis on functional characteristics distinctive from other RA therapeutics.
Collapse
Affiliation(s)
- Parastou Rahimizadeh
- Department of Chemical Engineering, Pukyong National University, Busan 48513, South Korea
| | - Zahra Rezaieyazdi
- Rheumatic Disease Research Center, Mashhad University of Medical Science, Mashhad, Iran
| | - Faezeh Behzadi
- Department of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Abbas Hajizade
- Biology Research Centre, Faculty of Basic Sciences, Imam Hossein University, Tehran, Iran.
| | - Sung In Lim
- Department of Chemical Engineering, Pukyong National University, Busan 48513, South Korea.
| |
Collapse
|
11
|
Bhagavatham SKS, Khanchandani P, Kannan V, Potikuri D, Sridharan D, Pulukool SK, Naik AA, Dandamudi RB, Divi SM, Pargaonkar A, Ray R, Santha SSR, Seshagiri PB, Narasimhan K, Gumdal N, Sivaramakrishnan V. Adenosine deaminase modulates metabolic remodeling and orchestrates joint destruction in rheumatoid arthritis. Sci Rep 2021; 11:15129. [PMID: 34301999 PMCID: PMC8302689 DOI: 10.1038/s41598-021-94607-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 07/14/2021] [Indexed: 02/07/2023] Open
Abstract
Rheumatoid Arthritis (RA) is a chronic autoimmune disease associated with inflammation and joint remodeling. Adenosine deaminase (ADA), a risk factor in RA, degrades adenosine, an anti-inflammatory molecule, resulting in an inflammatory bias. We present an integrative analysis of clinical data, cytokines, serum metabolomics in RA patients and mechanistic studies on ADA-mediated effects on in vitro cell culture models. ADA activity differentiated patients into low and high ADA sets. The levels of the cytokines TNFα, IFNγ, IL-10, TGFβ and sRANKL were elevated in RA and more pronounced in high ADA sets. Serum metabolomic analysis shows altered metabolic pathways in RA which were distinct between low and high ADA sets. Comparative analysis with previous studies shows similar pathways are modulated by DMARDs and biologics. Random forest analysis distinguished RA from control by methyl-histidine and hydroxyisocaproic acid, while hexose-phosphate and fructose-6-phosphate distinguished high ADA from low ADA. The deregulated metabolic pathways of High ADA datasets significantly overlapped with high ADA expressing PBMCs GEO transcriptomics dataset. ADA induced the death of chondrocytes, synoviocyte proliferation, both inflammation in macrophages and their differentiation into osteoclasts and impaired differentiation of mesenchymal stem cells to osteoblasts and mineralization. PBMCs expressing elevated ADA had increased expression of cytokines and P2 receptors compared to synovial macrophages which has low expression of ADA. Our data demonstrates increased cytokine levels and distinct metabolic signatures of RA based on the ADA activity, suggests an important role for ADA in the pathophysiology of RA joints and as a potential marker and therapeutic target in RA patients.
Collapse
Affiliation(s)
- Sai Krishna Srimadh Bhagavatham
- grid.444651.60000 0004 0496 6988Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Puttaparthi, 515134 India
| | - Prakash Khanchandani
- grid.496668.30000 0004 1767 3076Department of Orthopedics, Sri Sathya Sai Institute of Higher Medical Sciences, PG, Puttaparthi, 515134 India
| | - Vishnu Kannan
- grid.444651.60000 0004 0496 6988Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Puttaparthi, 515134 India ,grid.411552.60000 0004 1766 4022Present Address: Department of Botany/Biotechnology, CMS College, Kottayam, 686001 India
| | | | - Divya Sridharan
- grid.34980.360000 0001 0482 5067Molecular Reproduction and Developmental Genetics, Indian Institute of Science, Bengaluru, 560012 India
| | - Sujith Kumar Pulukool
- grid.444651.60000 0004 0496 6988Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Puttaparthi, 515134 India
| | - Ashwin Ashok Naik
- grid.444651.60000 0004 0496 6988Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Puttaparthi, 515134 India
| | - Rajesh Babu Dandamudi
- grid.444651.60000 0004 0496 6988Department of Chemistry, Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, India ,Present Address: Phenomenex India, Hyderabad, Telangana 500084 India
| | - Sai Mangala Divi
- grid.496668.30000 0004 1767 3076Department of Biochemistry, Sri Sathya Sai Institute of Higher Medical Sciences, PG, Puttaparthi, 515134 India
| | - Ashish Pargaonkar
- grid.464737.50000 0004 1775 153XAgilent Technologies India Pvt Ltd, Bengaluru, 560048 India
| | - Rahul Ray
- grid.496668.30000 0004 1767 3076Department of Orthopedics, Sri Sathya Sai Institute of Higher Medical Sciences, PG, Puttaparthi, 515134 India
| | - Saibharath Simha Reddy Santha
- grid.444651.60000 0004 0496 6988Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Puttaparthi, 515134 India
| | - Polani B. Seshagiri
- grid.34980.360000 0001 0482 5067Molecular Reproduction and Developmental Genetics, Indian Institute of Science, Bengaluru, 560012 India
| | - K. Narasimhan
- Sri Sathya Sai General Hospital, Puttaparthi, 515134 India
| | | | - Venketesh Sivaramakrishnan
- grid.444651.60000 0004 0496 6988Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Puttaparthi, 515134 India
| |
Collapse
|
12
|
Dedmon LE. The genetics of rheumatoid arthritis. Rheumatology (Oxford) 2021; 59:2661-2670. [PMID: 32638005 DOI: 10.1093/rheumatology/keaa232] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/03/2020] [Indexed: 12/14/2022] Open
Abstract
RA is a chronic systemic inflammatory disease that primarily affects the small joints of the hands and feet, and results in a mean reduction in life expectancy of 3-10 years. RA is a multigene disorder with a substantial genetic component and a heritability estimate of 60%. Large-scale Genome-Wide Association Studies (GWAS) and meta-analyses have revealed common disease-associated variants in the population that may contribute cumulatively to RA pathogenesis. This review identifies the most significant genetic variants associated with RA susceptibility to date, with particular focus on the contribution of the HLA class II genes across different ethnic groups. Also discussed are the potential applications of pharmacogenomics to RA management by identifying polymorphisms associated with variation in treatment response or toxicity. The use of genetic variants to guide treatment strategy has the potential to not only reduce National Health Service costs, but also drastically improve patient experience and quality of life.
Collapse
|
13
|
Mikhaylenko DS, Nemtsova MV, Bure IV, Kuznetsova EB, Alekseeva EA, Tarasov VV, Lukashev AN, Beloukhova MI, Deviatkin AA, Zamyatnin AA. Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response. Int J Mol Sci 2020; 21:E4911. [PMID: 32664585 PMCID: PMC7402327 DOI: 10.3390/ijms21144911] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Rheumatoid arthritis (RA) is the most common inflammatory arthropathy worldwide. Possible manifestations of RA can be represented by a wide variability of symptoms, clinical forms, and course options. This multifactorial disease is triggered by a genetic predisposition and environmental factors. Both clinical and genealogical studies have demonstrated disease case accumulation in families. Revealing the impact of candidate gene missense variants on the disease course elucidates understanding of RA molecular pathogenesis. A multivariate genomewide association study (GWAS) based analysis identified the genes and signalling pathways involved in the pathogenesis of the disease. However, these identified RA candidate gene variants only explain 30% of familial disease cases. The genetic causes for a significant proportion of familial RA have not been determined until now. Therefore, it is important to identify RA risk groups in different populations, as well as the possible prognostic value of some genetic variants for disease development, progression, and treatment. Our review has two purposes. First, to summarise the data on RA candidate genes and the increased disease risk associated with these alleles in various populations. Second, to describe how the genetic variants can be used in the selection of drugs for the treatment of RA.
Collapse
Affiliation(s)
- Dmitry S. Mikhaylenko
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (I.V.B.); (E.B.K.); (E.A.A.); (A.N.L.); (M.I.B.); (A.A.D.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115478 Moscow, Russia
| | - Marina V. Nemtsova
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (I.V.B.); (E.B.K.); (E.A.A.); (A.N.L.); (M.I.B.); (A.A.D.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115478 Moscow, Russia
| | - Irina V. Bure
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (I.V.B.); (E.B.K.); (E.A.A.); (A.N.L.); (M.I.B.); (A.A.D.)
| | - Ekaterina B. Kuznetsova
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (I.V.B.); (E.B.K.); (E.A.A.); (A.N.L.); (M.I.B.); (A.A.D.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115478 Moscow, Russia
| | - Ekaterina A. Alekseeva
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (I.V.B.); (E.B.K.); (E.A.A.); (A.N.L.); (M.I.B.); (A.A.D.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115478 Moscow, Russia
| | - Vadim V. Tarasov
- Department of Pharmacology and Pharmacy, Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
| | - Alexander N. Lukashev
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (I.V.B.); (E.B.K.); (E.A.A.); (A.N.L.); (M.I.B.); (A.A.D.)
- Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov First Moscow State Medical University, 119435 Moscow, Russia
| | - Marina I. Beloukhova
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (I.V.B.); (E.B.K.); (E.A.A.); (A.N.L.); (M.I.B.); (A.A.D.)
| | - Andrei A. Deviatkin
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (I.V.B.); (E.B.K.); (E.A.A.); (A.N.L.); (M.I.B.); (A.A.D.)
| | - Andrey A. Zamyatnin
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (I.V.B.); (E.B.K.); (E.A.A.); (A.N.L.); (M.I.B.); (A.A.D.)
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| |
Collapse
|
14
|
Guan Y, Zhang H, Quang D, Wang Z, Parker SCJ, Pappas DA, Kremer JM, Zhu F. Machine Learning to Predict Anti-Tumor Necrosis Factor Drug Responses of Rheumatoid Arthritis Patients by Integrating Clinical and Genetic Markers. Arthritis Rheumatol 2019; 71:1987-1996. [PMID: 31342661 DOI: 10.1002/art.41056] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 07/18/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Accurate prediction of treatment responses in rheumatoid arthritis (RA) patients can provide valuable information on effective drug selection. Anti-tumor necrosis factor (anti-TNF) drugs are an important second-line treatment after methotrexate, the classic first-line treatment for RA. However, patient heterogeneity hinders identification of predictive biomarkers and accurate modeling of anti-TNF drug responses. This study was undertaken to investigate the usefulness of machine learning to assist in developing predictive models for treatment response. METHODS Using data on patient demographics, baseline disease assessment, treatment, and single-nucleotide polymorphism (SNP) array from the Dialogue on Reverse Engineering Assessment and Methods (DREAM): Rheumatoid Arthritis Responder Challenge, we created a Gaussian process regression model to predict changes in the Disease Activity Score in 28 joints (DAS28) for the patients and to classify them into either the responder or the nonresponder group. This model was developed and cross-validated using data from 1,892 RA patients. It was evaluated using an independent data set from 680 patients. We examined the effectiveness of the similarity modeling and the contribution of individual features. RESULTS In the cross-validation tests, our method predicted changes in DAS28 (ΔDAS28), with a correlation coefficient of 0.405. It correctly classified responses from 78% of patients. In the independent test, this method achieved a Pearson's correlation coefficient of 0.393 in predicting ΔDAS28. Gaussian process regression effectively remapped the feature space and identified subpopulations that do not respond well to anti-TNF treatments. Genetic SNP biomarkers showed small contributions in the prediction when added to the clinical models. This was the best-performing model in the DREAM Challenge. CONCLUSION The model described here shows promise in guiding treatment decisions in clinical practice, based primarily on clinical profiles with additional genetic information.
Collapse
Affiliation(s)
| | | | | | | | | | - Dimitrios A Pappas
- Columbia University College of Physicians and Surgeons, New York, New York, and Corrona LLC, Waltham, Massachusetts
| | - Joel M Kremer
- Corrona LLC, Waltham, Massachusetts, and Albany Medical College and The Center for Rheumatology, Albany, New York
| | - Fan Zhu
- Chinese Academy of Sciences, Chongqing, China
| |
Collapse
|
15
|
Hernández-Palma LA, García-Arellano S, Bucala R, Llamas-Covarrubias MA, De la Cruz-Mosso U, Oregon-Romero E, Cerpa-Cruz S, Parra-Rojas I, Plascencia-Hernández A, Muñoz-Valle JF. Functional MIF promoter haplotypes modulate Th17-related cytokine expression in peripheral blood mononuclear cells from control subjects and rheumatoid arthritis patients. Cytokine 2019; 115:89-96. [DOI: 10.1016/j.cyto.2018.11.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 11/12/2018] [Accepted: 11/13/2018] [Indexed: 12/21/2022]
|
16
|
Are There Any Common Genetic Risk Markers for Rheumatoid Arthritis and Periodontal Diseases? A Case-Control Study. Mediators Inflamm 2019; 2019:2907062. [PMID: 30890897 PMCID: PMC6390239 DOI: 10.1155/2019/2907062] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 01/14/2019] [Accepted: 01/29/2019] [Indexed: 12/15/2022] Open
Abstract
Background Several studies suggest that there is a biologically plausible connection between rheumatoid arthritis (RA) and periodontal diseases (PD). Both disorders are characterized as multifactorial diseases potentially sharing common risk factors. Based on the inflammatory nature of RA and PD, the impact of genetic variations of genes of the immune system on both diseases was studied in this study. Materials and Methods We conducted a case-control study (n = 201) comparing 101 RA patients suffering from periodontal disease of different severities (no/mild PD vs. severe PD) with 100 systemically healthy controls without RA and severe PD. The genotype, allele, and haplotype distributions of 22 SNPs of 13 pro- and anti-inflammatory cytokines were assessed applying sequence-specific PCR. Results Evaluating the impact of cytokine SNPs in RA, we identified the G allele of rs1801275 in IL4Rα (p = 0.043) and the G allele of rs361525 in TNFα (p = 0.005) as disease-associated risk factors in bivariate analyses. In multivariate analyses, these significant associations could not be proven. The A allele of rs2430561 in IFNγ was indicative for severe periodontitis among the patients with rheumatoid arthritis (p = 0.039). Investigating the impact of rs2430561 in IFNγ on comorbidity using binary logistic regression analyses, the A allele was confirmed as an independent risk factor for severe periodontal disease and RA (p = 0.024). Conclusions These results emphasize the association of genetic variations in proinflammatory cytokines (TNFα and IFNγ) and cytokine receptor (IL4Rα) and RA and periodontal diseases. In multivariate analyses, the A allele of IFNγ was proven to be a significant marker of RA and PD comorbidities. The study broadens the knowledge about disease-specific differences in genetic composition and provides an improved understanding of a possible association of both diseases.
Collapse
|
17
|
Crincoli V, Anelli MG, Quercia E, Piancino MG, Di Comite M. Temporomandibular Disorders and Oral Features in Early Rheumatoid Arthritis Patients: An Observational Study. Int J Med Sci 2019; 16:253-263. [PMID: 30745806 PMCID: PMC6367523 DOI: 10.7150/ijms.28361] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 11/29/2018] [Indexed: 01/04/2023] Open
Abstract
Aims: Temporomandibular disorders (TMD) represent a heterogeneous group of inflammatory or degenerative diseases of the stomatognatic system, with algic and/or dysfunctional clinical features involving temporomandibular joint (TMJ) and related masticatory muscles. Rheumatoid Arthritis (RA) is an autoimmune polyarthritis characterized by the chronic inflammation of synovial joints and oral implications such as hyposalivation, difficulty in swallowing and phoning, feeling of burning mouth, increased thirst, loss of taste or unpleasant taste and smell, dental sensitivity. The aim of this observational study was to investigate the prevalence of TMD symptoms and signs as well as oral implications in patients with Early Rheumatoid Arthritis (ERA), that is a RA diagnosed within 12 months, compared with a control group. Methods: The study group included 52 ERA patients (11 men, 41 women) diagnosed according to the 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis. A randomly selected group of 52 patients not affected by this disease, matched by sex and age, served as the control group. The examination for TMD signs and symptoms was based on the standardized Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) by means of a questionnaire and through clinical examination. Results: Regarding the oral kinematics, the left lateral excursion of the mandible was restricted in statistically significant way in ERA patients (p=0.017). The endfeel values were significantly increased in ERA group (p=0.0017), thus showing the presence of a higher muscle contracture. On the other side, the study group complained less frequently (67.3%) of TDM symptoms (muscle pain on chewing, pain in the neck and shoulders muscles, difficulty in mouth opening, arthralgia of TMJ, tinnitus) than controls (90.4%) (χ2= 8.301 p=0.0039). The presence of TMJ noises was significantly lower in the study group (χ2= 3.869 p=0.0049), as well as presence of opening derangement (χ2= 14.014 p=0.0002). The salivary flow was significantly decreased in the study group respect to the control one (p<0.0001). Conclusions: The data collected show a weak TMJ kinematic impairment, a paucisymptomatic muscle contracture (positive endfeel) and a remarkable reduction of salivary flow in ERA patients. Myofacial pain (MP) evoked by palpation was more frequent and severe in the control group than in the study one, this result being highly significant.
Collapse
Affiliation(s)
- Vito Crincoli
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, "Aldo Moro" University of Bari, Italy
| | | | | | | | - Mariasevera Di Comite
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, "Aldo Moro" University of Bari, Italy
| |
Collapse
|
18
|
Dai C, Kuo SJ, Zhao J, Jin L, Kang L, Wang L, Xu G, Tang CH, Su CM. Correlation between genetic polymorphism of angiopoietin-2 gene and clinical aspects of rheumatoid arthritis. Int J Med Sci 2019; 16:331-336. [PMID: 30745815 PMCID: PMC6367530 DOI: 10.7150/ijms.30582] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023] Open
Abstract
The Angiopoietin-2 (Ang2) gene encodes angiogenic factor, and the polymorphisms of Ang2 gene predict risk of various human diseases. We want to investigate whether the single nucleotide polymorphisms (SNPs) of the Ang2 gene can predict the risk of rheumatoid arthritis (RA). Between 2016 and 2018, we recruited 335 RA patients and 700 control participants. Comparative genotyping for SNPs rs2442598, rs734701, rs1823375 and rs12674822 was performed. We found that when compared with the subjects with the A/A genotype of SNP rs2442598, the subjects with the T/T genotype were 1.78 times likely to develop RA. The subjects with C/C genotype of SNP rs734701 were 0.53 times likely to develop RA than the subjects with TT genotype, suggesting the protective effect. The subjects with G/G genotype of SNP rs1823375 were 1.77 times likely to develop RA than the subjects with C/C genotype. The subjects with A/C and C/C genotype of SNP rs11137037 were 1.65 and 2.04 times likely to develop RA than the subjects with A/A genotype. The subjects with G/T and T/T genotype of SNP rs12674822 were 2.42 and 2.25 times likely to develop RA than the subjects with G/G genotype. The T allele over rs734701 can lead to higher serum erythrocyte sedimentation rate level (p = 0.006). The A allele over rs11137037 was associated with longer duration between disease onset and blood sampling (p = 0.003). Our study suggested that Ang2 might be a diagnostic marker and therapeutic target for RA therapy. Therapeutic agents that directly or indirectly modulate the activity of Ang2 may be the promising modalities for RA treatment.
Collapse
Affiliation(s)
- Chengqian Dai
- Department of Orthopedics, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Shu-Jui Kuo
- School of Medicine, China Medical University, Taichung, Taiwan.,Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Jin Zhao
- Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Lulu Jin
- Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Le Kang
- Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Lihong Wang
- Department of Orthopedics, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Guohong Xu
- Department of Orthopedics, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Chih-Hsin Tang
- School of Medicine, China Medical University, Taichung, Taiwan.,Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
| | - Chen-Ming Su
- Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| |
Collapse
|
19
|
Shao L. DNA Damage Response Signals Transduce Stress From Rheumatoid Arthritis Risk Factors Into T Cell Dysfunction. Front Immunol 2018; 9:3055. [PMID: 30619377 PMCID: PMC6306440 DOI: 10.3389/fimmu.2018.03055] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 12/10/2018] [Indexed: 12/18/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune-mediated disease that is associated with significant cartilage damage and immunosenescence. Despite decades of research, the major signal pathways that initiate RA are still unclear. The DNA damage response (DDR) is a specific and hierarchical network that includes cell cycle checkpoints, DNA repair, and DNA-damage tolerance pathways. Recent studies suggest that this condition is associated with deficits in telomere maintenance and overall genomic instability in the T cells of RA patients. Analysis of the underlying mechanisms has revealed defects in DDR pathways. Particularly, the DNA repair enzyme, ataxia telangiectasia mutated (ATM), is downregulated, which leaves the damaged DNA breaks in RA-associated T cells unrepaired and pushes them to apoptosis, exhausts the T cell pool, and promotes the arthritogenesis effector function of T cells. This review discusses recent advancements and illustrates that risk factors for RA, such as viral infections, environmental events, and genetic risk loci are combat with DDR signals, and the impaired DDR response of RA-associated T cells, in turn, triggers disease-related phenotypes. Therefore, DDR is the dominant signal that converts genetic and environmental stress to RA-related immune dysfunction. Understanding the orchestration of RA pathogenesis by DDR signals would further our current knowledge of RA and provide novel avenues in RA therapy.
Collapse
Affiliation(s)
- Lan Shao
- The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
20
|
Abo Alchamlat S, Farnir F. Aggregation of experts: an application in the field of "interactomics" (detection of interactions on the basis of genomic data). BMC Bioinformatics 2018; 19:445. [PMID: 30497383 PMCID: PMC6267805 DOI: 10.1186/s12859-018-2447-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 10/25/2018] [Indexed: 12/03/2022] Open
Abstract
Background Despite the successful mapping of genes involved in the determinism of numerous traits, a large part of the genetic variation remains unexplained. A possible explanation is that the simple models used in many studies might not properly fit the actual underlying situations. Consequently, various methods have attempted to deal with the simultaneous mapping of genomic regions, assuming that these regions might interact, leading to a complex determinism for various traits. Despite some successes, no gold standard methodology has emerged. Actually, combining several interaction mapping methods might be a better strategy, leading to positive results over a larger set of situations. Our work is a step in that direction. Results We first have demonstrated why aggregating results from several distinct methods might increase the statistical power while controlling the type I error. We have illustrated the approach using 6 existing methods (namely: MDR, Boost, BHIT, KNN-MDR, MegaSNPHunter and AntEpiSeeker) on simulated and real data sets. We have used a very simple aggregation strategy: a majority vote across the best loci combinations identified by the individual methods. In order to assess the performances of our aggregation approach in problems where most individual methods tend to fail, we have simulated difficult situations where no marginal effects of individual genes exist and where genetic heterogeneity is present. we have also demonstrated the use of the strategy on real data, using a WTCCC dataset on rheumatoid arthritis. Since we have been using simplistic assumptions to infer the expected power of the aggregation method, the actual power we estimated from our simulations has turned out to be a bit smaller than theoretically expected. Results nevertheless have shown that grouping the results of several methods is advantageous in terms of power, accuracy and type I error control. Furthermore, as more methods should become available in the future, using a grouping strategy will become more advantageous since adding more methods seems to improve the performances of the aggregated method. Conclusions The aggregation of methods as a tool to detect genetic interactions is a potentially useful addition to the arsenal used in complex traits analyses. Electronic supplementary material The online version of this article (10.1186/s12859-018-2447-0) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Sinan Abo Alchamlat
- Department of Biostatistics, Faculty of Veterinary Medicine, University of Liège, Sart Tilman B43, 4000, Liege, Belgium
| | - Frédéric Farnir
- Department of Biostatistics, Faculty of Veterinary Medicine, University of Liège, Sart Tilman B43, 4000, Liege, Belgium.
| |
Collapse
|
21
|
Zhou M, Jiang B, Xiong M, Zhu X. An Updated Meta-Analysis of the Associations Between MicroRNA Polymorphisms and Susceptibility to Rheumatoid Arthritis. Front Physiol 2018; 9:1604. [PMID: 30498453 PMCID: PMC6249421 DOI: 10.3389/fphys.2018.01604] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 10/25/2018] [Indexed: 01/03/2023] Open
Abstract
Aims: Rheumatoid arthritis (RA) is characterized by cartilage and bone damage leading to disability. Here, the association between microRNA (miRNA) polymorphisms and susceptibility to RA was evaluated by performing an updated meta-analysis and systematic review. Main methods: An electronic search of databases including PubMed and Embase was performed from inception to December 8, 2017 to retrieve studies investigating the association between miRNA polymorphisms and RA risk. Two reviewers independently screened literature according to the inclusion and exclusion criteria and extracted data. The meta-analysis was conducted using Stata 14.0 software. Key findings: Thirteen case-control studies with 2660 cases and 4098 controls were screened out after a systematic search. One study from the miR-146a rs2910164 G > C polymorphism group and two from the miR-499 rs3746444 T > C polymorphism group were excluded because of deviations from Hardy-Weinberg equilibrium. Pooled analysis demonstrated that miR-146a rs2910164 G > C polymorphism was not significantly associated with susceptibility to RA. However, a significant association was observed between miR-499 rs3746444 T > C polymorphism and RA risk (C vs. T: OR = 1.22, 95% CI = 1.05–1.42, P = 0.008; TC vs. TT: OR = 1.26, 95% CI = 1.05–1.50, P = 0.011; TC/CC vs. TT: OR = 1.26, 95% CI = 1.07–1.5, P = 0.007). Subgroup analysis based on ethnicity showed no significant association between miR-499 T > C polymorphism and susceptibility to RA in the Asian population (P > 0.05). However, in Caucasian population, the C allele in the miR-499 T > C polymorphism was a contributor to RA susceptibility in some genetic models (C vs. T: OR = 1.64, 95% CI = 1.28–2.11, P < 0.001; TC vs. TT: OR = 1.95, 95% CI = 1.40–2.71, P < 0.001; TC/CC vs. TT: OR = 1.96, 95% CI = 1.43–2.69, P < 0.001). Significance: The miR-146a rs2910164 G > C polymorphism was not associated with susceptibility to RA. In the Caucasian population, the C allele in the miR-499 T > C polymorphism contributed to RA susceptibility.
Collapse
Affiliation(s)
- Mi Zhou
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Jiang
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mao Xiong
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Zhu
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
22
|
Genomic Profile and Pathologic Features of Diffuse Large B-Cell Lymphoma Subtype of Methotrexate-associated Lymphoproliferative Disorder in Rheumatoid Arthritis Patients. Am J Surg Pathol 2018; 42:936-950. [DOI: 10.1097/pas.0000000000001071] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
|
23
|
Chemokine C-C Motif Ligand 4 Gene Polymorphisms Associated with Susceptibility to Rheumatoid Arthritis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:9181647. [PMID: 29955612 PMCID: PMC6000874 DOI: 10.1155/2018/9181647] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 04/26/2018] [Accepted: 04/30/2018] [Indexed: 01/22/2023]
Abstract
Chemokine C-C motif ligand 4 (CCL4) gene is a chemokine-encoding gene, and the polymorphism of CCL4 gene has been shown to predict risk of various diseases. We want to investigate whether the single nucleotide polymorphisms (SNPs) of the CCL4 gene can predict the risk of rheumatoid arthritis (RA). Between 2007 and 2015, we recruited 217 patients diagnosed with RA and 371 control participants. Comparative genotyping of the rs1634507, rs10491121, and rs1719153 SNPs was performed. When compared with participants with the A/A genotype of rs1719153, those with the A/T genotype were less likely to develop RA, as were those with the A/T+T/T genotype. The protective effect of the T-containing genotype was even more prominent among females. Those with A/T in rs1719153 were 56% less likely to develop RA compared with females with A/A; a similar protective effect was seen for females with the A/T+T/T genotype compared with those with A/A. The GTEx database revealed that patients carrying the T/T genotype had lower levels of CCL4 gene expression than those carrying the A/A genotype. These results indicate that the nucleotide T over the rs1719153 is associated with decreased CCL4 gene expression and decreased risk for RA.
Collapse
|
24
|
Okada Y, Kishikawa T, Sakaue S, Hirata J. Future Directions of Genomics Research in Rheumatic Diseases. Rheum Dis Clin North Am 2018; 43:481-487. [PMID: 28711147 DOI: 10.1016/j.rdc.2017.04.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Recent developments in human genome genotyping and sequencing technologies, such as genome-wide association studies and whole-genome sequencing analyses, have successfully identified several risk genes of rheumatic diseases. Fine-mapping studies using the HLA imputation method revealed that classical and non-classical HLA genes contribute to the risk of rheumatic diseases. Integration of human disease genomics with biological, medical, and clinical databases should contribute to the elucidation of disease pathogenicity and novel drug discovery. Disease risk genes identified by large-scale genetic studies are considered to be promising resources for novel drug discovery, including drug repositioning and biomarker microRNA screening for rheumatoid arthritis.
Collapse
Affiliation(s)
- Yukinori Okada
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Toshihiro Kishikawa
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Otorhinolaryngology, Head and Neck Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Saori Sakaue
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Jun Hirata
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Pharmaceutical Discovery Research Laboratories, Teijin Pharma Limited, 4-3-2, Asahigaoka, Hino-shi, Tokyo 191-8512, Japan
| |
Collapse
|
25
|
Jahid M, Rehan-Ul-Haq, Avasthi R, Ahmed RS. Interleukin10-1082 A/G polymorphism: Allele frequency, correlation with disease markers, messenger RNA and serum levels in North Indian rheumatoid arthritis patients. Clin Biochem 2018; 55:80-85. [PMID: 29621504 DOI: 10.1016/j.clinbiochem.2018.03.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 03/15/2018] [Accepted: 03/30/2018] [Indexed: 01/07/2023]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder of unknown etiology. IL-10 stimulates B cell survival and is involved in antibody isotype switching. The serum IL-10 levels are increased in RA patients. Ethnicity influences polymorphisms in cytokine genes. Therefore, this study was designed to explore possible association, if any, between polymorphism of IL10-1082 A/G, serum cytokine levels, inflammatory markers and gene expression in RA patients of North India. METHODOLOGY A total of 187 RA patients classified according to American college of rheumatology 2010 criteria and 214 controls were included in the study. Levels of serum IL-10 and inflammatory markers were estimated by ELISA. PCR-RFLP was used to analyze IL10-1082 A/G polymorphism. Quantitative real time PCR was used to measure the mRNA expression of IL-10 gene. RESULTS The serum inflammatory markers were significantly higher in RA patients. Circulating IL-10 levels were positively and significantly correlated with RF (r = 0.28), anti-CCP (r = 0.26), CRP (r = 0.17) and mRNA expression levels (r = 0.59) among RA patients. Homozygous mutant variant (GG) and heterozygous mutant variant (AG) were associated with patients of RA (OR = 2.87 and 1.55, p < 0.05) as compared to controls. The association still persisted when the heterozygous and homozygous mutants (AG + GG) were clubbed together (OR = 1.67, p < 0.05). The mRNA expression of IL-10 was found to be 3.63 folds higher (housekeeping gene, β-actin) and 2.42 folds higher (housekeeping gene, 18S rRNA) in RA patients as compared to controls. CONCLUSION The results indicate that IL10-1082 A/G polymorphism is associated with genetic susceptibility/predisposition to RA in North Indian population.
Collapse
Affiliation(s)
- Mohd Jahid
- Department of Biochemistry, Dilshad Garden, Delhi 110095, India
| | - Rehan-Ul-Haq
- Department of Orthopedics, Dilshad Garden, Delhi 110095, India
| | - Rajnish Avasthi
- Department of Medicine University, College of Medical Sciences, GTB Hospital, University of Delhi, Dilshad Garden, Delhi 110095, India
| | | |
Collapse
|
26
|
Jiang L, Jiang D, Han Y, Shi X, Ren C. Association of HLA-DPB1 polymorphisms with rheumatoid arthritis: A systemic review and meta-analysis. Int J Surg 2018; 52:98-104. [PMID: 29425827 DOI: 10.1016/j.ijsu.2018.01.046] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/04/2018] [Accepted: 01/31/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND The current reports on the association between HLA-DPB1 alleles and rheumatoid arthritis (RA) results were controversial. Thus, we conducted a meta-analysis to assess whether DPB1 alleles are associated with increased risk of rheumatoid arthritis. METHODS Systematic searches on PubMed, Embase, Elsevier, CNKI (China National Knowledge Infrastructure), Wanfang data and Cochrane Library prior to July 2017 were performed. The pooled odds ratios (ORs) and 95% confidence interval (95% CI) was used to assess the association between frequencies of DPB1 alleles and RA patients. RESULTS Eight studies with 592 cases and 935 controls were included in this meta-analysis. Overall, the pooled ORs showed that frequencies of DPB1*0401 and *0601 were higher in the RA group compared with controls (*0401: OR: 1.586, 95%CI: 1.296-1.941, P<0.001; *0601: OR: 1.921, 95%CI: 1.142-3.229, P=0.014). Whereas, the frequencies of DPB1*0101, *0402 and *0501 were lower in the RA control than the controls (*0101: OR: 0.691, 95%CI: 0.481-0.993, P=0.046; *0402: OR: 0.707, 95%CI: 0.555-0.902, P=0.005; *0501: OR: 0.502, 95%CI: 0.329-0.767, P=0.001). No associations were observed for DPB1*0201, *0202, *0301 and *0901 (*0201: OR: 1.129, 95%CI: 0.882-1.446, P = 0.335; *0202: OR: 0.840, 95%CI: 0.940-1.441, P = 0.527; *0301: OR: 0.769, 95%CI: 0.577-1.026, P = 0.074; *0901: OR: 1.221, 95% CI: 0.541-2.755, P = 0.630). CONCLUSIONS This meta-analysis demonstrates that high frequency expression of DPB1*0401 and *0601 are significantly associated with susceptibility to RA, it may be a risk factor for occurrence of RA. Low frequency expression of DPB1*0101, *0402 and *0501 may be negatively associated with RA, it may be a protective factor for occurrence of RA.
Collapse
Affiliation(s)
- Lu Jiang
- Dalian Medical University, China; Department of Joint Surgery, The Dalian Municipal Center Hospital Affiliated of Dalian Medical University, China
| | - Dongdong Jiang
- Dalian Medical University, China; Department of Joint Surgery, The Dalian Municipal Center Hospital Affiliated of Dalian Medical University, China
| | - Yao Han
- Dalian Medical University, China; Department of Joint Surgery, The Dalian Municipal Center Hospital Affiliated of Dalian Medical University, China
| | - Xian Shi
- Dalian Medical University, China; Department of Joint Surgery, The Dalian Municipal Center Hospital Affiliated of Dalian Medical University, China
| | - Changle Ren
- Department of Joint Surgery, The Dalian Municipal Center Hospital Affiliated of Dalian Medical University, China.
| |
Collapse
|
27
|
Human genetics contributes to the understanding of disease pathophysiology and drug discovery. J Orthop Sci 2017; 22:977-981. [PMID: 28830696 DOI: 10.1016/j.jos.2017.07.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 07/09/2017] [Accepted: 07/29/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND Today, sequencing technology has markedly reduced the cost and time needed to read the human genome than ever before. Genome-wide association studies have successfully identified a number of disease risk genes. CONTRIBUTION TO UNDERSTANDING OF DISEASE PATHOPHYSIOLOGY Recent advancements in genomic technology have substantially furthered our understanding of the pathophysiology of many diseases, such as rheumatoid arthritis. TOWARD DRUG DISCOVERY AND FUTURE DIRECTION Accumulating genomic information is now expected to accelerate the discovery of novel drugs. Rapidly growing multi-dimensional information in life sciences would make human genetics significantly important in the near future.
Collapse
|
28
|
Jahid M, Rehan-Ul-Haq, Chawla D, Avasthi R, Ahmed RS. Association of polymorphic variants in IL1B gene with secretion of IL-1β protein and inflammatory markers in north Indian rheumatoid arthritis patients. Gene 2017; 641:63-67. [PMID: 29054755 DOI: 10.1016/j.gene.2017.10.051] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 07/04/2017] [Accepted: 10/16/2017] [Indexed: 01/17/2023]
Abstract
The proinflammatory cytokine interleukin-1beta (IL-1β) is a key mediator of inflammation which affects cell proliferation and differentiation. IL-1β is considered to contribute to the pathophysiology of rheumatoid arthritis (RA). Polymorphisms in cytokine genes are highly influenced by ethnicity. Hence, in this study polymorphism of the IL1B-511(C/T) within promoter region was analyzed by using polymerase chain reaction-restriction fragment length Polymorphism (PCR-RFLP) in 187 RA patients and 214 controls. The prevalence of different genotypes and allelic frequency distribution was compared in RA patients and controls. Levels of inflammatory markers and serum levels of IL-1β were estimated by ELISA The serum inflammatory markers levels were significantly higher in RA patients as compared to controls (RF=127.3±21.3U/mL, Anti-CCP=17.8±8.3U/mL, CRP=17.86±7.1mg/L and IL-1β=21.25±4.19pg/mL in RA patients p<0.01). The frequency of heterozygous mutant (C/T) and homozygous mutant (T/T) variants were significantly higher in RA patients as compared to controls and the odds ratios by logistic regression were (OR=2.2, p<0.001) and (OR=3.21, p<0.01) respectively. The association persisted on combining the heterozygous mutant and homozygous mutant (CT+TT) together as compared to controls (OR=2.39; p<0.001). Positive and significant (p<0.05) correlation of circulating IL-1β levels with RF (r=0.232), anti-CCP (r=0.207) and CRP (r=0.166) among RA patients were found. The levels of anti-CCP were significantly higher in homozygous mutant variants (TT) as well as the heterozygous mutant variants (C/T) in comparison to the wild variants (CC) (p<0.01). The results of this study reveal that mutant allele (T) of IL1B-511 promoter SNP tends to be associated with elevated anti-CCP and IL-1β levels as observed in RA patients and hence disease susceptibility.
Collapse
Affiliation(s)
- Mohd Jahid
- Department of Biochemistry, University College of Medical Sciences and GTB Hospital (University of Delhi), Dilshad Garden, Delhi 110095, India
| | - Rehan-Ul-Haq
- Department of Orthopedics, University College of Medical Sciences and GTB Hospital (University of Delhi), Dilshad Garden, Delhi 110095, India
| | - Diwesh Chawla
- Central Research Laboratory, University College of Medical Sciences and GTB Hospital (University of Delhi), Dilshad Garden, Delhi 110095, India
| | - Rajnish Avasthi
- Department of Medicine, University College of Medical Sciences and GTB Hospital (University of Delhi), Dilshad Garden, Delhi 110095, India
| | - Rafat Sultana Ahmed
- Department of Biochemistry, University College of Medical Sciences and GTB Hospital (University of Delhi), Dilshad Garden, Delhi 110095, India.
| |
Collapse
|
29
|
Halling ML, Kjeldsen J, Knudsen T, Nielsen J, Hansen LK. Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases. World J Gastroenterol 2017; 23:6137-6146. [PMID: 28970729 PMCID: PMC5597505 DOI: 10.3748/wjg.v23.i33.6137] [Citation(s) in RCA: 155] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 05/30/2017] [Accepted: 07/12/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate whether immune mediated diseases (IMD) are more frequent in patients with inflammatory bowel disease (IBD).
METHODS In this population based registry study, a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16, 2013. Controls were randomly selected from the Danish Civil Registration System (CRS) and matched for sex, age, and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis (UC), Crohn’s disease (CD) and Both the latter referring to those registered with both diagnoses. Subsequently, odds-ratios (OR) and 95%CI were obtained separately for each group and their respective controls. The use of Bonferoni post-test correction adjusted the significance level to P < 0.00125. P-values were estimated using Fisher’s exact test.
RESULTS There were significantly more women than men in the registry, and a greater percentage of comorbidity in the IBD groups (P < 0.05). Twenty different IMDs were all significantly more frequent in the IBD group. Sixteen were associated with UC versus twelve with CD. In both UC and CD ORs were significantly increased (P < 0.00125) for primary sclerosing cholangitis (PSC), celiac disease, type 1 diabetes (T1D), sarcoidosis, asthma, iridocyclitis, psoriasis, pyoderma gangrenosum, rheumatoid arthritis, and ankylosing spondylitis. Restricted to UC (P < 0.00125) were autoimmune hepatitis, primary biliary cholangitis, Grave’s disease, polymyalgia rheumatica, temporal arteritis , and atrophic gastritis. Restricted to CD (P < 0.00125) were psoriatic arthritis and episcleritis. Restricted to women with UC (P < 0.00125) were atrophic gastritis, rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica. Restricted to women with CD were episcleritis, rheumatoid arthritis, and psoriatic arthritis. The only disease restricted to men (P < 0.00125) was sarcoidosis.
CONCLUSION Immune mediated diseases were significantly more frequent in patients with IBD. Our results strengthen the hypothesis that some IMDs and IBD may have overlapping pathogenic pathways.
Collapse
Affiliation(s)
- Morten L Halling
- Department of Gastroenterology and Hepatology, Hospital of Southwest Jutland, 6700 Esbjerg, Denmark
| | - Jens Kjeldsen
- Department of Medical Gastroenterology S, Odense University Hospital, 5000 Odense, Denmark
| | - Torben Knudsen
- Department of Gastroenterology and Hepatology, Hospital of Southwest Jutland, 6700 Esbjerg, Denmark
| | - Jan Nielsen
- Center for Clinical Epidemiology, Odense University Hospital, 5000 Odense, Denmark
| | - Lars Koch Hansen
- Department of Medical Gastroenterology S, Odense University Hospital, 5000 Odense, Denmark
| |
Collapse
|
30
|
Muñoz-Valle JF, Padilla-Gutiérrez JR, Hernández-Bello J, Ruiz-Noa Y, Valle Y, Palafox-Sánchez CA, Parra-Rojas I, Gutiérrez-Ureña SR, Rangel-Villalobos H. Polimorfismo −1123G>C en el gen PTPN22 y anticuerpos antipéptido citrulinado cíclico en la artritis reumatoide. Med Clin (Barc) 2017; 149:95-100. [DOI: 10.1016/j.medcli.2017.01.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 01/10/2017] [Accepted: 01/12/2017] [Indexed: 01/08/2023]
|
31
|
Tumor necrosis factor-α -308 polymorphism in North Indian rheumatoid arthritis patients and association with mRNA and serum TNF-α. Clin Rheumatol 2017; 36:2209-2216. [DOI: 10.1007/s10067-017-3774-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 07/12/2017] [Accepted: 07/18/2017] [Indexed: 10/19/2022]
|
32
|
How to manage rheumatoid arthritis according to classic biomarkers and polymorphisms? ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s11515-017-1452-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
|
33
|
Song X, Lin Q. Genomics, transcriptomics and proteomics to elucidate the pathogenesis of rheumatoid arthritis. Rheumatol Int 2017; 37:1257-1265. [DOI: 10.1007/s00296-017-3732-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 04/29/2017] [Indexed: 01/23/2023]
|
34
|
Matrix Metalloproteinase Gene Activation Resulting from Disordred Epigenetic Mechanisms in Rheumatoid Arthritis. Int J Mol Sci 2017; 18:ijms18050905. [PMID: 28441353 PMCID: PMC5454818 DOI: 10.3390/ijms18050905] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/18/2017] [Accepted: 04/19/2017] [Indexed: 12/29/2022] Open
Abstract
Matrix metalloproteinases (MMPs) are implicated in the degradation of extracellular matrix (ECM). Rheumatoid arthritis (RA) synovial fibroblasts (SFs) produce matrix-degrading enzymes, including MMPs, which facilitate cartilage destruction in the affected joints in RA. Epigenetic mechanisms contribute to change in the chromatin state, resulting in an alteration of gene transcription. Recently, MMP gene activation has been shown to be caused in RASFs by the dysregulation of epigenetic changes, such as histone modifications, DNA methylation, and microRNA (miRNA) signaling. In this paper, we review the role of MMPs in the pathogenesis of RA as well as the disordered epigenetic mechanisms regulating MMP gene activation in RASFs.
Collapse
|
35
|
Gabbani T, Deiana S, Marocchi M, Annese V. Genetic risk variants as therapeutic targets for Crohn's disease. Expert Opin Ther Targets 2017; 21:381-390. [PMID: 28281904 DOI: 10.1080/14728222.2017.1296431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/14/2017] [Indexed: 02/06/2023]
Abstract
The pathogenesis of Inflammatory bowel diseases (IBD) is multifactorial, with interactions between genetic and environmental factors. Despite the existence of genetic factors being largely demonstrated by epidemiological data and several genetic studies, only a few findings have been useful in term of disease prediction, disease progression and targeting therapy. Areas covered: This review summarizes the results of genome-wide association studies in Crohn's disease, the role of epigenetics and the recent discovery by genetic studies of new pathogenetic pathways. Furthermore, it focuses on the importance of applying genetic data to clinical practice, and more specifically how to better target therapy and predict potential drug-related toxicity. Expert opinion: Some genetic markers identified in Crohn`s disease have allowed investigators to hypothesize about, and in some cases, prove the usefulness of new specific therapeutic agents. However, the heterogeneity and complexity of this disease has so far limited the daily clinical use of genetic information. Finally, the study of the implications of genetics on therapy, either to predict efficacy or avoid toxicity, is considered still to be in its infancy.
Collapse
Affiliation(s)
- Tommaso Gabbani
- a Gastroenterology UO , Azienda Unita Sanitaria Locale della Romagna , Forlì , Italy
| | - Simona Deiana
- b Division of Gastroenterology , AOU Careggi University Hospital , Florence , Italy
| | - Margherita Marocchi
- c Division of Gastroenterology , AOU Modena University Hospital , Modena , Italy
| | - Vito Annese
- d Department of Gastroenterology , Valiant Clinic , Dubai , UAE
| |
Collapse
|
36
|
Choi CW, Eun SH, Choi KH, Bae JM. Increased risk of comorbid rheumatic disorders in vitiligo patients: A nationwide population-based study. J Dermatol 2017; 44:909-913. [DOI: 10.1111/1346-8138.13846] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 02/16/2017] [Indexed: 11/30/2022]
Affiliation(s)
- Chong Won Choi
- Department of Dermatology; Seoul National University Hospital; Seoul Korea
| | - Sung Hye Eun
- Department of Dermatology; Veterans Health Service Medical Center; Seoul Korea
| | - Kwang Hyun Choi
- Department of Dermatology; St Vincent's Hospital; College of Medicine; The Catholic University of Korea; Suwon Korea
| | - Jung Min Bae
- Department of Dermatology; Veterans Health Service Medical Center; Seoul Korea
| |
Collapse
|
37
|
Levels MJ, Van Tok MN, Cantaert T, Cañete JD, Kroese FGM, Germar K, Spits H, Baeten DLP, Yeremenko NG. The Transcriptional Coactivator Bob1 Is Associated With Pathologic B Cell Responses in Autoimmune Tissue Inflammation. Arthritis Rheumatol 2017; 69:750-762. [DOI: 10.1002/art.39993] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 11/08/2016] [Indexed: 12/18/2022]
Affiliation(s)
- Maria J. Levels
- Academic Medical Center, University of AmsterdamAmsterdam The Netherlands
| | - Melissa N. Van Tok
- Academic Medical Center, University of AmsterdamAmsterdam The Netherlands
| | - Tineke Cantaert
- Academic Medical Center, University of AmsterdamAmsterdam The Netherlands
| | - Juan D. Cañete
- Hospital Clinic of Barcelona and Institut d'Investigacions Biomèdiques August Pi i SunyerBarcelona Spain
| | | | - Kristine Germar
- Academic Medical Center, University of AmsterdamAmsterdam The Netherlands
| | - Hergen Spits
- Academic Medical Center, University of Amsterdam and AIMM TherapeuticsAmsterdam The Netherlands
| | | | | |
Collapse
|
38
|
Koushik S, Joshi N, Nagaraju S, Mahmood S, Mudeenahally K, Padmavathy R, Jegatheesan SK, Mullangi R, Rajagopal S. PAD4: pathophysiology, current therapeutics and future perspective in rheumatoid arthritis. Expert Opin Ther Targets 2017; 21:433-447. [PMID: 28281906 DOI: 10.1080/14728222.2017.1294160] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Peptidyl arginine deiminase 4 (PAD4) is an enzyme that plays an important role in gene expression, turning out genetic code into functional products in the body. It is involved in a key post translational modification, which involves the conversion of arginine to citrulline. It regulates various processes such as apoptosis, innate immunity and pluripotency, while its dysregulation has a great impact on the genesis of various diseases. Over the last few years PAD4 has emerged as a potential therapeutic target for the treatment of rheumatoid arthritis (RA). Areas covered: In this review, we discuss the basic structure and function of PAD4, along with the role of altered PAD4 activity in the onset of RA and other maladies. We also elucidate the role of PAD4 variants in etiology of RA among several ethnic groups and the current pre-clinical inhibitors to regulate PAD4. Expert opinion: Citrullination has a crucial role in RA and several other disorders. Since PAD4 is an initiator of the citrullination, it is an important therapeutic target for inflammatory diseases. Therefore, an in depth knowledge of the roles and activity of PAD4 is required to explore more effective ways to conquer PAD4 related ailments, especially RA.
Collapse
Affiliation(s)
- Sindhu Koushik
- a Bioinformatics , Jubilant Biosys Ltd ., Bangalore , India
| | - Nivedita Joshi
- a Bioinformatics , Jubilant Biosys Ltd ., Bangalore , India
| | | | - Sameer Mahmood
- a Bioinformatics , Jubilant Biosys Ltd ., Bangalore , India
| | | | | | | | | | | |
Collapse
|
39
|
Wang LH, Wu MH, Chen PC, Su CM, Xu G, Huang CC, Tsai CH, Huang YL, Tang CH. Prognostic significance of high-mobility group box protein 1 genetic polymorphisms in rheumatoid arthritis disease outcome. Int J Med Sci 2017; 14:1382-1388. [PMID: 29200952 PMCID: PMC5707755 DOI: 10.7150/ijms.21773] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 10/11/2017] [Indexed: 12/23/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory disease that causes chronic inflammation of the joints. Analysis of genetic variants offers promise for guiding treatment and improving outcomes in RA. High-mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein found in all mammal eukaryotic cells that participates in several biological functions including immune response, cell survival and apoptosis. We investigated the effects of HMGB1 gene polymorphisms on the risk of RA disease progression in a cohort of Chinese Han individuals. Four single nucleotide polymorphisms (SNPs) from the HMGB1 gene were selected and genotyped in 232 patients with RA and 353 healthy controls. We found that having one C allele in rs1360485 and one G allele in rs2249825 polymorphisms lowered the risk of RA in females. Moreover, among healthy controls, those who bore the C/G/T haplotype at SNPs rs1360485, rs2249825 and rs1412125 were at reduced risk of developing RA by 0.13-fold (p <0.05). This is the first report to examine the risk factors associated with HMGB1 SNPs in the development of RA disease in the Chinese Han population.
Collapse
Affiliation(s)
- Li-Hong Wang
- Department of Orthopedics, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Min-Huan Wu
- Physical Education Office, Tunghai University, Taichung, Taiwan.,Sports Recreation and Health Management Continuing Studies, Tunghai University, Taichung, Taiwan
| | - Po-Chun Chen
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
| | - Chen-Ming Su
- Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Guohong Xu
- Department of Orthopedics, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Chien-Chung Huang
- Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
| | - Chun-Hao Tsai
- School of Medicine, China Medical University, Taichung, Taiwan.,Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Yuan-Li Huang
- Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan.,School of Medicine, China Medical University, Taichung, Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
| |
Collapse
|
40
|
The Mechanisms Underlying Chronic Inflammation in Rheumatoid Arthritis from the Perspective of the Epigenetic Landscape. J Immunol Res 2016; 2016:6290682. [PMID: 28116320 PMCID: PMC5225373 DOI: 10.1155/2016/6290682] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Revised: 11/21/2016] [Accepted: 12/07/2016] [Indexed: 12/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that is characterized by synovial hyperplasia and progressive joint destruction. The activation of RA synovial fibroblasts (SFs), also called fibroblast-like synoviocytes (FLS), contributes significantly to perpetuation of the disease. Genetic and environmental factors have been reported to be involved in the etiology of RA but are insufficient to explain it. In recent years, accumulating results have shown the potential role of epigenetic mechanisms, including histone modifications, DNA methylation, and microRNAs, in the development of RA. Epigenetic mechanisms regulate chromatin state and gene transcription without any change in DNA sequence, resulting in the alteration of phenotypes in several cell types, especially RASFs. Epigenetic changes possibly provide RASFs with an activated phenotype. In this paper, we review the roles of epigenetic mechanisms relevant for the progression of RA.
Collapse
|
41
|
Okada Y, Suzuki A, Ikari K, Terao C, Kochi Y, Ohmura K, Higasa K, Akiyama M, Ashikawa K, Kanai M, Hirata J, Suita N, Teo YY, Xu H, Bae SC, Takahashi A, Momozawa Y, Matsuda K, Momohara S, Taniguchi A, Yamada R, Mimori T, Kubo M, Brown M, Raychaudhuri S, Matsuda F, Yamanaka H, Kamatani Y, Yamamoto K. Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis. Am J Hum Genet 2016; 99:366-74. [PMID: 27486778 DOI: 10.1016/j.ajhg.2016.06.019] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 06/21/2016] [Indexed: 01/11/2023] Open
Abstract
Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.
Collapse
|