Association between MEFV Mutations M694V and M680I and Behçet’s Disease: A Meta-Analysis

PLOS ONE, Dec 2019

Objective Several studies have identified an association between Behçet’s disease (BD) and mutations in the Mediterranean fever (MEFV) gene, which was originally linked to the autosomal recessive disease, Familial Mediterranean fever. However, no consensus has been reached. Here, a meta-analysis was conducted on published data to comprehensively evaluate this relationship. Methods Literature searches were performed in Pubmed, Embase, the Web of Science, and HuGE Navigator databases, in order to identify studies pertaining to the association between MEFV mutations and BD. Two investigators independently extracted and evaluated the data from eligible studies. The association between MEFV mutations (M694V, M680I, and E148Q) and BD was estimated overall by the odds ratio (OR) and 95% confidence intervals (95% CI). Further analysis was conducted with STATA 12.0 software (Stata Corp.; College Station, TX). Results Eligible studies (n=8) included genotyping data obtained from 2538 BD patients and 2792 healthy controls. Of the three mutations, M694V (pooled OR: 2.60, 95% CI: 2.02-3.34) and M680I (pooled OR: 1.74, 95% CI: 1.23-2.46) were found to be associated with BD in the overall analysis. The third mutation, E148Q, however, was not found to be linked with BD (pooled OR: 1.26, 95% CI: 0.69-2.31). Subgroup analysis furthermore revealed that M694V and M680I were risk loci for BD specifically in Turkish patients. Conclusions The meta-analysis confirmed that MEFV mutations M694V and M680I were associated with BD. Additional studies from other ethnic populations and functional experiments are necessary to determine the extent to which the MEFV gene underlies the development of BD.

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Association between MEFV Mutations M694V and M680I and Behçet’s Disease: A Meta-Analysis

July Association between MEFV Mutations M694V and M680I and Behçet's Disease: A Meta-Analysis Ziyan Wu☯ 0 1 Shulan Zhang☯ 0 1 Jing Li☯ 0 1 Si Chen 0 1 Ping Li 0 1 Fei Sun 0 1 Xiaoting Wen 0 1 Wenjie Zheng 0 1 Fengchun Zhang 0 1 Yongzhe Li 0 1 0 Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education , Beijing , China 1 Editor: Graham R. Wallace, University of Birmingham , UNITED KINGDOM - Funding: This work was supported by the Research Special Fund for Public Welfare Industry of Health No. 201202004 (to F-C. Z.); the National Natural Science Foundation of China Grants No. 81373188, 81172857 (to Y.-Z. L.), and 81302592 (to S.-L. Z.); the Chinese National High Technology Research and Development Program, Ministry of Science and Technology Grant No. 2011AA02A113; the National Science Technology Pillar Program in the 12nd Fiveyear Plan No. 2014BAI07B00; and the capital health Several studies have identified an association between Behçet’s disease (BD) and mutations in the Mediterranean fever (MEFV) gene, which was originally linked to the autosomal recessive disease, Familial Mediterranean fever. However, no consensus has been reached. Here, a meta-analysis was conducted on published data to comprehensively evaluate this relationship. Literature searches were performed in Pubmed, Embase, the Web of Science, and HuGE Navigator databases, in order to identify studies pertaining to the association between MEFV mutations and BD. Two investigators independently extracted and evaluated the data from eligible studies. The association between MEFV mutations (M694V, M680I, and E148Q) and BD was estimated overall by the odds ratio (OR) and 95% confidence intervals (95% CI). Further analysis was conducted with STATA 12.0 software (Stata Corp.; College Station, TX). Eligible studies (n=8) included genotyping data obtained from 2538 BD patients and 2792 healthy controls. Of the three mutations, M694V (pooled OR: 2.60, 95% CI: 2.02-3.34) and M680I (pooled OR: 1.74, 95% CI: 1.23-2.46) were found to be associated with BD in the overall analysis. The third mutation, E148Q, however, was not found to be linked with BD (pooled OR: 1.26, 95% CI: 0.69-2.31). Subgroup analysis furthermore revealed that M694V and M680I were risk loci for BD specifically in Turkish patients. Competing Interests: The authors had declared that no competing interests existed. The meta-analysis confirmed that MEFV mutations M694V and M680I were associated with BD. Additional studies from other ethnic populations and functional experiments are necessary to determine the extent to which the MEFV gene underlies the development of BD. Behçet’s disease (BD) is a systemic vasculitis characterized by recurrent aphthous ulceration, genital ulcers, ocular inflammation, and skin lesions. The disease has been considered as a seronegative spontaneous arthritis, autoimmune disease, or auto-inflammatory disorder with a probable genetic basis [1]. Familial Mediterranean fever (FMF) is also a genetic autoinflammatory syndrome presenting with episodes of fever, with or without serositis, synovitis, or rashes [2]. Interestingly, certain clinical characteristics are shared by BD and FMF patients, including a unique ethnic prevalence, pathogenesis, and treatment protocols, despite a wide range in clinical manifestations [3,4]. Both BD and FMF, for example, are observed all around the Mediterranean basin, with BD occurring more frequently along the ancient Silk Road, which extended from Asia to the Mediterranean [5,6]. In addition, there are case reports of the co-existence of BD and FMF in individual patients. The intersection of some disease characteristics has therefore led to the proposal that a common genetic susceptibility exists between BD and FMF [7–9]. Specific genes have been associated with BD. So far, HLA-B 51 has been shown to share the strongest association with BD in several different populations [10]. However, genome-wide association studies (GWAS) have also revealed other potential susceptibility loci for BD, such as HLA-A 26, IL10, IL23R-IL12RB2, STAT4, GIMAP, CCR1, and KLRC4 [11–15]. Although several GWAS and numerous candidate gene association studies have been conducted to identify susceptibility loci [11–18], they have all been based on the hypothesis-‘common variants and common disease’-which places the emphasis on the identification of common variants [minor allele frequency (MAF) > 5%] rather than rare and/or genetic structure variations. These common variants only explain ~20% heritability, and thus, the existence of a genetic component, the so-called ‘missing heritability’, is indisputable [19]. The Mediterranean fever (MEFV) gene encodes pyrin, a protein of 781 amino acids, which has been associated with the development of FMF. Pyrin is expressed primarily in the (...truncated)


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Ziyan Wu, Shulan Zhang, Jing Li, Si Chen, Ping Li, Fei Sun, Xiaoting Wen, Wenjie Zheng, Fengchun Zhang, Yongzhe Li. Association between MEFV Mutations M694V and M680I and Behçet’s Disease: A Meta-Analysis, PLOS ONE, 2015, Volume 10, Issue 7, DOI: 10.1371/journal.pone.0132704