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
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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)