Originalien Z Rheumatol 2015 · 74:714–721 DOI 10.1007/s00393-014-1536-3 Published online: 18. Juli 2015 © Springer-Verlag Berlin Heidelberg 2015
Redaktion
U. Müller-Ladner, Bad Nauheim U. Lange, Bad Nauheim
Y.H. Lee · G.G. Song Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul
Associations between major histocompatibility complex class I chain-related gene A polymorphisms and susceptibility to Behcet’s disease A meta-analysis
Introduction Behcet’s disease (BD) is a chronic inflammatory disease that is characterized by recurrent oral and genital ulcers, skin lesions, and uveitis [1]. BD also affects all types and sizes of blood vessels, the joints, the central nervous system, the lungs, and the gastrointestinal system [2]. Although the etiology of BD is not fully understood, it has been suggested to occur given suitable interactions between a susceptible genetic background and environmental factors. The major histocompatibility complex class I chain-related gene A (MICA) functions as a stress-inducible antigen, and it plays a key role in innate and adaptive immune responses by interacting with the natural killer group 2 member D activating receptor of natural killer (NK) cells, CD8 T cells, and γδT cells [3]. MICA is expressed in fibroblasts, epithelial cell lines, gastrointestinal epithelium, keratinocytes, endothelial cells, and monocytes [4]. It is located at 46 kb centromeric to human leukocyte antigen-B51 (HLAB51), which is a strong candidate susceptibility gene of BD in various ethnic groups [5]. Exons 2, 3, and 4 of the MICA gene encode three extracellular domains, and exon 5 encodes the transmembrane (TM) domain [6]. MICA is highly polymorphic like HLA. Exons 2–4 have microsatellite
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Zeitschrift für Rheumatologie 8 · 2015
polymorphisms and exon 5 shows a variable number of GCT repeats with 4, 5, 6, and 9 triplets called as A, A5, A6, and A9, respectively. The A5.1 allele has a guanine insertion (GCT → GGCT) after two GCT triplets [7]. MICA polymorphisms have been studied in the context of BD. MICA exon 2–4 009 (MICA*009) and MICA-TM A6 allele have been reported to be associated with BD and HLA-B51 across different ethnicities by some but not all researchers, possibly because of small sample sizes, low statistical power, different ethnicities, and/or clinical heterogeneity [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. Therefore, in order to overcome the limitations of individual studies, resolve inconsistencies, and to reduce the likelihood that random errors were responsible for false-positive or false-negative associations, we performed a meta-analysis. The aim of the present study was to determine whether the MICA-TM A6 and MICA*009 alleles are associated with BD with or without HLA-B51 in various ethnic groups.
Materials and methods Identification of eligible studies and data extraction A literature search was conducted of studies that examined associations between
MICA polymorphisms and BD. We utilized the MEDLINE and EMBASE citation indexes to identify articles in which MICA polymorphisms were determined in BD patients and controls (from January 1997 to April 2013). In addition, all of the references that were mentioned in the identified articles were reviewed to identify studies that were not indexed by MEDLINE and EMBASE. The following key words and subject terms were searched: “major histocompatibility complex class I chain-related gene A,” “MICA,” “Behcet’s disease,” and “BD.” No language restriction was applied. The following information was extracted from each study that was identified: author, year of publication, ethnicity of the study population, demographics, numbers of cases and controls, and the frequencies of the genotypes and alleles of the MICA polymorphisms. Data were extracted from the original studies by two independent reviewers. Discrepancies between the reviewers were resolved by reaching a consensus or by a third reviewer.
Evaluation of publication bias and study quality Funnel plots are used for detecting publication bias, but they require a range of studies of varying sizes and subjective judgments. Thus, we evaluated publica-
Tab. 1 Characteristics of the individual studies that were included in the meta-analysis Author, year
Country Ethnicity
Polymorphisms studied
Association findings
Turkish European Asian European Iranian European Asian Asian European European European
Subjects (n) Case Control 33 65 42 165 23 23 56 90 84 83 10 20 108 204 95 132 55 52 22 28 58 194
Mizuki et al., 2007 [8] Munoz-Saa et al., 2006 [9] Nishiyama, 2006 [10] Hughes et al., 2005 [11] Mizuki et al., 2002 [12] Picco et al., 2002 [13] Park et al., 2002 [14] Mizuki-1 et al., 2000 [15] Mizuki-2 et al., 2000 [15] Mizuki-3 et al., 2000 [15] Gonzalez-Escribano et al., 1999 [16] Yabuki et al., 1999 [17] Salvarani et al., 2001 [18] Cohen-1 et al., 2002 [19] Cohen-2 et al., 2002 [19]
Turkey Spain Japan UK Iran Italy Korea Japan Greece Italy Spain
MICA*009, HLA-B51 MICA*009, HLA-B51 MICA-TM A6 MICA*009, HLA-B51 MICA-TM A6, HLA-B51 MICA-TM A6, HLA-B51 MICA-TM A6, HLA-B51 MICA-TM A6 MICA-TM A6 MICA-TM A6 MICA-TM A6, HLA-B51
*009 (p=0.000005), *009+/B51+ (NS) *009 (p
Redaktion
U. Müller-Ladner, Bad Nauheim U. Lange, Bad Nauheim
Y.H. Lee · G.G. Song Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul
Associations between major histocompatibility complex class I chain-related gene A polymorphisms and susceptibility to Behcet’s disease A meta-analysis
Introduction Behcet’s disease (BD) is a chronic inflammatory disease that is characterized by recurrent oral and genital ulcers, skin lesions, and uveitis [1]. BD also affects all types and sizes of blood vessels, the joints, the central nervous system, the lungs, and the gastrointestinal system [2]. Although the etiology of BD is not fully understood, it has been suggested to occur given suitable interactions between a susceptible genetic background and environmental factors. The major histocompatibility complex class I chain-related gene A (MICA) functions as a stress-inducible antigen, and it plays a key role in innate and adaptive immune responses by interacting with the natural killer group 2 member D activating receptor of natural killer (NK) cells, CD8 T cells, and γδT cells [3]. MICA is expressed in fibroblasts, epithelial cell lines, gastrointestinal epithelium, keratinocytes, endothelial cells, and monocytes [4]. It is located at 46 kb centromeric to human leukocyte antigen-B51 (HLAB51), which is a strong candidate susceptibility gene of BD in various ethnic groups [5]. Exons 2, 3, and 4 of the MICA gene encode three extracellular domains, and exon 5 encodes the transmembrane (TM) domain [6]. MICA is highly polymorphic like HLA. Exons 2–4 have microsatellite
714 |
Zeitschrift für Rheumatologie 8 · 2015
polymorphisms and exon 5 shows a variable number of GCT repeats with 4, 5, 6, and 9 triplets called as A, A5, A6, and A9, respectively. The A5.1 allele has a guanine insertion (GCT → GGCT) after two GCT triplets [7]. MICA polymorphisms have been studied in the context of BD. MICA exon 2–4 009 (MICA*009) and MICA-TM A6 allele have been reported to be associated with BD and HLA-B51 across different ethnicities by some but not all researchers, possibly because of small sample sizes, low statistical power, different ethnicities, and/or clinical heterogeneity [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. Therefore, in order to overcome the limitations of individual studies, resolve inconsistencies, and to reduce the likelihood that random errors were responsible for false-positive or false-negative associations, we performed a meta-analysis. The aim of the present study was to determine whether the MICA-TM A6 and MICA*009 alleles are associated with BD with or without HLA-B51 in various ethnic groups.
Materials and methods Identification of eligible studies and data extraction A literature search was conducted of studies that examined associations between
MICA polymorphisms and BD. We utilized the MEDLINE and EMBASE citation indexes to identify articles in which MICA polymorphisms were determined in BD patients and controls (from January 1997 to April 2013). In addition, all of the references that were mentioned in the identified articles were reviewed to identify studies that were not indexed by MEDLINE and EMBASE. The following key words and subject terms were searched: “major histocompatibility complex class I chain-related gene A,” “MICA,” “Behcet’s disease,” and “BD.” No language restriction was applied. The following information was extracted from each study that was identified: author, year of publication, ethnicity of the study population, demographics, numbers of cases and controls, and the frequencies of the genotypes and alleles of the MICA polymorphisms. Data were extracted from the original studies by two independent reviewers. Discrepancies between the reviewers were resolved by reaching a consensus or by a third reviewer.
Evaluation of publication bias and study quality Funnel plots are used for detecting publication bias, but they require a range of studies of varying sizes and subjective judgments. Thus, we evaluated publica-
Tab. 1 Characteristics of the individual studies that were included in the meta-analysis Author, year
Country Ethnicity
Polymorphisms studied
Association findings
Turkish European Asian European Iranian European Asian Asian European European European
Subjects (n) Case Control 33 65 42 165 23 23 56 90 84 83 10 20 108 204 95 132 55 52 22 28 58 194
Mizuki et al., 2007 [8] Munoz-Saa et al., 2006 [9] Nishiyama, 2006 [10] Hughes et al., 2005 [11] Mizuki et al., 2002 [12] Picco et al., 2002 [13] Park et al., 2002 [14] Mizuki-1 et al., 2000 [15] Mizuki-2 et al., 2000 [15] Mizuki-3 et al., 2000 [15] Gonzalez-Escribano et al., 1999 [16] Yabuki et al., 1999 [17] Salvarani et al., 2001 [18] Cohen-1 et al., 2002 [19] Cohen-2 et al., 2002 [19]
Turkey Spain Japan UK Iran Italy Korea Japan Greece Italy Spain
MICA*009, HLA-B51 MICA*009, HLA-B51 MICA-TM A6 MICA*009, HLA-B51 MICA-TM A6, HLA-B51 MICA-TM A6, HLA-B51 MICA-TM A6, HLA-B51 MICA-TM A6 MICA-TM A6 MICA-TM A6 MICA-TM A6, HLA-B51
*009 (p=0.000005), *009+/B51+ (NS) *009 (p
