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Rheumatology Advance Access originally published online on September 26, 2006
Rheumatology 2007 46(3):426-430; doi:10.1093/rheumatology/kel331
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

MHC class I chain-related gene B (MICB) is associated with rheumatoid arthritis susceptibility

R. López-Arbesu, F. J. Ballina-García1, M. Alperi-López1, A. López-Soto, S. Rodríguez-Rodero2, J. Martínez-Borra2, A. López-Vázquez2, J. L. Fernández-Morera2, J. L. Riestra-Noriega1, R. Queiro-Silva1, A. Quiñones-Lombraña, C. López-Larrea and S. González

Department of Functional Biology, University of Oviedo, 1Department of Rheumatology and 2Histocompatibility and Transplantation Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.

Correspondence to: Segundo González, MD, PhD, Department of Functional Biology, Instituto Oncológico del principado de Asturias, Universidad de Oviedo, Facultad de Medicina, Julián Clavería sn, 33006, Oviedo, Spain. E-mail: segundog{at}uniovi.es


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. Several recent studies have shown that the MHC class III region, located telomeric to HLA-DRB1, contains an additional genetic factor that predisposes to rheumatoid arthritis (RA). In this study, we investigate whether inhibitor of {kappa}B-like (I{kappa}BL), MICB or MICA located in the MHC class III region are the second susceptibility gene associated with RA.

Methods. A total of 154 healthy controls and 140 RA patients were genotyped for HLA-DRB1, MICA, MICB and the polymorphism –62 of the I{kappa}BL gene.

Results. A significant increase of HLA-DRB1 shared epitope (SE) alleles was detected in RA patients (61.4 vs 43.5%, Pc = 0.01, OR = 2.1, 95% CI = 1.3–3.3). Among SE alleles, the HLA-DRB1*0401 (13.5 vs 5.1%, Pc = 0.04, OR = 3.2, 95% CI = 1.3–8.1) and HLA-DRB1*0404 (6.4 vs 1.2%, P = 0.02, Pc = NS) showed the most significantly association with RA. No increase of risk was associated with HLA-DRB1*01. Remarkably, the allele MICB*004 was also significantly associated with RA susceptibility (40.7 vs 23.3%, Pc = 0.01, OR = 2.2, 95% CI = 1.3–3.7). MICB*004 was in linkage disequilibrium with HLA-DRB1*0404 ({lambda}s = 0.33) and HLA-DRB1*0405 ({lambda}s = 0.34). However, MICB*004 was also increased in HLA-DRB1 SE negative patients (37 vs 21.5%, P = 0.04). No significant association between I{kappa}BL and MICA with RA was found.

Conclusions. MICB*004 allele was associated with RA susceptibility. This allele was in linkage disequilibrium with HLA-DRB1*0404 and DRB1*0405. The association of MICB with RA susceptibility and the functional role of MIC genes in the pathogenesis of RA converts MICB into a candidate to be an additional MHC gene associated with RA susceptibility.

KEY WORDS: Rheumatoid arthritis, MHC, HLA-DR, MICB, MICA, I{kappa}BL


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Rheumatoid arthritis (RA) is a chronic disease characterized by inflammatory synovitis leading to joint destruction that affects around 1% of the Caucasian population. RA is a complex disorder, with both environmental and genetic factors contributing to disease susceptibility. Studies in twins suggest that the genetic component of RA accounts for ~60% of disease susceptibility [1]. Several genome-wide linkage analyses documented a number of RA susceptibility loci scattered across the human genome; however, they have consistently demonstrated that the MHC region provides the main genetic contribution to RA susceptibility [2, 3]. The MHC region occupies a 3.6-Mb region on the short arm of chromosome 6 and contains more than 200 genes, many of which are involved in the immune function. Initial serological studies on human leucocyte antigen (HLA) have demonstrated a strong association between HLA-DR4 and susceptibility to RA [4, 5]. More recently, DNA typing techniques have shown that the susceptibility to disease is associated with HLA-DRB1*0404, HLA-DRB1*0405 and HLA-DRB1*0101 [6, 7]. These alleles contain a shared epitope (SE) of a 5-amino-acid sequence motif rich in basic residues, QKRAA or QRRAA, from amino acid position 70–74 in the third hypervariable region of the DRß chain [8]. It has been reported that these SE alleles are strongly associated with the susceptibility and severity of RA [9, 10].

Several recent studies using microsatellite markers have documented that the telomeric region of the MHC region contains an additional genetic factor that predisposes to RA [11–17]. Interestingly, this region has been limited to within a short interval of 70 Kb between tumour necrosis factor-{alpha} (TNF-{alpha}) and MHC class I chain-related gene A (MICA) genes [13]. This candidate region comprises four expressed genes (I{kappa}BL, ATP6G, BAT1 and MHC class I chain-related gene B (MICB) (Fig. 1). Despite the fact that the TNF-{alpha} gene has been reported as a possible candidate for RA susceptibility [18, 19], this study excluded the possibility that TNF-{alpha} or MICA genes are associated with RA susceptibility. Among these four candidate genes, inhibitor of {kappa}B-like (I{kappa}BL) was first defined as a good candidate to be the second RA susceptibility gene, because it is a putative member of I{kappa}BL family of transcription factors and may be involved in the regulation of pro-inflammatory cytokines such as TNF-{alpha}. Thus, a polymorphism –62 in the promoter region of I{kappa}BL has been found to be involved in the susceptibility of RA in a Japanese population [20]. However, analysis in Caucasian populations revealed no evidence of the association of I{kappa}BL with RA [15, 21].


Figure 1
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  		FIG. 1. Schematic representation of a second susceptibility region for rheumatoid arthritis in the MHC class III region [13].

 
Other additional interesting candidate genes found to be associated with RA susceptibility are MICA and MICB. These genes are aberrantly expressed on the synoviocytes of RA patients, and the expression of MICA and MICB stimulates the autoreactive T-cell response against the synoviocytes [22]. Additionally, in RA the severity of autoimmune and inflammatory joint disease correlates with the presence of these autoreactive T-cells. This suggests that a profound dysregulation of MICA and MICB expression may cause autoreactive T-cell stimulation, thus promoting and perpetuating the inflammatory and autoimmune disease in RA patients. The association of several polymorphic markers that include the MICB locus with RA susceptibility has been analysed [11, 13, 15]; however, the analysis of the distribution of MICB alleles in RA has not been performed. Here, we provide evidence, for the first time, that the MICB*004 allele is associated with the susceptibility to RA. This suggests that the genetic background of different MICB alleles may contribute to the autoreactive T-cell stimulation observed in RA patients.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
One hundred and forty consecutive RA patients were recruited from the outpatients clinic of the Hospital Central de Asturias, Spain (39 males vs 101 females). All patients were diagnosed in the Department of Rheumatology. A standard diagnostic evaluation was performed based on the history of the patient, physical and laboratory examinations and radiographs of the hands and feet. All patients were diagnosed as RA according to the revised criteria of American College of Rheumatology [23]. The laboratory examination included an enzyme-linked immunosorbent assay for IgM anti-rheumatoid factor and an anti-cyclic citrullinated peptides (CCP) antibody ELISA (Euro-Diagnostica AB). The clinical features of the patients are shown in Table 1. A total of 154 random healthy blood donors (63 males vs 91 females; mean age 44.3 years, range 18–66) from the Spanish population were included in this study for genetic comparison. The controls and patients were of Spanish Caucasian ethnicity. Controls had no history of any rheumatic disease or any abnormality in biochemical studies. This study was approved by the ethics committee of our hospital, and informed consent was obtained from all patients.


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  		TABLE 1. Clinical features of the patients enrolled in this study

 
HLA typing
HLA-DRB1 alleles were typed and subtyped by performing polymerase chain reaction using specific primers (PCR–SSP) [24] and by sequence specific oligonucleotide probes (PCR-SSOP; INNO-LiPA, Innogenetics, NV Ghent, Belgium). MICB was typed performing twenty-eight PCR amplifications using specific primers for the MICB alleles (PCR–SSP) as we have previously described [25]. The nomenclature of the MICB alleles was updated as described [26]. For the analysis of microsatellite repeat polymorphism in the MICA gene, PCR was carried out using primers labelled at the 5' end with the fluorescent reagent Cy5 as previously described [27]. The primers flanking the transmembrane region were: sense MICA: 5'-ACATTCCATGTTTCTGCTGTTG-3' and antisense primer 5'-TCACCTGGACCCTCTGCAG-3'. Fragment sizes were determined automatically using Alf express II (Amershan Pharmacia Biotech). The polymorphism at the position -62 A/T of the I{kappa}BL gene was typed by PCR–SSP using the sense primer 5'-CCCGGCAGACAGATGTGG-3' and the antisense 5'-CACTTCCGTCCTCCACCT-3' or 5'-CACTTCCGTCCTCCACCA-3'.

Statistical analysis
Allelic frequencies were calculated by direct counting and the significance of the association was determined using the chi-square test. The OR was calculated by the cross-product ratio. For the ORs 95% CI were calculated. The P-values were corrected (Pc) by multiplying these by the number of comparisons at every locus. The extent of linkage disequilibrium between the two loci is expressed as the observed disequilibrium value ({lambda}s), that is, a proportion of the theoretical maximum disequilibrium value ({lambda}max) achievable for this combination of alleles. The {lambda}s were calculated using the formula: {lambda}s = {lambda}/{lambda}max = Pab – (Pa x Pb)/Pa x (1 – Pb). Where Pa is the frequency of allele A, Pb is the frequency of allele B and Pab is the frequency of the haplotype that consist of the allele A and B.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
HLA-DRB1 distribution
A total of 140 RA patients and 154 matched healthy controls were analysed in this study (Table 1). All HLA–DRB1 alleles studied in our patient and control population were in Hardy-Weinberg disequilibrium. Table 2 shows the distribution of SE HLA-DRB1 alleles. The analysis of all SE alleles together showed that they were significantly increased in RA patients (61.4 vs 43.5%, Pc = 0.01, OR = 2.1, 95% CI=1.3–3.3). Significant differences were observed in the distribution of HLA-DRB1*04 alleles between patients and controls (35 vs 20.1%, Pc = 0.02, OR = 2.1, 95% CI = 1.2–3.6). This was largely due to the increase of HLA-DRB1*0401 (13.5 vs 5.1%, Pc = 0.04, OR = 3.2, 95% CI = 1.3–8.1) and HLA-DRB1*0404 (6.4 vs 1.2%, P = 0.02, Pc = NS) (Table 2). No significant increase of risk was associated with HLA-DRB1*01 (37.1 vs 31.1%).


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  		TABLE 2. Distribution of shared epitope HLA-DRB1 alleles

 
Analysis of genes located telomeric to HLA-DRB1 gene
To analyse whether other genes located in the telomeric part of HLA-DRB1 may contribute to the susceptibility to RA, the association of I{kappa}BL, MICA and MICB genes was also examined in this study (Fig. 1). All the alleles analysed were in Hardy–Weinberg disequilibrium. Initially, we studied the polymorphism –62 located in the promoter of I{kappa}BL gene, previously reported to be associated with higher susceptibility to RA [20]. No statistically significant differences were observed in the distribution of allelic (a frequency was 30.7% in patients vs 29.8% in controls) or genotypic frequencies of I{kappa}BL polymorphism -62 between patients and controls (Table 3). In addition, no differences in I{kappa}BL distribution were found when patients and controls were stratified by either the presence or absence of the SE alleles (data not shown).


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  		TABLE 3. Distribution of the I{kappa}BL -62 genotypes and alleles in RA patients and controls

 
Second, the distribution of MICB alleles between RA patients and controls was analysed by performing 28 sequence specific PCR reactions [25] (Table 4). Remarkably, the allele MICB*004 (formerly named MICB*0104) [26] was significantly increased in patients (40.7 vs 23.3%, Pc = 0.01, OR = 2.2, 95% CI = 1.3–3.7). Analysis of linkage disequilibrium indicated that MICB*004 was not in linkage disequilibrium with HLA-DRB1*01 or DRB1*0401 (only 3 of 19 DRB1*0401 patients were also MICB*004). Nevertheless, MICB*004 was in linkage disequilibrium with the SE alleles HLA-DRB1*0404 (6 of 11 DRB1*0404 individuals were MICB*004; {lambda}s = 0.33) and with HLA-DRB1*0405 (10 of 18 DRB1*0405 individuals were MICB*004; {lambda}s = 0.34). To analyse whether MICB*004 was associated to RA independent of linkage disequilibrium, we stratified the controls and patients by the presence or absence of SE alleles. MICB*004 was also increased in SE negative patients (37 vs 21.5%, P = 0.04). This suggests that MICB could be also associated to RA susceptibility independently of HLA-DRB1. Last, the analysis of the microsatellite repeat polymorphism in the MICA gene revealed no significant differences between patients and controls (Table 5).


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  		TABLE 4. Distribution of MICB alleles between RA patients and controls

 

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  		TABLE 5. Distribution of MICA transmembrane repeat polymorphism between RA patients and controls

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
The results of this study show that SE HLA-DRB1 alleles were strongly associated with RA susceptibility in our patients. It has been known for more than 30 years that several HLA-DRB1 alleles play an important role in RA susceptibility. However, accumulating data obtained in the recent years suggest that the role of MHC genes in the susceptibility to RA should be more complex than previously thought. For instance, this model is difficult to reconcile with the fact that different SE alleles have different strengths of association with RA [28]. Thus, the association of SE alleles was largely due to HLA-DRB1*0401 or *0404, and it was clearly much stronger than HLA-DRB1*01. One possible explanation for the different strength of association of SE alleles with RA suggests that the variable risk among SE HLA-DRB1 alleles may not only be associated with HLA-DRB1 alleles themselves, but may also be due to the different haplotypic context of these alleles. In agreement with this idea, several recent studies using different approaches have shown that the telomeric region of the MHC contains an additional genetic factor to the HLA-DRB1 gene that predisposes to RA [11–17]. Interestingly, this area has been limited to 70 Kb and only four expressed genes (I{kappa}BL, ATP6G, BAT1 and MICB) by microsatellite analysis [13]. Initially, I{kappa}BL was defined as a second susceptibility gene for RA in the Japanese population [20]. However, we did not observe any differences among I{kappa}BL –62 allelic or genotypic frequencies between patients and controls in our population. These results confirm the recent finding of a study that revealed no differences in I{kappa}BL distribution in Caucasian populations [15, 21].

We also analysed whether MICA and MICB genes are associated with RA. MICA and MICB belong to a family of genes located in the MHC class I region [29]. There is increasing evidence that MIC genes may play an important role in the pathogenesis of several autoimmune diseases, such as diabetes mellitus or celiac disease. Consequently, MICA and MICB alleles have also been associated with the susceptibility to several autoimmune diseases [27, 30–33]. Evidence also exists that the MIC genes may be involved in the pathogenesis of RA. On one hand, most of the circulating and synovial T-cells of RA patients express NKG2D [22]. NKG2D is an activating receptor of T-cells that recognize MIC molecules among other ligands [34, 35]. On the other hand, MICA and MICB are expressed in the synoviocytes of RA patients. Thus, it has been proposed that an aberrant up-regulation of MIC genes in RA patients may cause autoreactive T-cell stimulation, therefore promoting the self perpetuating pathology in RA [22]. The association of several polymorphic markers that include the MICB locus with RA susceptibility has been analysed [11, 13, 15], but this is the first study that analyses the complete distribution of MICB alleles in RA. Here, we provide evidence that the MICB*004 allele is associated with the susceptibility to RA. MICB*004 was significantly increased when patients and controls were stratified by the presence of SE alleles. This indicates that MICB*004 may increase the susceptibility to RA in the absence of SE alleles; however, our results also indicate that MICB*004 was in linkage disequilibrium with HLA-DRB1*0404 and HLA-DRB1*0405. These data suggest that the presence of MICB*004 on RA susceptible haplotypes could modify the risk of the HLA-DRB1 gene. In accordance with our data, it has been shown that HLA-DRB1*0401 and *0404 have different grades of association with RA, thus suggesting the presence of an additional non-HLA-DRB1 RA susceptibility gene or genes on these haplotypes that could modify the risk of the HLA-DRB1 gene [16]. Despite the fact that MICA has the same function of MICB and that it is located 70 Kb telomeric to MICB gene, we did not detect an association of the MICA gene with RA. This is quite consistent with the fact that the genetic recombination hotspot is present between MICA and MICB [36].

Indirectly, our results suggest that the genetic background of MICB may contribute to the profound dysregulation of MIC genes leading to autoreactive T-cell stimulation observed in RA patients. Little is currently known about the potential functionality or expression of MICB alleles. Nevertheless, the majority of polymorphisms of MICB gene are not synonymous, suggesting the influence of selection pressure [37]. Thus, a functional significance of MICB alleles may be assumed, and may involve, for example, a quantitive influence on the receptor/ligand interaction and the cytotoxic activity observed in the synovia of RA patients. In spite of the fact that MICB*004 allele has also been associated with the susceptibility to celiac disease [38], there is no information about its functionality or expression. Thus, functional analyses are necessary in order to study the characteristics of the allele MICB*004 and how it may affect the autoimmune response observed in RA patients.

To conclude, we have found that the MICB*004 allele was significantly associated with RA. This allele was in linkage disequilibrium with HLA-DRB1*0404 and DRB1*0405, suggesting that MICB could modify the risk of the HLA-DRB1 genes. However, MICB*004 was also associated independent of SE HLA-DRB1 alleles. These data together with the previously described functional role of MICB in the pathogenesis of RA, convert a MICB into the main candidate for being an additional MHC gene associated with RA susceptibility.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
This work was supported in part by Spanish grant FIS 03/0067, from the Fondo de Investigaciones Sanitarias del Ministerio de Sanidad and by grant SAF2004-02669 from the Spanish Ministry of Education and Science. J.M.-B is supported by Spanish Post-MIR program from ‘Fondo de Investigaciones Sanitarias’.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 21 July 2006; revised version accepted 15 August 2006.
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