Contribution of MHC class I chain-related A (MICA) gene polymorphism to genetic susceptibility for systemic lupus erythematosus
G. Gambelunghe1,5,
R. Gerli2,
E. Bartoloni Bocci2,
P. Del Sindaco4,
M. Ghaderi6,
C. B. Sanjeevi5,
O. Bistoni2,
V. Bini3 and
A. Falorni1
1 Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, 2 Center for the Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine and 3 Department of Gynaecology, Obstetrics and Paediatric Sciences, University of Perugia, Perugia, 4 Division of Medicine, Todi Hospital, Todi, Italy, 5 Department of Molecular Medicine, Karolinska Institute, Stockholm and 6 Division of Biomedicine, Institution for Healthcare Sciences, Örebro University, Örebro, Sweden.
Correspondence to: A. Falorni, Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, Via E. Dal Pozzo, 06126 Perugia, Italy. E-mail: falorni{at}dimisem.med.unipg.it
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Abstract
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Objective. To evaluate the contribution of the MHC class I chain-related A (MICA) gene polymorphism to the genetic risk of systemic lupus erythematosus (SLE).
Methods. HLA-DRB1-DQA1-DQB1 genotyping, MICA exon 5 microsatellite genotyping and HLA-B8 genotyping were performed in 48 Italian SLE patients and in 158 healthy control subjects.
Results. Of HLA class II haplotypes, only DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) was significantly more frequent among SLE patients than among healthy control subjects [odds ratio (OR) = 6.5, corrected P<0.0026]. HLA-B8 was detected in 31% SLE patients and 13% healthy control subjects (OR = 3.0, P = 0.005). The allele-wise comparison between patients and controls showed that both MICA5 (OR = 2.5, corrected P<0.0005) and MICA5.1 (OR = 2.4, corrected P<0.0005) were positively and MICA9 (OR = 0.2, corrected P<0.0005) was negatively associated with the disease. The MICA5/5.1 genotype was positively associated with SLE (OR = 28.9, corrected P<0.0015) also in subjects negative for DR3-DQ2 (OR>22.6, corrected P<0.011). The simultaneous presence of DR3-DQ2 and MICA5.1 was detected in 15/48 (31%) SLE and in 10/158 (6%) healthy control subjects (OR = 6.7, corrected P<0.011). The simultaneous combination of DR3-DQ2 and MICA5 was found in 10/48 (21%) SLE patients and in only 1/158 healthy control subjects (OR = 41.3, corrected P<0.011). Logistic regression analysis showed the independent positive associations of MICA5 and MICA5.1 and negative association of MICA9 with the disease, and revealed that the interaction of the three major markers (DR3-DQ2, MICA5 and MICA5.1) was associated with increasing genetic risk, which was highest (OR>30.3) in DR3-DQ2-positive subjects carrying the MICA5-5.1 genotype.
Conclusions. Our study provides the first demonstration of the independent association of the MICA gene polymorphism with genetic risk of SLE.
KEY WORDS: Autoimmunity, Immunogenetics, HLA, MICA gene, systemic lupus erythematosus
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Introduction
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Systemic lupus erythematosus (SLE) is a disease of unknown aetiology in which tissues and cells are damaged by pathogenic autoantibodies and immune complexes. The risk of SLE is strongly influenced by familial association for the disease, and a predisposing genetic background is required (but not sufficient) for the development of clinical autoimmunity. SLE does not exhibit typical Mendelian inheritance that can be attributed to a single locus but is a complex genetic disease [1, 2]. The strongest genetic association so far identified is that with HLA class I and class II genes located on the short arm of chromosome 6, particularly with DRB1*03-DQA1*0501-DQB1*0201-B8 (DR3-DQ2-B8) [1, 2], and, in some studies, with DRB1*1501-DQB1*0602 (DR2-DQ6) [3, 4]. Other HLA class II haplotypes, such as DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8), have been found associated with some expressions of the disease (such as arthritis and/or myositis, renal involvement, CNS involvement or vasculitis). Only a small minority of subjects carrying the high-risk HLA haplotypes develop the disease, which suggests that additional genes (as well as environmental factors) must play a crucial role in conferring susceptibility.
A distinct family of MHC genes has been identified between the class I and III regions and denominated MHC class I chain-related genes (MIC) [5]. The polymorphism of exon 5 of the MICA gene is determined by four, five, six and nine repetitions of a GCT trinucleotide or five repetitions of GCT with an additional insertion (G), and identifies five alleles named MICA4, 5, 6, 9 and 5.1 [6, 7], respectively. Their organization, expression and products differ considerably from those of classical HLA class I genes. The MIC gene products are expressed on the gut-associated lymphoid tissue, endothelial cells, fibroblast, dendritic cells, synoviocytes and monocytes but are not present on CD4+ and CD8+ T cells or B cells [8]. MICA interacts with an activating receptor, NKG2D, expressed at the surface of most circulating
ß CD8 T cells, 
T cells and NK cells in humans [9]. In CD8
ß T cells, NKG2D/MIC engagement delivers a costimulatory signal that complements TCR-mediated antigen recognition on target cells [10]. For this reason, the MICA gene product could play a major role in the autoimmune process and MICA gene polymorphism could modulate immune pathways which are complementary and synergistic to those modulated by the classical HLA class II genes. The results of several investigations, performed in different ethnic groups, suggest a strong association between the MICA gene and the risk of the development of several autoimmune or immune-mediated diseases [1021]. The location of the MICA gene inside the HLA system and the functional role of MICA as a ligand of the activating receptor of NK cells provide a sound rationale for the study of the association of its polymorphism with human immune-mediated diseases, such as SLE.
In the present study, we evaluated the association of SLE with MICA gene polymorphism in a population from central Italy. Our data are consistent with a primary association of SLE with the exon 5 microsatellite polymorphism of the MICA gene.
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Methods
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Subjects and samples
Genomic DNA was obtained from EDTA-treated peripheral blood samples from 48 unrelated SLE patients (age at diagnosis 971 yr, median 42 yr; 32 females and 16 males), diagnosed according to the revised criteria of the American College of Rheumatology [22], and from 158 unrelated healthy control subjects (schoolchildren and employees of the University of Perugia; age 669 yr, median 39 yr; 85 females and 73 males), with no family history of SLE or any other autoimmune disease and geographically matched with the SLE patients. All SLE patients were recruited at the Center for the Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia. Neither the patients nor the healthy controls were related to each other and no sib pairs were included in this study. The DNA samples were purified by standard phenolchloroform extraction, dissolved in sterile double-distilled water and stored at 4°C. All patients and healthy individuals gave their informed consent for the study, and the study was approved by the local ethical committee.
MICA genotyping
The exon 5 of the MICA gene was PCR amplified using 5'-CCTTTTTTTCAGGGAAAGTGC-3' as forward and 5'-CCTTACCATCTCCAGAAACTGC-3' as reverse primer labelled at the 5' end with fluorescent reagent 6-HEX (Amersham Pharmacia Biotech, Uppsala, Sweden). Following amplification, the number of GCT triplet repeat units was determined using an ABI Prism automated DNA sequencer [15]. Each analysis included internal control samples with known MICA alleles, as revealed by direct DNA sequencing.
HLA class II genotyping
The polymorphic second exon of the DQA1, DQB1 and DRB1 genes was amplified by the polymerase chain reaction (PCR), and the PCR products were manually dotted onto nylon membranes (Amersham Pharmacia Biotech). The membranes were hybridized with sequence-specific oligonucleotides (SSOs), 3' end-labelled with digoxigenin (Roche Molecular Biochemicals, Mannheim, Germany) and washed in stringency conditions. Chemiluminescence detection used an alkaline phosphatase-labelled anti-digoxigenin antibody (Roche) and CSPD (Roche) before exposure to X-ray film [15]. The membranes were stripped of the labelled probe under alkaline conditions and reused for probing with other oligonucleotides.
HLA-B8 genotyping
HLA-B8 genotyping was done by PCR-SSP technique as described previously [23]. As positive controls, we used genomic DNA samples from four healthy subjects, identified as B8-positive by low-resolution typing method (Biotest, Dreieich, Germany). Each PCR test included an internal positive control primer pair amplifying a segment of human growth hormone gene.
Statistical analysis
In the univariate analysis, differences in allele, haplotype or genotype frequencies between SLE patients and healthy control subjects were tested by the
2 method. Yates's correction or Fisher's exact test was used when necessary. When appropriate, the probability (P) values were corrected (Pc) for the number of comparisons made: five for MICA alleles, 15 for MICA genotypes and 26 for HLA-DR-DQ haplotypes. Pairwise linkage disequilibrium with the permutation test using the EM algorithm (gametic phase unknown) and the HardyWeinberg equilibrium were tested using Arlequin v. 2.000 software for population genetics data analysis [24]. For fitting logistic regression models, the patient status was used as a binary dependent variable (1 = disease presence, 0 = disease absence), and the following independent predictor variables, expressed as presence/absence, were used: DR3-DQ2, DR4-DQ8, DR2-DQ6, B8, MICA4, MICA5, MICA5.1, MICA6 and MICA9. Results for logistic regression were reported both in terms of the odds ratio (OR), with 95% confidence interval (CI), and in terms of predicted disease probability. The predicted probability of SLE in our sample population was determined for all combinations of DR3-DQ2 with MICA alleles. Univariate analysis and logistic regression analysis were performed using SPSS for Windows (release 11.0.1; SPSS, Chicago, IL, USA). The power (
) of each analysis was the likelihood of rejecting a false null hypothesis. A P or Pc value less than 0.05 was considered significant in all tests.
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Results
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In our population, both MICA5 and MICA5.1 were significantly more frequent among 48 Italian SLE patients than among 158 healthy control subjects (Table 1). MICA5 was present in 22% of SLE alleles and in only 10% of healthy subject alleles (OR = 2.5, Pc = 0.023,
= 0.82), whilst MICA5.1 was present in 37% SLE alleles and in 20% of healthy subjects alleles (OR = 2.4, Pc = 0.0045,
= 0.93). Conversely, MICA9 appeared negatively associated with SLE (OR = 0.2, Pc = 0.005,
= 0.90). MICA5 and MICA5.1 were present in 44 and 71% SLE patients, respectively, compared with 15% and 33% healthy control subjects, respectively (OR = 4.3, Pc<0.0005,
= 0.99 for MICA5 and OR = 4.9, Pc<0.0005,
= 0.99 for MICA5.1).
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TABLE 1. MICA allelic and genotypic frequencies in patients with SLE and in healthy control subjects from central Italy
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Among MICA genotypes, only 5/5.1 was significantly and positively associated with the risk of SLE, and it was observed in 27% patients and in only 1.3% healthy controls (OR = 28.9, Pc<0.0015,
= 1.0).
Among HLA class II alleles, we observed a positive association only with DRB1*03-DQA1*0501-DQB1*0201: 24/48 (50%) SLE patients were carrying this haplotype, compared with only 21/158 (13%) healthy controls (OR = 6.5, Pc<0.0026,
= 0.99) (Table 2). More specifically, the frequency of other HLA class II haplotypes found in association with SLE in some studies, such as DRB1*04-DQA1*0301-DQB1*0302 and DRB1*1501-DQB1*0602, was not significantly increased among our SLE patients (Table 2). HLA-B8 was detected in 15/48 (31%) SLE patients and in 21/158 (13%) healthy control subjects (P = 0.005, OR = 3.0, 95% CI:1.386.37,
= 0.76).
Pairwise linkage disequilibrium analysis, with the permutation test using the EM algorithm, did not show a statistically significant linkage disequilibrium between any of the selected DR-DQ markers (DR3-DQ2 or DR4-DQ8 or DR2-DQ6) and any MICA allele (exact P>0.35 in all tests), but revealed a highly significant linkage disequilibrium between MICA5.1 and HLA-B8 (exact P and
2, P<0.001). None of the selected markers showed significant deviations from the HardyWeinberg equilibrium. Although linkage disequilibrium between HLA class II and MICA genes cannot be ruled out by our results, it must be noted that previous studies in the Italian population [25] had shown, similarly, no detectable linkage disequilibrium among these markers, but identified an extended DRB1*03-DQA1*0501-DQB1*0201-MICA5.1-B8 haplotype. The simultaneous presence of DRB1*03-DQA1*0501-DQB1*0201 and MICA5.1 was found in our study in 10/158 healthy control subjects (6.3%), a frequency slightly higher than that expected by chance (4.3%). HLA-DRB1*03-DQA1*0501-DQB1*0201-MICA5.1 was significantly more frequent among SLE patients than among healthy control subjects (OR = 6.7; Pc<0.011,
= 0.99) (Table 2). The simultaneous presence in the same subject of HLA-DRB1*03-DQA1*0501-DQB1*0201 and MICA5 was found in 21% of SLE patients and in fewer than 1% of healthy control subjects (OR = 41.3; Pc<0.011,
= 0.99) (Table 2). This combination was less frequent among our healthy control subjects (0.6%) than expected by chance (2%).
None of the SLE patients was negative for all the three major genetic markers considered (MICA5, MICA5.1, HLA-DRB1*03-DQA1*0501-DQB1*0201) compared with 75/158 (47%) healthy controls (OR <0.02; Pc <0.0008,
= 1.0) (Table 3). A total of 7/48 (15%) SLE patients were carrying all these three genetic markers, whilst no healthy control was found simultaneously positive for MICA5, MICA5.1 and DRB1*03-DQA1*0501-DQB1*0201 (OR>30.1, Pc<0.0008,
= 0.99) (Table 3). The risk of SLE was significantly increased also in the presence of only two of the three major genetic markers (OR = 6.2, Pc<0.0008,
= 0.99), but not when only one marker was present, irrespective of the marker considered (OR = 1.2, Pc = not significant,
<0.1). The MICA5/5.1 genotype was strongly and significantly associated with SLE also in the absence of DRB1*03-DQA1*0501-DQB1*0201 [6/48 (12%) patients and 0/158 healthy controls (OR>22.6, Pc<0.0008,
= 0.99)].
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TABLE 3. Combination of MICA5, MICA5.1 and HLA-DRB1*03-DQA1*0501-DQB1*0201 in SLE and healthy control subjects from central Italy
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To better define the relative contribution of each selected marker to the genetic risk of SLE, we performed logistic regression analysis. Both DR3-DQ2 (OR = 6.29, 95% CI 2.913.6, P<0.0001) and MICA5.1 (OR = 4.38, 95% CI 2.19.3, P<0.0001) were positively and independently associated with SLE. HLA-B8 was not significantly and independently associated with SLE. Disease probability of DR3-DQ2-positive subjects increased from 33.7% in the absence to 69% in the presence of MICA5.1 (Table 4). Similarly, when the genetic contribution to SLE of MICA5 was tested, it showed significant and positive association with the disease also when corrected for both DR3-DQ2 (OR = 5.8, 95% CI 2.613.1, P<0.0001) and MICA5.1 (OR = 11.2, 95% CI 4.229.9, P<0.0001). On the other hand, both DR3-DQ2 (OR = 7.6, 95% CI 3.416.9, P<0.0001) and MICA5.1 (OR = 9.6, 95% CI 3.824.4, P<0.0001) were significantly associated with SLE independently of MICA5. Accordingly, a strong interaction among the three markers that conferred an independent risk of SLE was observed, and the highest disease probabilities were those of the DR3-DQ2-MICA5.1 haplotype (69%), the DR3-DQ2-MICA5 haplotype (82%) and the MICA5/5.1 genotype (83%) (Table 4). Among negatively associated MICA alleles, only MICA9 continued to be consistently and independently associated with a lower risk of SLE in all tests (OR<0.317, 95% CI 0.1230.810, P<0.02), while the reduced frequency of MICA6 observed among SLE patients appeared to be only a secondary consequence of the relative increases in MICA5 and MICA5.1. In addition, the association between MICA gene polymorphism and the risk of SLE was not dependent on gender but was significantly dependent on age at clinical diagnosis. More specifically, MICA5 was negatively (P = 0.006) and MICA5.1 positively (P = 0.01) associated with age at diagnosis.
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TABLE 4. Results of the logistic regression analysis expressed as disease probability (in %) for SLE of DR3-DQ2/MICA combinations
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Discussion
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SLE is a relatively rare disease and 90% of newly diagnosed individuals have no first-degree relative affected with the disease. Evidence for genetic predisposition includes increased concordance for disease in monozygotic twins (2458%) compared with dizygotic (06%) twins and the repeatedly demonstrated association with the polymorphism of HLA class II genes. More specifically, HLA-DRB1*03-DQA1*0501-DQB1*0201 shows the strongest genetic association with the disease so far reported [1, 2]. It must, however, be noted that the large majority of HLA-DRB1*03-DQA1*0501-DQB1*0201-positive individuals do not develop the disease and that not all SLE patients are carrying this haplotype. Accordingly, other unknown genetic factors, as well as still unidentified environmental agents, must play a critical role in the pathogenesis of this disease.
In this study, we analysed the frequency of MICA transmembrane alleles in Italian SLE patients and healthy controls and we report the first demonstration of the strong association of MICA gene polymorphism with this autoimmune disease. Such an association was not observed in a previous study in Yunnan Hans [26], but this could be explained by the different ethnic group studied and by the criteria used for selection of patients and healthy controls. Our results can be interpreted to indicate that both classical HLA class II haplotypes (DRB1*03-DQA1*0501-DQB1*0201) and MICA alleles (namely 5 and 5.1) are important in conferring genetic susceptibility to SLE. The similarities with other autoimmune diseases are striking, especially if we consider that similarly to what has been observed in diabetic patients [15, 16], also in SLE MICA5 appears to be predominantly associated with young-onset and MICA5.1 with adult-onset disease. Thus, the two at-risk MICA gene markers may be the expression of different predisposing genetic backgrounds that influence the progression of the autoimmune process. The expression of the MIC proteins in the gut epithelium is mostly intriguing as it is currently believed that the stimulation of the gut-associated lymphoid tissue may influence the way the immune system discriminates between self and non-self antigens. Allele MICA5.1 is characterized by a frame-shift mutation leading to a premature intradomain stop codon. Suemizu et al. [27] demonstrated the aberrant expression of the MICA5.1 gene product at the apical surface of human intestinal epithelial cells instead of the basolateral surface, the site of putative interaction with intraepithelial T and NK lymphocytes. Thus, MICA5.1-homozygous individuals may have altered immunological surveillance by NK and T cells [27].
The HLA system is an extremely gene-rich region of the human genome, with strong linkage disequilibrium among its gene components [28]. Thus, it can be hypothesized that the association of MICA gene polymorphism with SLE might be a consequence of linkage disequilibrium with predisposing DR and DQ alleles. Indeed, MICA5.1 is part of an extended HLA-DRB1*0301-DQA1*0501-DQB1*0201-TNFa2-MICA5.1-MICBCA24-HLA-B*0801 haplotype, as shown in both the Italian [25] and other populations [19, 29]. On the other hand, no linkage disequilibrium between DR3-DQ2 and MICA5 has so far been shown. Not surprisingly, only 0.6% of our healthy control subjects were found to be positive for both DR3-DQ2 and MICA5, a frequency lower than that expected by chance (2%). On the other hand, the frequency of the coexistence of HLA-DRB1*03-DQA1*0501-DQB1*0201 and MICA5.1 was 6.3% among our healthy control subjects, which is higher than the 4.3% expected by random combination. It is nevertheless important to note that the majority of MICA5.1-positive individuals are negative for DR3-DQ2 in Italy (representing approximately 27% of the general population). Indeed, among the most likely MICA5.1 combinations in extended HLA haplotypes [24] are also HLA-DRB1*1501-TNFa11-MICA5.1-MICBCA17-HLA-B*0702, HLA-DRB1*0701-TNFa7-MICA5.1-MICBCA18-HLA-B*1302 and HLA-DRB1*1101-TNFa4-MICA*5.1-MICBCA15-HLA-B*4402, but DRB1*1501, DRB1*0701 and DRB1*1101 were not associated with SLE in our study.
Several lines of evidence support the hypothesis that the association between the MICA gene polymorphism and SLE is not simply derived from linkage disequilibrium with HLA-DRB1*03-DQA1*0501-DQB1*0201. (i) In our study, two distinct MICA alleles were associated with SLE compared with only one HLA class II marker; (ii) in subjects negative for HLA-DRB1*03-DQA1*0501-DQB1*0201, the MICA5/5.1 genotype was still strongly and significantly associated with SLE; (iii) the independent linkage of the MICA region with autoimmune diseases, such as type 1 diabetes mellitus [30] and rheumatoid arthritis [31], has been demonstrated in different ethnic groups; and (iv) more importantly, the logistic regression analysis showed the independent associations of both MICA5 and MICA5.1 with SLE.
The three major markers (DR3-DQ2, MICA5 and MICA5.1) strongly interact to confer genetic risk of SLE. Thus, the diagnostic accuracy of genetic markers for SLE is high when combining the presence/absence of HLA-DRB1*03-DQA1*0501-DQB1*0201 with that of MICA5 and/or MICA5.1. Although our study did not have the aim of testing the diagnostic use of the combination of different MHC-linked gene markers for SLE, it is noteworthy that all 48 SLE patients were positive for at least one of the three gene markers. Furthermore, the concomitant absence of all the three markers appears to have a high negative predictive value, as it excluded the diagnosis of SLE in our population. In conclusion, the results of our study can be interpreted to indicate that MICA gene polymorphism influences the genetic susceptibility to SLE, independently of HLA class II gene polymorphism. The highest genetic risk of SLE is observed in subjects carrying both high-risk HLA class II haplotypes and high-risk MICA alleles.
The authors have declared no conflicts of interest.
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Submitted 5 May 2004;
revised version accepted 30 September 2004.