Tissue Antigens ISSN 0001-2815
CD11a, CD11c, and CD18 gene polymorphisms and susceptibility to Behçet’s disease in Koreans S. R. Park1 , K. S. Park1 , Y. J. Park2 , D. Bang3 & E.-S. Lee2 1 School of Biological Science and Chemistry, Sungshin Women’s University, Seoul, Korea 2 Department of Dermatology, Ajou University School of Medicine, Suwon, Korea 3 Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea
Key words Behçet’s disease; CD11a; CD11c; CD18 Correspondence Eun-So Lee Department of Dermatology Ajou University School of Medicine 164 Worldcup-ro Yeongtong-gu Suwon Gyeonggi-do 443-380 Korea Tel: +82 31 219 5190 Fax: +82 31 219 5189 e-mail:
[email protected] Received 14 June 2013; revised 4 May 2014; accepted 14 July 2014 doi: 10.1111/tan.12420
Abstract Lesions of Behçet’s disease (BD) show vascular infiltrates of immune cells expressing integrins. β2 integrins (CD11/CD18) play a major role in cell migration to the inflammatory lesion and also induce cytokine production. Thus, genetic polymorphisms of CD11/CD18 may be associated with the pathogenesis of BD. In this study, nine single nucleotide polymorphisms (SNPs) of the CD11a, CD11c, and CD18 were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and haplotype analysis in 305 BD patients and 266 healthy controls. The frequencies of genotype rs11574944 CC and haplotype rs11574944C–rs2230433G–rs8058823A in CD11a were significantly lower in BD patients. The frequencies of genotype rs2230429 CC, rs2929 GG, and haplotype rs2230429C–rs2929G in CD11c were higher in BD patients. The frequencies of genotype rs235326CC and haplotype rs2070946A–rs235326C–rs760456G–rs684G in CD18 were significantly higher in the BD patients than in the controls. Other SNPs in CD11a, CD11c, and CD18 gene were not significantly different. Therefore, the major genotype and haplotype of CD11a/CD18 may play a role in decreasing the susceptibility of BD, whereas the major genotype and haplotype of CD11c/CD18 may play a role in increasing the susceptibility of BD.
Introduction
Behçet’s disease (BD) is a recurrent systemic inflammatory disease characterized by major symptoms such as orogenital ulcers, skin lesions, and ocular involvement. Other symptoms include involvement of the vascular system, central nervous system, gastrointestinal tract, and joints (1, 2). The pathogenesis of BD remains unclear; however, some evidence confirms the involvement of immune dysfunction. One such finding is that the mucocutaneous lesions of BD show infiltrates composed of neutrophils, Th1 and Th17 cells, and monocytes, similar to other inflammatory diseases (3–5). In addition, multiple studies from different geographical sites revealed that excessive Th1-associated cytokines including interferon-γ (IFN-γ) and interleukin (IL)-12 are found in the blood of patients with BD, assuring that BD is an inflammatory disease (6–10). The neutrophils and monocytes of patients with BD exhibit increased motility, and are prone to adhere to endothelial cells caused by increased expression of leukocyte integrins (11). The β2 integrins (CD11/CD18) are cell adhesion molecules that are expressed on all leukocyte surfaces. These membrane molecules are essential for neutrophil recruitment to 398
inflammatory lesions. They also involve in induction of cellular signaling after ligand binding (12). As soluble adhesion molecules, the β2 integrins may play a role in inhibiting or balancing leukocyte adhesion and in regulating inflammation in chronic inflammatory diseases. These integrins are known to mediate differential expression of proinflammatory cytokines from neutrophils during the inflammatory response as well (13, 14). The chemokines function as chemoattractants for leukocytes, recruiting neutrophils, and other effector cells from the blood to inflammatory sites. They also arrest signals to integrins, which trigger the bidirectional occupancy of heterodimers by extracellular and cytoplasmic ligands (15, 16). Activation of CD11/CD18 by chemokines, tumor necrosis factor-α (TNF-α), and IL-8 allows the neutrophils to undergo arrest, allowing the neutrophils to firmly adhere to the endothelial cells and express intercellular adhesion molecules (ICAMs) in BD (2, 17, 18). Four types of the β2 integrins have been identified to date. The most abundant β2 integrin, CD11a/CD18 (lymphocyte function-associated antigen-1, LFA-1) is expressed on neutrophils and CD4 and CD8 T cells. It plays a central role © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 398–404
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in leukocyte intercellular adhesion through an interaction with its ligands and ICAM-1, 2, 3 (19). It also involves in lymphocyte costimulatory signaling, which is essential for neutrophil recruitment to inflamed tissue (20). Interactions between CD11a/CD18 and ICAM 1–3 are implicated in immune pathologies and autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (21, 22). Activation of CD11a/CD18 on neutrophils and T cells is a crucial costimulatory process in the formation of the immunological synapse and may contribute to the development of BD. Another β2 integrin member, CD11c/CD18 (complement receptor 4; CR4; p150/95), is expressed on dendritic cells, neutrophils, T cells, B cells, and macrophages. It is important in complement-mediated phagocytosis, and binds to a variety of ligands including ICAM-1, 2, fibrinogen, collagen, inactivated-C3b (iC3b), and lipopolysaccharides (19). CR4 mediates signaling by upregulating the DNA-binding activity of nuclear factor-κB and the subsequent secretion of IL-8, macrophage inflammatory protein (MIP)-1α, and MIP-1ß (23). These cytokines play an important role in the recruitment of other inflammatory cells during the initiation of the inflammatory response and phagocytosis of particles opsonized by iC3b (14, 23–25). Cytokines such as IL-8 and MIP-1α and complement receptors including their regulation are some of the most important components for the innate immunity of BD (26, 27). As numerous studies exhibit, persistent inflammation exists in the mucosal tissues of oral and genital ulcers and skin lesions of BD patients depicted by an intense neutrophilic and T cell infiltration (1, 5, 28). On the other hand, complement proteins are deposited on the basement membrane of patients with BD (29). Also, the complement system itself is suggested to be essential in pathogenesis of BD (30, 31). Thus, it appears that CR4, which binds to the complement proteins and recruits inflammatory cells, may also have a role in the pathogenesis of BD. As LFA-1 and CR4 play a major role in leukocyte motility, cytokine production, and phagocytosis, all of which may mediate the immunopathogenesis of BD, the genetic variations of β2 integrins may affect BD pathogenesis. As the polymorphisms of CD11b and CD11d are rarely found, we analyzed single nucleotide polymorphisms (SNPs) of the CD11a, CD11c, CD18 genes, and their haplotypes based on the relation to the BD susceptibility in Korean individuals.
Patients and methods Patients
A total of 305 BD patients (148 men and 157 women) and 266 healthy controls from Korea were included in this case–control study. BD patients were recruited from Ajou University Hospital, Suwon, Korea and Behçet’s Disease Specialty Clinic of Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. All patients fulfilled the diagnostic criteria for BD proposed by the International Study Group for BD and the modified © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 398–404
Gene polymorphisms as a hint to understanding Behçet’s disease
Table 1 Clinical characteristics of Behçet’s disease (BD) patients Clinical features BD patients Age (years) Major symptoms Oral ulcers Skin lesions Genital ulcers Ocular lesions Minor symptoms Arthritis Vascular involvement Gastrointestinal involvement Neurologic involvement
Total (%)
Male (%)
Female (%)
305 16–64
148 (48.5) 19–62
157 (51.5) 16–64
293 (96.1) 262 (85.9) 238 (78.0) 186 (61.0)
144 (97.3) 129 (87.2) 107 (72.3) 97 (65.6)
149 (95.0) 133 (84.7) 131 (83.4) 89 (56.7)
95 (30.1) 35 (11.5) 18 (5.9) 10 (3.3)
44 (30.0) 30 (20.1) 9 (6.1) 3 (2.0)
51 (32.5) 5 (3.2) 9 (5.7) 7 (4.5)
Japanese criteria (32, 33). Informed consents were obtained from the subjects, and the Institutional Review Board approved the study protocols (number: AJIRB-GEN-GEN-10-119). The demographic characteristics and frequency of the BD patients’ clinical features are shown in Table 1. SNP genotyping
Genomic DNA was extracted from peripheral blood using a QIAamp Blood kit (Qiagen, Hilden, Germany). The SNP genotyping of rs11574944C>T, rs2230433G>C, and rs8058823A>G in the CD11a gene, rs2230429C>G, and rs2929G>A in the CD11c gene, and rs2070946A>G, rs235326T>C, rs760456C>G, and rs684G>A in the CD18 gene was determined by the restriction fragment length polymorphism analysis of polymerase chain reaction-amplified fragments (PCR-RFLP) method (Table S1, Supporting Information). Statistical analysis
The differences of allele frequencies and genotype distribution between the BD patients and the controls were examined by the χ2 test using SAS v.9.1.3 (SAS Institute, Cary, NC). Odds ratios (ORs) with 95% confidence intervals (CIs) were obtained. The P-values < 0.05 were regarded as statistically significant. Comparison analysis using the version 4.2 of the HAPLOVIEW program (http://www.broadinstitute.org/ haploview/haploview) and the GPLINK version 2.05 (http:// pngu.mgh.harvard.edu/∼purcell/plink/) were subjected to permutation correction: the permutation P-values were obtained by running 1000 permutations per mutation, Bonferroni correction, and logistic regression under a log additive model. The Hardy–Weinberg equilibrium and linkage disequilibrium (LD) were analyzed using the R program V.2.12.2 (http://www.r-profects.org/). The most frequently used LD value is D′ > 0.8 (34). To assess whether any of the clinical features were associated with the SNPs, allele, and genotype 399
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frequencies were analyzed using the χ2 test between the BD patients with and without certain clinical features. Results
The genotype and allele for rs11574944, rs2230433, rs8058823, rs2230429, rs2929, rs2070946, rs235326, rs760456, and rs684 in BD patients and controls did not deviate from the Hardy–Weinberg equilibrium. The frequency of the CD11a rs11574944CC genotype was significantly lower in BD patients than in controls (P = 0.026, OR = 0.7, 95% CI = 0.49 − 0.96). The frequencies of the genotype of rs2230429CC (Pro517Arg) and allele C in the CD11c gene were significantly higher in patients than in controls (P = 0.0004, OR = 1.8, 95% CI = 1.31 − 2.56 and P < 0.0001, OR = 1.7, 95% CI = 1.31 − 2.26, permutation P = 0.001, respectively). The frequencies of the CD11c rs2929GG genotype and G allele were significantly higher in BD patients than in controls (P = 0.021, OR = 1.5, 95% CI = 1.06 − 2.05 and P = 0.013, OR = 1.4, 95% CI = 1.07 − 1.78, respectively). The frequencies of the rs235326CC (Val441Val) genotype and C allele in the CD18 gene were significantly higher in BD patients than in controls (P = 0.002, OR = 1.7, 95% CI = 1.20 − 2.36 and P = 0.001, OR = 1.6, 95% CI = 1.20 − 2.10, permutation P = 0.007, respectively). The genotypes and allele frequencies of other SNPs in the CD11a rs2230433G>C, rs8058823A>G, and CD18 rs2070946A>G, rs760456C>G, did not differ significantly between patients and controls (Table 2). Between two SNPs of CD18 (rs235326 and rs684), there was strong LD in controls and in BD (D′ = 0.997, r2 = 0.038; D′ = 0.806, r2 = 0.017, respectively, however LD in SNP of CD11a and CD11c was not observed either in controls or in BD. The frequency of the major CD11a haplotype rs11574944C–rs2230433G–rs8058823A was significantly lower in BD patients than in controls (permutation P = 0.011), while that of TGA and CCG was significantly higher in BD patients than in controls (permutation P = 0.026 and permutation P = 0.011, respectively). The major CD11c haplotype rs2230429C–rs2929G was significantly more common in BD patients compared with controls (permutation P = 0.001). However, that of GG (P = 0.044) and GA (permutation P = 0.004) less frequently appeared in BD patients compared with controls. The CD18 haplotype rs2070946A–rs235326C–rs760456G–rs684G was significantly more common in BD patients compared with controls (P = 0.007), and that of ATCG less frequently appeared in BD patients compared with controls (permutation P = 0.012) (Table 3). We analyzed the relationship between the genetic backgrounds of SNPs in CD11/CD18 and BD with various clinical features. The frequency of the major CD11a genotype rs11574944CC was significantly lower in BD patients with all major symptoms (oral ulcers: P = 0.031, OR = 0.7; skin lesions: P = 0.008, OR = 0.6; genital ulcers: P = 0.023, 400
OR = 0.7; ocular lesions: P = 0.011, OR = 0.6) and in those with two minor symptoms (arthritis: P = 0.0005, OR = 0.4; vascular: P = 0.022, OR = 0.4) than in controls. On the other hand, the frequency of the major CD11c genotype rs2230429CC was significantly higher in BD patients with all major symptoms (oral ulcers: P = 0.0005, OR = 1.8; skin lesions: P = 0.0004, OR = 1.9; genital ulcers: P = 0.0002, OR = 2.0; ocular lesions: P = 0.0008, OR = 1.9) and in those with one minor symptom (gastrointestinal lesions: P = 0.051, OR = 2.8). The frequency of the major CD11c genotype rs2929GG was also significantly higher in patients with all major symptoms (oral ulcers: P = 0.030, OR = 1.4; skin lesions: P = 0.024, OR = 1.4; genital ulcers: P = 0.034, OR = 1.5; ocular lesions: P = 0.045, OR = 1.5) and in those with two minor symptoms (arthritis: P = 0.0003, OR = 2.4; vascular: P = 0.043, OR = 2.1) than in controls. The frequency of the major CD18 genotype rs235326CC was significantly higher in patients with major symptoms (oral ulcers: P = 0.004, OR = 1.6; skin lesions: P = 0.005, OR = 1.6; genital ulcers: P = 0.0003, OR = 1.9; ocular lesions: P = 0.015, OR = 1.6) and in those with two minor symptoms (arthritis: P = 0.009, OR = 1.9; neurologic involvement: P = 0.025, OR = 7.6) than in controls (Table S2). The patients were grouped according to the presence or absence of clinical features (data not shown). There were no differences between the patients with or without major symptoms. However, the CD11a genotype rs11574944CC was significantly less frequent in patients with arthritis than in those without (33.7% vs 50.7%, P = 0.006). The CD11c genotype rs2929GG was significantly more frequent in the patients with arthritis than in those without (66.3% vs 49.1%, P = 0.012). In addition, the frequency of CD11c haplotype rs2230429G–rs2929G was significantly higher in the patients with arthritis than in those without (P = 0.005, OR = 1.9, 95% CI = 1.21–3.00, permutation P = 0.016). Although the number of patients with a neurologic involvement was small, the CD11c genotype rs2929GG was significantly less frequent in the patients with neurologic involvement than those without (10.0% vs 55.9%, P = 0.012). The CD18 genotype rs234326CC was significantly more frequent in the patients with genital ulcers than in those without (69.8% vs 55.2%, P = 0.026). Despite the small number of patients with gastrointestinal lesions, the CD18 genotype was significantly less frequent in patients with gastrointestinal lesions than in those without (44.4% vs 68.0%, P = 0.04). Discussion
The genetic polymorphisms of CD11a, CD11c, and CD18 genes might alter normal immune function by affecting the tertiary structures of LFA-1 and CR4 and their ligand-binding activity. Changes in the protein structure might result in alterations in inflammatory responses such as leukocyte trafficking and activation, cytokine production, and phagocytosis. The © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 398–404
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Gene polymorphisms as a hint to understanding Behçet’s disease
Table 2 Genotype and allele frequencies of CD11a, CD11c, and CD18 genes in Behçet’s disease (BD) BD n = 305 (%)
Controls n = 266 (%)
CC CT TT C:T GG CG CC G:C AA AG GG A:G
139 (45.6) 134 (43.9) 32 (10.5) 0.68:0.32 196 (64.3) 97 (31.8) 12 (3.9) 0.80:0.20 190 (62.3) 102 (33.4) 13 (4.3) 0.79:0.21
146 (54.9) 102 (38.3) 18 (6.8) 0.74:0.26 159 (59.8) 93 (34.9) 14 (5.3) 0.77:0.23 179 (67.3) 78 (29.3) 9 (3.4) 0.82:0.18
0.026a
0.7 (0.49–0.96)
CC CG GG C:G GG GA AA G:A
193 (63.3) 99 (32.4) 13 (4.3) 0.80:0.20 166 (54.4) 117 (38.4) 22 (7.2) 0.74:0.26
129 (48.5) 113 (42.5) 24 (9.0) 0.70:0.30 119 (44.7) 118 (44.4) 29 (10.9) 0.67:0.33
0.0004a
1.8 (1.31–2.56)
AA AG GG A:G CC CT TT C:T CC CG GG C:G GG GA AA G:A
249 (81.7) 51 (16.7) 5 (1.6) 0.90:0.10 203 (66.5) 92 (30.2) 10 (3.3) 0.82:0.18 68 (22.3) 150 (49.2) 87 (28.5) 0.47:0.53 245 (80.3) 56 (18.4) 4 (1.3) 0.90:0.10
200 (75.2) 62 (23.3) 4 (1.5) 0.86:0.14 144 (54.1) 104 (39.1) 18 (7.8) 0.74:0.26 69 (25.9) 134 (50.4) 63 (23.7) 0.51:0.49 217 (81.6) 46 (17.3) 3 (1.1) 0.90:0.10
rs number CD11a Intron15
rs11574944 C>T
Exon21 (Arg707Thr)
rs2230433 G>C
3′ UTR
rs8058823 A>G
CD11c Exon15 (Pro517Arg)
3′ UTR
CD18 5′ near gene
rs2230429 C>G
rs2929 G>A
rs2070946 A>G
Exon11 (Val441Val)
rs235326 T>C
Intron
rs760456 C>G
3′ UTR
rs684 G>A
P
Odds ratio (95% confidence interval)
0.021b T–rs2230433 G>C–rs8058823 A>G CGA 0.429 0.388 TGA 0.216 0.247 CCA 0.119 0.111 CCG 0.115 0.142 CGG 0.043 0.035 TCA 0.040 0.045 TGG 0.028 0.026 CD11c rs2230429 C>G–rs2929 G>A CG 0.536 0.588 CA 0.213 0.207 GG 0.169 0.148 GA 0.082 0.057 CD18 rs2070946 A>G–rs235326 T>C–rs760456 C>G–rs684 G>A ACCG 0.363 0.370 ACGG 0.250 0.283 ATGG 0.128 0.119 ACGA 0.061 0.067 ATCG 0.052 0.034 GCGG 0.038 0.037 ACCA 0.030 0.026 GCCG 0.030 0.026 GTGG 0.029 0.022
0.354 0.213 0.139 0.055 0.073 0.039 0.034 0.033 0.041
0.007
0.003
0.012
P-value was derived from chi-squared statistics from simple 2 × 2 tables based on the frequency of each haplotype vs all others combined between the BD patients and control groups.
The 3′ UTR (rs2929) variant of CD11c might be responsible for alterations in translation, localization, and stability of the mRNA and protein translation rate. The CD11c genotype rs2230429 (Pro517Arg) may change the conformation of the CR4 protein, especially the β-propeller domain of the α-subunit as part of FG-GAP. The CD11c I domain recognizes ligands and the β-propeller domain plays an important role in ligand binding (25, 37, 38). A previous study showed that CR4-mediated inflammatory responses were enhanced by increased CR4 expression and ligand binding (14). Therefore, a CD11c gene variant is most likely to affect ligand binding, resulting in an abnormal inflammatory response. The fact that CD11c/CD18 are involved in cellular signaling and immune regulation of various inflammatory diseases such as experimental autoimmune encephalomyelitis, autoimmune rheumatoid arthritis, colitis, hypertriglyceridemia, and multiple sclerosis via T cell activation and cytokine production also reinforces our explanation (24, 39, 40). In addition, the CD11c gene contributes to the susceptibility of inflammatory diseases such as inflammatory bowel disease and gastric ulcer disease, another prototype of chronic inflammation (41, 42). It is likely that on the contrary to the SNP mutation in LFA-1, the SNP mutation of CR4 may act to disturb the binding of the ligands, resulting in the termination or reduction of a single or multiple inflammatory process involved in the BD pathogenesis. The patients had a higher percentage of the CD18 rs235326CC (Val441Val) genotype and rs2070946A–rs235326 402
C–rs760456G–rs684G haplotype compared to controls (P = 0.002, OR = 1.7 and P = 0.007, respectively). The CD18 genotype rs235326 (Val441Val) does not have an amino acid change, although this SNP may possess different biological functions in mRNA synthesis, maturation, transport, translation, or degradation. Also, as the CD18 rs235326 SNP is located in the metal ion-dependent adhesion site of the β-subunit, it might play a substantial role in ligand binding. The clinical phenotypes of BD are changing. There has been a recent decrease in the proportion of patients with all of the major symptoms, which include oral ulcers, genital ulcers, and eye and skin lesions, whereas the proportion of patients with arthritis and gastrointestinal and vascular involvement has increased (28). Our results showed that CD11a rs11574944 and CD11c rs2929 genotypes were significantly different in frequency in the patients with arthritis compared to those without arthritis (33.7% vs 50.7%, P = 0.006; 66.3% vs 49.1%, P = 0.012, respectively). Although CD11a, CD11c, and CD18 gene variants do not provide evidence of direct linkage to the immune response of BD, it might be suggested that the major genotype and haplotype of LFA-1 (CD11a/CD18) plays a role in decreasing the susceptibility to BD, whereas that of CR4 (CD11c/CD18) is involved in increasing the susceptibility to BD. LFA-1 and CR4 interact between the endothelium and leukocytes, which subsequently leads to leukocyte migration to areas of inflammation. Variants of the CD11/CD18 genes seem to be involved in the © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 398–404
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signaling and recruitment of immune cells through cytokine production and infiltration of neutrophils and T cells into inflammatory BD lesions. In conclusion, our study suggests that β2 integrins are involved in the susceptibility to the development of BD. The frequencies of the major CD11a genotype rs11574944CC and the major haplotype rs11574944C–rs2230433G–rs8058823A were markedly reduced in the BD patients, whereas the frequencies of the major CD11c genotypes rs2230429CC and rs2929GG and the major haplotype rs2230429C–rs2929G were significantly increased in the BD patients. Further studies are needed to evaluate whether these polymorphisms affect the function or expression of β2 integrins in BD. Acknowledgments
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A3009767).
Conflicts of interest
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Supporting Information
The following supporting information is available for this article: Table S1. Primers and restriction enzymes used for restriction fragment length polymorphism analysis Table S2. Genotype distribution of CD11a rs11574944, CD11c rs2230429 and rs2929, and CD18 rs235326 according to Behçet’s disease (BD) clinical features
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Tissue Antigens, 2014, 84, 398–404