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. Author manuscript; available in PMC: 2013 Aug 12.
Published in final edited form as: Genes Immun. 2008 Jul 17;9(8):680–688. doi: 10.1038/gene.2008.56

A transmembrane polymorphism in FcγRIIb (FCGR2B) is associated with the production of anti-cyclic citrullinated peptide autoantibodies in Taiwanese RA

J-Y Chen 1, C-M Wang 2, C-C Ma 1, L-A Hsu 3, H-H Ho 1, Y-JJ Wu 1, S-N Kuo 1, J Wu 4
PMCID: PMC3740516  NIHMSID: NIHMS496630  PMID: 18633424

Abstract

The aim of the current study was to determine whether the FcγRIIb 187-Ile/Thr polymorphism is a predisposition factor for subtypes of RA defined by disease severity and production of autoantibodies against cyclic citrullinated peptides (anti-CCPs) in Taiwanese RA patients. Genotype distributions and allele frequencies of FcγRIIb 187-Ile/Thr were compared between 562 normal healthy controls and 640 RA patients as stratified by clinical parameters and autoantibodies. Significant enrichment of 187-Ile allele was observed in RA patients positive for anti-CCP antibodies as compared with the anti-CCP negative RA patients (P=0.001, OR 1.652 (95% CI 1.210–2.257)) or as compared with the normal controls (P =0.005, OR 1.348 (95% CI 1.092–1.664)). In addition, 187-Ile allele was found to be enriched in RA patients positive for rheumatoid factor (RF) compared to the RF negative RA patients (P=0.024, OR 1.562 (95% CI 1.059–2.303)). Furthermore, the homozygotes were enriched in destructive male RA patients (P =0.035; OR 2.038 (95% CI 1.046–3.973)) and the 187-Ile allele was associated with early-onset of RA in Taiwanese patients (P=0.045, OR 1.548 (95% CI 1.007–2.379)). Thus, FcγRIIb SNP 187-Ile/Thr may influence the RA phenotypes in Taiwanese RA.

Keywords: rheumatoid arthritis, anti-CCP antibody, FcγR, polymorphism

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, infiltration of immune cells, proliferation of synovial cells, destruction of cartilage and bony erosion in multiple joints. The functional disability caused by RA leads to severe work and daily living disturbance. Although the precise etiology and pathogenesis remain incompletely understood, multiple factors including genetic composition, possible infection triggering and other immune dysfunction all are thought to contribute to RA pathogenesis.1 The important contribution of genetic factors in RA development was demonstrated by twin and genome-scan studies.2–6 The identification of genetic factors associated with destructive forms of RA will aid the treatment of those patients with early aggressive Disease Modifying Anti-Rheumatic Drugs that could thwart the progression of the pathologic process.

Immunoglobulin molecules mediate various immune-related functions including phagocytosis, degranulation, antibody-dependent cell-mediated cytotoxicity, cytokine release and antigen presentation through binding of their Fc portions to specific cell surface receptors. In humans, eight genes (FcγRIA, FcγRIB, FcγRIC, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA and FcγRIIIB) encoding the classical Fcγ receptors are clustered in the 1q21–23 region of chromosome 1. Polymorphisms in human FcγR genes significantly affect the receptor functions and play important roles in modulating the immune response and in the pathogenesis of autoimmune diseases.7,8

FcγRIIb (CD32B) is generally considered as an inhibitory Fcγ receptor in both humans and mice.9–11 Cross-linking of FcγRIIb leads to the downregulation of B-cell activation and immunoglobulin production and therefore, FcγRIIb is the major receptor that provides feedback inhibitory signals for cell activation by immune com-plexes.9,11,12 On the other hand, myeloid cells (monocytes and neutrophils) and follicular dendritic cells also express FcγRIIb. FcγRIIb on follicular dendritic cells is critical to mediate B cell recall responses.13–16 Therefore, FcγRIIb has multiple functions in different cell systems.

FcγRIIb 187-Ile/Thr polymorphism (rs1050501) is located in the transmembrane segment of the receptor and the amino acid change significantly affects receptor-mediated functions.17–19 We hypothesize that this functional polymorphism might play an important role in the pathogenesis of human rheumatoid arthritis. In the current study we demonstrated that FcγRIIb 187-Ile allele (the allele mediating more potent inhibitory signal and the allele being more effectively recruited to lipid rafts) is significantly associated with anti-CCP antibody production, RF production, destructive RA and early onset of RA in Taiwanese patients. Our observations may provide new insights into the role of FcγRIIb in the pathogenesis of human RA and other human autoimmune diseases driven by autoantibody production and immune complex formation.

Results

Demographic and clinical characteristics of rheumatoid arthritis in Taiwan

The present study cohort included 550 female and 90 male Taiwanese RA patients with a mean age ± s.d. at RA disease onset of 46.5 ± 13.4 years (range, 10–80). These RA patients had the mean disease duration of 13.4 ± 8.0 years and had been followed up for at least 2 years to assess the disease course. Five hundred and ten of the total 640 RA patients (79.7%) were positive for rheumatoid factor (RF). Among 574 RA patients assayed for antinuclear antibodies (ANA), 308 patients (53.7%) were positive for ANA (titers ≥1:80). Based on X-ray radiography data of hands and wrist joints, 513 patients displayed bony erosion (X ray stage ≥II), 401 patients demonstrated destruction of joint subluxation and/or ankylosis (X ray stage ≥ III) and 204 patients documented cervical spine involvement.

In the current study, 640 Taiwanese RA patients and 562 healthy controls were genotyped using the MALDI-TOF genotyping method for FCGR2B SNP c775T > C. The reliability of the genotyping with MALDI-TOF was confirmed as described previously20 We did not observe any significant deviations from Hardy-Weinberg equilibrium in RA patients (χ2 = 0.580, P = 0.748) and in the normal controls (χ2 = 0.000, P = 1.00) by 3 × 2 contingency table analyses. As shown in Table 1, there were trends toward the increased 187-Ile homozygosity and the increased 187-Ile allele frequency in RA patients as compared with those in normal healthy controls, but these increases did not reach statistical significance (P = 0.098 and P = 0.138 respectively).

Table 1.

Distribution of genotypes and allele frequencies of FcγRIIb 187-Ile/Thr polymorphism in Taiwanese normal controls and RA patients

Controls (N = 562) RA patients (N = 640) OR (95% CI) P-value
Genotype frequency, no. (%)
    187-I/I 316 (56.2) 390 (60.9) 1.223 (0.960–1.556) 0.102
    187-I/T 211 (37.6) 213 (33.3) 1
    187-T/T 35 (6.2) 37 (5.8) 1.047 (0.635–1.726) 0.856
    187-I/I 316 (56.2) 390 (60.9) 1.214 (0.965–1.529) 0.098
    187-I/T+187-T/T 246 (43.8) 250 (39.1)
Allele frequency, no. (%)
    187-I allele 843 (75.0) 993 (77.6) 1.153 (0.955–1.392) 0.138
    187-T allele 281 (25.0) 287 (22.4)
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The χ2 test was used to calculate the P-values. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated by comparing the genotype and allele frequency differences between RA patients and normal controls.

The common 187-Ile allele is associated with anti-CCP+ RA

Anti-CCP antibodies are highly specific for RA and are predictive of the progression of undifferentiated arthritis toward RA.21,22 In addition, anti-CCP antibodies are associated with erosive disease in RA patients.23 To determine whether FCGR2B SNP c775T > C is associated with production of anti-CCP antibodies; we stratified RA patients based on presence and absence of anti-CCP antibodies. Among 595 RA patients assayed for anti-CCP antibodies, 464 patients (78.0%) were positive for anti-CCP+ (titers ≥ 40 IU ml−1). As shown in Table 2, we observed significant differences in the genotype distribution between anti-CCP+and anti-CCP RA patients (3×2 contingency table, χ2 = 9.819, P = 0.007). The 187-Ile homozygous donors were significantly increased in anti-CCP+RA patients compared with anti-CCP RA patients (P = 0.003, odds ratio 1.819 (95% CI 1.229– 2.691)). Multiple variable logistic regression analysis adjusted for age, sex, anti-CCP antibody, RF and ANA revealed significant enrichment of the 187-Ile homozygotes in anti-CCP+RA patients as compared with anti-CCP patients (P = 0.007, odds ratio 1.876 (95% CI 1.187–2.965)) (Table 2). The 187-Ile allele frequency was also significantly increased in anti-CCP+RA patients compared with anti-CCP RA patients (P = 0.001 odds ratio 1.652 (95% CI 1.210–2.257)). Additionally, we observed a significant enrichment of 187-Ile allele in anti-CCP+RA patients as compared with normal healthy controls (P = 0.005; odds ratio 1.348 (95% CI 1.092–1.664)) and a significant enrichment of 187-Ile homozygotes in anti-CCP+ RA patients as compared with normal controls (χ2 = 7.920, P = 0.005; odds ratio 1.438 (95% CI 1.116–1.852)). Our data suggest that 187-Ile allele is an important genetic risk factor for anti-CCP antibody production in Taiwanese RA patients.

Table 2.

Distribution of genotypes and allele frequencies of FcγRIIb 187-Ile/Thr polymorphism in anti-CCP positive (anti-CCP+) and negative (anti-CCP−) Taiwanese RA patients

Anti-CCP− (n = 131) Anti-CCP+ (n = 464) χ2 P OR 95% CI
Genotype frequency, no. (%)
    187-I/I 66 (50.4) 301 (64.9) 9.820 0.007
    187-I/T 54 (41.2) 142 (30.6)
    187-T/T 11 (8.4) 21 (4.5)
    187-I/I 66 (50.4) 301 (64.9)a 9.074 0.003 1.819b 1.229–2.691
    187-I/T+187-T/T 65 (49.6) 163 (35.1)
Allele frequency, no. (%)
    187-I allele 186 (71.0) 744 (80.2)a 10.084 0.001 1.652 1.210–2.257
    187-T allele 76 (29.0) 184 (19.8)
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The χ2 test was used to calculate the P-values. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated by comparing the genotype and allele frequency differences between anti-CCP positive patients and anti-CCP negative patients.

a

Significant enrichment of 187-Ile homozygotes was observed in anti-CCP+ RA patients as compared with normal controls (χ2 = 7.920,P=0.005; odds ratio 1.438 (95% CI 1.116–1.852)) and a significant enrichment of 187-Ile allele was also observed in anti-CCP+ RA patients as compared with normal controls ( χ2 = 7.760, P = 0.005; odds ratio 1.348 (95% CI 1.092–1.664)).

b

Multiple variable logistic regression analysis was also performed by adjusting for age, sex, autoantibody production and severity phenotypes (P = 0.007, odds ratio 1.876 (95% CI 1.187–2.965))

Association of 187-Ile allele with rheumatoid factor production in RA patients

Human rheumatoid arthritis patients produce a range of autoantibodies including antibodies against Fc portion of immunoglobulin (rheumatoid factors or RF) and antibodies against nuclear antigens (ANA). These autoantibodies mediate reactivity against self antigens and play important roles in the pathogenesis of RA as either disease initiator or perpetrator. The presence of RF can usually predict a more aggressive and destructive course for RA.24 We stratified FCGR2B SNP c775T > C genotype and allele distributions in RA patients based on production of RF and ANA. As shown in Table 3, we observed a significant enrichment of 187-Ile homozygotes in RA patients positive for rheumatoid factor production (RF+) in comparison to the healthy controls (P = 0.021, odds ratio 1.333 (95% CI 1.043–1.704)). The 187-Ile allele frequency was also significantly increased in RF+ RA patients as compared with the healthy controls (P = 0.036, odds ratio 1.241 (95% CI 1.014–1.518)). Among RA patients, there was a significant enrichment of 187-Ile homozygotes in RA patients positive for rheumatoid factor production (RF+) in comparison to RA patients negative for rheumatoid factor (RF−) (P = 0.024, odds ratio 1.562 (95% CI 1.059–2.303)). A significant increase of 187-Ile allele frequency was also observed in RF+ RA patients as compared with RF− RA patients (P = 0.034, odds ratio 1.398 (95% CI 1.024–1.909)). On the other hand, there were no significant differences in the distribution of genotypes and allele frequencies between RA patients positive for antinuclear antibody (ANA+) and RA patients negative for antinuclear antibody (ANA−) nor between RA patients (ANA+ or ANA−) and normal controls (P>0.05). Taken together, these data imply that the 187-Ile allele is associated with RF production but not with ANA production in RA patients.

Table 3.

Distribution of genotypes and allele frequencies for FcγRIIb 187-Ile/Thr polymorphism in RF positive (RF+), RF negative (RF−), anti nuclear antibody positive (ANA+), and anti nuclear antibody negative (ANA−) negative RA patients

Controls
N = 562		 RF+
N = 510		 RF−
N = 130		 ANA+
N = 308		 ANA−
N = 266
Genotype frequency, no. (%)
    187-I/I 316 (56.2) 322 (63.1) 68 (52.3) 185 (60.1) 163 (61.3)
    187-I/T 211 (37.6) 160 (31.4) 53 (40.8) 107 (34.7) 89 (33.4)
    187-T/T 35 (6.2) 28 (5.5) 9 (6.9) 16 (5.2) 14 (5.3)
    187-I/I 316 (56.2) 322 (63.1)a 68 (52.3) 185 (60.1) 163 (61.3)
    187-I/T+187-T/T 246 (43.8) 188 (36.9) 62 (47.7) 123 (39.9) 103 (38.7)
Allele frequency, no. (%)
    187-I allele 843 (75.0) 804 (78.8)b 189 (72.7) 477 (77.4) 415 (78.0)
    187-T allele 281 (25.0) 216 (21.2) 71 (27.3) 139 (22.6) 117 (22.0)
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a

Significant enrichment of 187-Ile homozygotes was observed in RA patients positive for rheumatoid factor (RF+) as compared with normal controls (χ2 = 5.298, P = 0.021; odds ratio 1.333 (95% CI 1.043–1.704)) or as compared with RA patients negative for RF (RF−) (χ2 = 5.104, P = 0.024; odds ratio 1.562 (95% CI 1.059–2.303)).

b

The 187-Ile allele frequency was also significantly increased in RF+ RA patients as compared with that in normal controls (χ2 = 4.390, P = 0.036; odds ratio 1.241 (95% CI 1.014–1.518)) or as compared with RF− RA patients (χ2 = 4.209, P = 0.034; odds ratio 1.398 (95% CI 1.024–1.909)).

The 187-Ile is associated with disease severity in RA patients

Next, we stratified the RA patients based on their disease severity using the criteria as described in the section of Patients and Methods. As shown in, Table 4 we observed a significant enrichment of 187-Ile homozygotes in destructive RA patients (patients with, joint subluxation and/or ankylosis or X-ray stage ≥III) as compared with the healthy controls (P¼0.018, odds ratio 1.374 (95% CI 1.056–1.788)). Furthermore, the 187-Ile allele frequency was also significantly increased in destructive RA patients as compared with the healthy controls (P = 0.027, odds ratio 1.277 (95% CI 1.027–1.588)). On the other hand, the distributions of SNP 187I/T genotypes were very similar between 154 nondestructive RA patients (55.9% for genotype 187-Ile/Ile, 37.0% for genotype 187-Ile/Thr and 7.1% for genotype 187-Thr/Thr) and 562 normal controls (56.2% for genotype 187-Ile/Ile, 37.6% for genotype 187-Ile/Thr and 6.2% for genotype 187-Thr/Thr). We also observed a significant enrichment for 187-Ile allele (P = 0.046; odds ratio 1.325 (95% CI 1.004–1.749)) in 204 RA patients with C-spine involvement compared with normal controls (Table 4). These data indicate that the 187-Ile allele may be a risk factor for severe rheumatoid arthritis.

Table 4.

Distribution of genotypes and allele frequencies for FcγRIIb 187-Ile/Thr polymorphism in destructive RA patients and RA patients with C-spine involvement (C-spine+ RA)

Controls
N = 562		 Destructive+ RA
N = 401		 Destructive− RA
N = 154		 C-spine+ RA
N = 204		 C-spine− RA
N = 195
Genotype frequency, no. (%)
    187-I/I 316 (56.2) 256 (63.8) 86 (55.9) 129 (63.2) 118 (60.5)
    187-I/T 211 (37.6) 124 (30.9) 57 (37.0) 68 (33.3) 66 (33.9)
    187-T/T 35 (6.2) 21 (5.3)a 11 (7.1) 7 (3.5) 11 (5.6)
Allele frequency, no. (%)
    187-I/T+187-T/T 246 (43.8) 145 (36.2) 68 (44.1) 75 (37.8) 77 (39.5)
    187-I allele 843 (75.0) 636 (79.3)b 229 (74.6) 326 (79.9)b 302 (77.4)
    187-T allele 281 (25.0) 166 (20.7) 79 (25.4) 82 (20.1) 88 (22.6)
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a

The 187-Ile homozygotes were significantly enriched in destructive RA patients as compared with normal controls (χ2 = 5.623, P=0.018; odds ratio 1.374 (95% CI 1.056–1.788)).

b

The 187-Ile allele frequency was also significantly increased in destructive RA patients (χ2 = 4.860, P=0.027; odds ratio 1.277 (95% CI 1.027– 1.588)) and C-spine+ RA (χ2 = 3.978, P = 0.046; odds ratio 1.325 (95% CI 1.004–1.749)) as compared with that in normal controls.

Like most autoimmune diseases, RA has a predisposition for women and our study population contained more female patients than male RA patients (550 female and 90 male). To determine whether the FCGR2B SNP c775T>C has different effect between female and male RA patients; we stratified destructive RA patients based on sexes. As shown in Table 5, a significant enrichment of 187-Ile homozygotes was apparent in destructive male RA patients compared with male normal controls (P = 0.035; odds ratio 2.038 (95% CI 1.046–3.973)). There was also a significant increase of 187-Ile allele frequency in destructive male RA patients as compared with normal male controls (P=0.029; odds ratio 1.883 (95% CI 1.060–3.345)). Although the 187-Ile homozygotes tend to be enriched in destructive female RA patients in comparison to female normal controls, the increase did not reach statistical significance (P=0.113). Taken together, it seems likely that 187-Ile allele is a risk factor for destructive RA in men and that the 187-Ile allele might play a less important role for destructive RA in women in the Taiwanese population.

Table 5.

Distribution of genotypes and allele frequencies for FcγRIIb 187-Ile/Thr polymorphism in normal controls and destructive RA patients as stratified by sexes

Male
 Female
Controls
N = 130		 Destructive RA
N = 55		 Controls
N = 432		 Destructive RA
N = 346
Genotype frequency, no. (%)
    187-I/I 68 (52.3) 38 (69.1) 248 (57.4) 218 (63.0)
    187-I/T 54 (41.5) 16 (29.1) 157 (36.3) 108 (31.2)
    187-T/T 8 (6.2) 1 (1.8) 27 (6.3) 20 (5.8)
    187-I/I 68 (52.3) 38 (69.1)a 248 (57.4) 218 (63.0)
    187-I/T+187-T/T 62 (47.7) 17 (30.9) 184 (42.6) 128 (37.0)
Allele frequency, no. (%)
    187-I allele 190 (73.1) 92 (83.6)b 653 (75.6) 544 (78.8)
    187-T allele 70 (26.9) 18 (16.4) 211 (24.4) 148 (21.4)
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a

Significant enrichment of 187-Ile homozygotes was observed in destructive male RA patients as compared with male normal controls (χ2 = 4.449, P = 0.035; odds ratio 2.038 (95% CI 1.046–3.973) by 2 × 2 contingency table analysis).

b

The 187-Ile allele frequency was also significantly enriched in destructive male RA patients as compared with normal male controls (χ2 = 4.755, P = 0.029; odds ratio 1.883 (95% CI 1.060–3.345) by 2 × 2 contingency table analysis). The 187-Ile homozygotes tended to be enriched in destructive female RA patients as compared with female normal controls, but the enrichment did not reach statistical significance (P = 0.113).

Fcγ RIIb 187-Ile/Thr polymorphism is associated with early disease onset of RA in Taiwanese

We next explored whether the FCGR2B SNP c775T>C is associated with onset ages for rheumatoid arthritis. As shown in Table 6, after RA patients were stratified according to disease onset ages, we observed a sig-nificant enrichment of the 187-Ile allele frequency in the youngest RA patient group (<31 age range) as compared with the normal controls (P=0.045; OR 1.548 (95% CI 1.007–2.379)). The 187-Ile homozygotes also increased in the youngest RA patients (<31 age range) in comparison to the normal healthy controls, but the increase was at the border line for significance (P=0.067). We did not observe significant enrichment of 187-Ile homozygotes or 187-Ile allele frequency in any other age groups of RA patients (P>0.05). These data suggest that the 187-Ile allele might be a risk factor for the early onset of rheumatoid arthritis.

Table 6.

Distribution of genotypes and allele frequencies for FcγRIIb 187-Ile/Thr polymorphism among different onset age groups in Taiwanese RA patients

Onset age groups (age range) <31
N = 79		 31–45
N = 220		 46–60
N = 241		 460
N = 100
Genotype frequency, no. (%)
    187-I/I 53 (67.1) 128 (58.2) 147 (61.0) 62 (62.0)
    187-I/T 24 (30.4) 81 (36.8) 74 (30.7) 34 (34.0)
    187-T/T 2 (2.5) 11 (5.0) 20 (8.3) 4 (4.0)
    187-I/I 53 (67.1) 128 (58.2) 147 (61.0) 62 (62.0)
    187-I/T+187-T/T 26 (32.9) 92 (41.8) 94 (39.0) 38 (38.0)
Allele frequency, no. (%)
    187-I allele 130 (82.3)a 337 (76.6) 368 (76.3) 158 (79.0)
    187-T allele 28 (17.7) 103 (23.4) 114 (23.7) 42 (21.0)
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a

There was a significant enrichment of the 187-Ile allele frequency in the youngest RA patient group (16–29 years age range) as compared with the normal controls (χ2 = 4.012, P = 0.045; odds ratio 1.548 (95% CI 1.007–2.379)) by 2 × 2 contingency table analysis. The 187-Ile homozygotes also tended to be enriched in the youngest RA patients (<31 age range) as compared with the normal controls, but the enrichment did not reach statistical significance (P = 0.067). No significant enrichment of 187-Ile homozygotes or 187-Ile-allele frequency was observed in the other age groups of RA patients as compared with normal controls.

Discussion

On B cells, FcγRIIb mediates signals to downregulate B-cell activation and therefore, it facilitates the inhibition of immunoglobulin (Ig) production and promotes immune balance.10,11,25 Because FcγRIIb reduces ITAM-initiated calcium mobilization in various immune cells, FcγRIIb inhibits other calcium dependent processes such as phagocytosis, antibody-dependent cell-mediated cyto-toxicity, degranulation, cytokine release and cell proliferation.11 FcγRIIb-deficient mice with the targeted disruption of FcγRIIb gene have elevated serum Ig concentrations and, on the susceptible C57BL/6 background, are more likely to develop an autoimmune phenotype.26,27 Abundant evidence points to a critical role for FcγRIIb in the development of autoimmune diseases in mice.28–32 In humans, FcγRIIb polymorphisms are associated with human SLE, a prototypic human autoimmune disease.20,33–37 FcγRIIb plays an important role in modulating the immune system and therefore, it is reasonable to assume that functional FcγRIIb SNPs might determine susceptibility and severity of immune complex-mediated disease such as RA.

In the present study, we observed significant associations of FcγRIIb 187-Ile/Thr polymorphism with anti-CCP antibody production, RF production, RA destruction and early onset of disease in Taiwanese RA patients. Unexpectedly, we have found that FcγRIIb 187-Ile (major) allele, rather than the 187-Thr (minor) allele, was associated with more severe and early onset of RA in Taiwanese. Interestingly, the 187-Thr allele is associated with human SLE in Asian populations,20,33–35 we speculate that the FcγRIIb 187-Ile/Thr polymorphism may play a different role in the pathogenesis of rheumatoid arthritis in comparison to that in lupus.

Dendritic cells are professional antigen-presenting cells (APCs) that specialize in the capturing, processing and transport of antigens to lymphoid organs. Dendritic cells drive immune responses by producing cytokines and by sensitizing antigen-specific T cells and B cells. FcγRIIb engagement induces activation of follicular dendritic cells and promotes the development of secondary follicles in lymphoid organs.14 Furthermore, FcγRIIb on dendritic cells serve as a critical receptor in the uptake of immune complex and in the antigen presentation.13,38–42 FcγRIIb is frequently overexpressed in malignant lymphomas and acts as a tumorigenicity-enhancing factor in tumor progression.43,44 In B cells, the negative regulatory effects of FcγRIIb can be abolished by the presence of cytokine IL-4.45,46 Thus, FcγRIIb does not always serve as an inhibitory receptor in cell functions.

As the dendritic cells carrying 187-Ile allele internalize IgG immune complexes more efficiently,47 one can speculate that FcγRIIb 187-Ile allele may be more equipped and more efficient in processing and presenting antigens as FcγRIIb 187-Ile allele is more preferentially recruited into lipid rafts than 187-Thr allele.18,19 To define the functional FcγRIIb 187-Ile/Thr polymorphism in vivo, knock-in mice carrying two human FcγRIIb alleles (187-Ile and 187-Thr) replacing mouse FcγRIIb need to be generated for further study.

RA is an autoimmune joint disease with the hyperplasia of synovial tissue and formation of pannus, which grows aggressively into the cartilage and cause cartilage and bone destruction. Receptor carrying ITIM may be able to mediate survival and proliferation signals to cells through recruitment of SH2-containing phosphatases by ITIM.48 FcγRIIb is abundantly expressed in synovia of RA patients49 and DCs express significantly higher FcγRIIb in RA patients than those from healthy con-trols,50 suggesting a pivotal role for FcγRIIb function in sustaining persistent local inflammation. Therefore, it is possible that ITIM-containing FcγRIIb may provide surviving signals to immune cells (dendritic cells, macrophages, neutrophils and B cells) that are critical in the pathogenesis of RA.

Previous reports suggest that male patients may require more genetic risk factors to get beyond the threshold for RA disease development in comparison to female patients.51,52 In male RA population, FcγRIIIA-158VV genotype is a risk factor for RA development and for more severe disease in early RA.53 In the current study, we have identified that the 187-Ile allele is a risk factor for destructive RA in male RA patients and that the 187-Ile allele is not significantly associated with destructive RA in female RA patients in Taiwanese. Therefore, FcγRIIb function may have more impact on the development of RA in men than in women. Our data suggest that FcγRIIb 187-Ile allele may contribute to disease pathogenesis in a subgroup of RA patients (males with more destructive and earlier onset disease). In addition, our data indicate that stratification by clinical characteristics and sexes may provide further insights into the influence of FcγRIIb 187-Ile/Thr polymorphism on pathogenesis of rheumatoid arthritis. As with susceptibility genes in other complex autoimmune diseases, it is anticipated that the contribution of each gene will have a modest odds ratio.20,36

As seven laboratory and clinical parameters (anti-CCP, RF, ANA, destructive RA, C-spine involvement, sexes and disease-onset age groups) were analyzed for the association with FcγRIIb 187-Ile/Thr polymorphism, there may be some concerns about ‘significant’ associations that could be because of the high number of association studies performed. The logistic regression method was applied for the adjustment of the significance with a large number of parameters and the anti-CCP antibodies positivity displayed truly significant association with FcγRIIb 187-Ile/Thr polymorphism. Although other clinical and laboratory parameters (RF production, destructive RA, C-spine involvement and early onset age) were significantly associated with 187-Ile allele (P<0.05), the association may become insignificant in multiple variable analysis and therefore, these associations have to be interpreted cautiously and need to be independently confirmed in other cohorts. In the present study, the simple Steinbrocker evaluation system was used to evaluate the joint damage and the assessment of the radiological damage was cross-sectional. The progression of bone erosion and joint damage may vary in disease courses and may be affected by antirheumatic medications. Therefore, it is necessary to consider the above factors in the future genetic studies.

It was previously reported that FcγRIIb 187-Ile/Thr polymorphism was not significantly associated with RA in the European population47 and in the Japanese population.54 The FcγRIIb 187-Ile homozygotes tended to be enriched in European RA patients, but the enrichment was not statistically significant.47 Similarly, we observed a trend toward the increased 187-Ile homozygosity and the increased 187-Ile allele frequency in Taiwanese RA patients. However, the increases did not reach statistical significance without stratification (Table 1). The possible explanation for the lack of association in European, Japanese and Taiwanese populations without stratifications is that the FcγRIIb 187-Ile/Thr polymorphism may only affect the specific disease aspects such as anti-CCP, RF production and disease severity. To the best of our knowledge, the present study is the first to demonstrate the association between FcγRIIb 187-Ile/Thr polymorphism and anti-CCP antibody production. Previously, HLA-RB1 SE alleles, PTPN22 1858C/T polymorphism and the haplotypes of interferon regulatory factor 5 gene (IRF5) regulatory regions SNPs were found to be associated with the production of anti-CCP antibodies.55–60 Thus, there could be multiple genetic factors in shaping the RA phenotypes. Therefore, it might be difficult to detect the overall genetic effect of FcγRIIb 187-Ile/Thr polymorphism in a small number of study subjects as the genetic contribution of FcγRIIb may be modest as demonstrated in our study.

Interestingly, FcγRIIb 187-Thr allele, instead of 187-Ile allele, was found to be associated with joint damage in European whites.47 It is likely that the FcγRIIb 187-Ile/ Thr may play different roles in different genetic backgrounds and the SNP may require epistatic interaction with other genes to express the autoimmune phenotype. In human populations, the composition of epistatic modifiers may differ among different ethnic and admixed populations and therefore, the influence of FcγRIIb 187-Ile/Thr on autoimmunity may not be the same in different genetic backgrounds of various ethnicities. This phenomenon has been demonstrated in the association studies between FcγRIIb 187-Ile/Thr polymorphism and human SLE. Although FcγRIIb 187-Thr allele is a risk factor for SLE in Asians,20,33–35 the same SNP allele was not associated with SLE in Caucasian Americans, African Americans and Swedish populations.17,61

To conclude, we have demonstrated that the FcγRIIb 187-Ile allele is a susceptibility gene for anti-CCP production and for disease severity in Taiwanese RA patients. Our data suggest the FcγRIIb polymorphism may serve as a modifier in the pathogenesis of RA. Therefore, FcγRIIb potentially could be a therapeutic target for the treatment of destructive RA. Blockade of FcγRIIb may be an attractive strategy to break the vicious cycle of chronic inflammation initiated by immune complexes that activate DCs for antigen processing and presentation through the FcγRIIb.

Patients and methods

Study subjects

Anti-coagulated peripheral blood was obtained from healthy normal blood donors and from RA patients. The current study recruited 640 Taiwanese RA patients (90 males and 550 females). A total of 562 healthy blood donors (130 males and 432 females) were recruited following a questionnaire survey to exclude donors with autoimmune diseases (including RA, systemic lupus erythromatosus, ankylosing sopndylitis and autoimmune thyroiditis), diabetes mellitus (DM) and cardiovascular diseases. The age of healthy control donors range from 18 to 64 years with a mean age of 37.2 ± 11.5 years. The local ethics committee of Chang Gung Memorial Hospital approved the study and all donors provided written consent for the study. RA patients were diagnosed by rheumatology specialists according to the 1987 American Rheumatism Association criteria for RA.62 The RA patients were followed up for at least 2 years in the rheumatology clinics of Chang Gung Memorial Hospital to evaluate disease courses. Rheumatology specialists graded serial damage of both hands based on classical Steinbrocker staging system by analyzing X-ray films: soft tissue swelling and periarticular osteoporosis (stage I), bony erosion (stage II), joint subluxation (stage III) and joint ankylosis (stage IV). Cervical spine involvement was defined as C1–2 subluxation and/or subaxial subluxation. The X-ray radio-graphical changes were evaluated within a period of 2 years or more after RA disease onset. Two investigators independently verified the hand X-ray radiography and scored the stages of each patient using Steinbrocker criteria.63 The rare inconsistent cases with radiography scoring system were resolved through conferences among physicians and by assessing clinical functionality data. The severity of RA patients varied during disease course. The patients with destruction of joint subluxation and/or ankylosis (X-ray stage ≥III) during any time points of disease course were categorized as having destructive RA. The patients with non-destructive RA were defined when disease activities of patients remained either at stage I (X-ray radiographical grading) for ≥5 years or at stage II for ≥10 years. Antinuclear antibody was considered as positive if serum titers were ≥1:80 by Hep-2 cell assay. Rheumatoid factor (RF) was regarded as positive when the titer was ≥20 IU ml−1 in nepholometric assay. The titers of antibodies against cyclic citrullinated peptide (anti-CCP) were determined by a third-generation enzyme-linked immunoassay kit (Inova Diagnostics, USA). A cutoff value of 40 IU ml−1 was set to distinguish between anti-CCP-positive (≥40 IU ml 1) and anti-CCP-negative (<40 IU ml 1) RA patients.

Nucleic acid isolation

Genomic DNA was isolated from EDTA anti-coagulated peripheral blood using the Puregene DNA isolation kit (Gentra Systems, Minneapolis, MN, USA) as previously described.20

Genotyping of FCGR2B SNP c775T>C

Matrix-assisted Laser Desorption Ionization Time-of-flight (MALDI-TOF) mass spectrometry was used for the genotyping of SNP c775T>C as previously described.20 The FCGR2B-specific DNA amplicon containing exon 5 and parts of flanking introns (intron 4 and 5) was amplified as described previously in 96-well PCR plates with 10 ng of genomic DNA in a 10-µl reaction volume. The 494-bp PCR products were automatically purified on the MALDI-TOF Map II/8 Robotic Platform using a BRUKER Genopure DS Magnetic Bead DNA Purification kit. The purified DNA was extended by PCR with SNP detection primer 5’-TGGCTGTGGTCACTGG GA-3’ and termination mix of dCTP, ddGTP, ddATP and ddTTP. The PCR profile included a denaturing step at 94 °C for 5 min followed by 50 cycles of denaturing at 94 °C for 8 s, annealing at 52 °C for 8 s and extension at 72°C for 8 s. The cycle was completed with a final extension at 72 °C for 2min. The allele-specific products were purified with the BRUKER Genopure Oligo Magnetic Bead DNA Purification kit and samples were automatically spotted on the 384-well Anchor Chip plate and analyzed through Autoflex Mass Spectrometry. To validate the MALDI-TOF technique, 161 DNA samples were also genotyped by direct sequencing using the BigDye terminator sequencing kit on an ABI 3100 sequencer. There was complete concordance of genotyping by direct sequencing and by MALDI-TOF mass spectrometry.

Statistical analysis

Chi-square analyses were used to analyze the distribution of FcγRIIb genotypes and allele frequencies of SNP 187I/T in RA patients and controls using the SPSS 12 statistics package for Windows (SPSS, Chicago, IL, USA). The distribution of SNP 187I/T genotypes was also analyzed with χ2 tests among RA patients according to onset ages, disease severity and presence of auto-antibodies including anti-CCP antibody, RF or ANA. The multiple logistic regression models were applied as several independent variables demonstrated statistical significance on univariate analysis. The analysis was performed by using the presence or absence of SNP 187I/I genotype (yes/no) as the dependent variables adjusted for age, sex, autoantibody production and severity phenotypes. The null hypothesis was rejected at 5% level of significance (P<0.05).

Acknowledgements

We thank Shin Chu Blood Donor Center for sample collection and Dr Nengjun Yi for the help in statistical analysis. This study was supported by a grant from the Chang Gung Memorial Hospital (no. CMRPG 33070). Jianming Wu is partly supported by NIH Grant P01-AR49084.

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