Study of functional variants of the BANK1 gene in rheumatoid arthritis

Objective

To investigate 1 functional (rs17266594) and 2 potentially functional (rs10516487 and rs3733197) BANK1 variants, which were previously identified as systemic lupus erythematosus (SLE) susceptibility markers, to test whether they are associated with rheumatoid arthritis (RA).

Methods

Four different cohorts were included in the study: 1,080 RA patients and 1,368 healthy controls from Spain, 278 RA patients and 568 healthy controls from Sweden, 288 RA patients and 287 healthy controls from Argentina, and 288 RA patients and 288 healthy controls from Mexico. Samples were genotyped for BANK1 single‐nucleotide polymorphisms (SNPs) using a TaqMan 5′‐allele discrimination assay. Statistical analysis comparing allele and genotype distributions was performed with the chi‐square test.

Results

We did not find a significant association between RA and the rs10516487 and rs17266594 BANK1 polymorphisms. However, there was an increase in the major alleles among RA patients. Similarly, for rs3733197, there was an increase in the major allele among patients in every cohort. Nevertheless, this skewing reached statistical significance in the Spanish (P = 0.01, odds ratio [OR] 1.17 [95% confidence interval (95% CI) 1.03–1.32]) and Argentinean (P = 0.04, OR 1.31 [95% CI 1.00–1.72]) populations. We found a significant association of rs10516487 (P = 0.005, OR 1.15 [95% CI 1.04–1.28]) and rs3733197 (P = 0.0009, OR 1.17 [95% CI 1.07–1.29]) with RA in the pooled analysis. In a 3‐SNP haplotype analysis, we found that the major TGG haplotype was significantly associated with RA (P = 0.005, OR 1.14 [95% CI 1.04–1.25]). In addition, we found a common CAA haplotype that was protective against RA (P = 0.0004, OR 0.82 [95% CI 0.74–0.92]).

Conclusion

These results suggest that BANK1 SNPs and haplotypes may contribute to RA susceptibility with a low risk.

     

STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis

Objective

Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT‐4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single‐nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5.

Methods

Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects.

Results

STAT4 rs7574865 was shown to be associated with SSc (P = 0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11–1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiplicatively increased 1.28‐fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86–3.99) for combinations of genotypes with ≥3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P = 2.2 × 10⁻⁴, OR 1.97, 95% CI 1.28–3.04).

Conclusion

Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc‐related fibrosing alveolitis.

     

C8orf13–BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: Results from a large french cohort and meta‐analysis

Objective

Accumulating evidence suggests that B cells are involved in systemic sclerosis (SSc). BANK1 has been reproducibly reported to be associated with diffuse cutaneous SSc (dcSSc). BLK encodes another B cell signal transducer, and a functional variant at the C8orf13–BLK locus has been found to be associated with SSc in Caucasians. However, no independent replication has been reported, and there are discrepancies in the genotype–phenotype correlation between these studies in Caucasians and another study performed in the Japanese population. Therefore, in a large cohort of French Caucasians and using a meta‐analysis of the available data, this study was undertaken to determine whether the C8orf13–BLK locus is associated with SSc, and to assess the possibility of interaction between BLK and BANK1 in SSc.

Methods

The C8orf13–BLK rs13277113 genotype was determined in 1,031 patients with SSc and 1,014 control subjects for whom BANK1 genotypes were available. Meta‐analysis of the 3 available data sets (6,078 individuals) was also performed.

Results

Minor allele frequencies for rs13277113 revealed an association restricted to the dcSSc subtype (P = 0.012, odds ratio [OR] 1.29) in the French sample. Meta‐analysis of the combined Caucasian populations showed an association of this genotype with both SSc (P = 0.0013, OR 1.16, 95% confidence interval [95% CI] 1.06–1.26) and dcSSc (P = 0.0012, OR 1.23, 95% CI 1.08–1.39). Inclusion of the Japanese population confirmed the overall association with the disease, with the strongest association observed with dcSSc (P = 3.27 × 10⁻⁵, OR 1.27). Secondary analysis in the French sample revealed additive effects between C8orf13–BLK and BANK1, mainly in the dcSSc subset.

Conclusion

These results confirm C8orf13–BLK as an SSc risk locus. The strongest effects, and particularly additive effects, were observed in the interaction between C8orf13–BLK and BANK1 in the dcSSc subset.

     

Hemorheologic profile in systemic sclerosis: Role of NOS3 −786T>C and 894G>T polymorphisms in modulating both the hemorheologic parameters and the susceptibility to the disease

Objective

Microvascular disorders are relevant in systemic sclerosis (SSc). Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of microcirculatory disorders. An impaired availability of nitric oxide, related to polymorphisms in NOS3, the gene for endothelial cell nitric oxide synthase, might influence erythrocyte deformability. We undertook this study to investigate the hemorheologic profile in SSc and the role of NOS3 polymorphisms in modulating the hemorheologic status of SSc patients.

Methods

We studied 113 consecutive SSc patients (75 with limited cutaneous SSc [lcSSc] and 38 with diffuse cutaneous SSc [dcSSc]) and 113 healthy controls. The hemorheologic profile was obtained by assessing whole blood viscosity (WBV; at shear rates of 0.512 and 94.5 seconds⁻¹), plasma viscosity (PLV; at a shear rate of 94.5 seconds⁻¹), and erythrocyte deformability index (DI). We determined NOS3 polymorphisms by molecular analysis.

Results

A marked alteration of hemorheologic parameters was found both in patients with lcSSc and in those with dcSSc compared with controls (P < 0.0001). In multivariate analysis, rheologic variables were significantly associated with the disease (for WBV at a shear rate of 94.5 seconds⁻¹, odds ratio [OR] 5.4, 95% confidence interval [95% CI] 1.4–19.9, P = 0.01; for PLV, OR 2.8, 95% CI 1.2–6.5, P = 0.01; for DI, OR 3.9, 95% CI 1.4–10.8, P = 0.007), and NOS3 −786C and 894T alleles significantly affected the DI (for −786C allele, OR 2.3, 95% CI 1.01–5.4, P = 0.04; for 894T allele, OR 2.2, 95% CI 1.01–4.8, P = 0.04). The simultaneous presence of the −786C and 894T alleles represented a susceptibility factor for SSc (OR 2.8, 95% CI 1.4–5.7, P = 0.004).

Conclusion

Our findings document an altered rheologic profile in SSc and demonstrate a relationship between this alteration and NOS3 polymorphisms, thus shedding light on a potential novel mechanism influencing the microcirculation in this disease.

     

Association of the CD226 Ser307 variant with systemic sclerosis: Evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis

Objective

The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell costimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations.

Methods

CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361.

Results

The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10–1.34), P = 5.69 × 10^–5. The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti–topoisomerase I antibody–positive, and SSc‐related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42–2.43), P = 5.15 × 10^–6, OR 1.82 (95% CI 1.38–2.40), P = 2.16 × 10^–5, and OR 1.61 (95% CI 1.25–2.08), P = 2.73 × 10^–4, respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated.

Conclusion

Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.

     

Association of the PTPN22 R620W polymorphism with anti–topoisomerase I– and anticentromere antibody–positive systemic sclerosis

Objective

To determine any associations of the PTPN22 R620W single‐nucleotide polymorphism (SNP) with systemic sclerosis (SSc) or with anticentromere antibody (ACA)–positive or anti–topoisomerase I (anti–topo I) antibody–positive SSc, in a case–control study of US white, black, Hispanic, and Choctaw Indian individuals.

Methods

A total of 850 white, 130 black, 120 Hispanic, and 20 Choctaw Indian patients with SSc were compared with 430 white, 164 black, 146 Hispanic, and 76 Choctaw Indian control subjects, respectively. All subjects were living in the US. PTPN22 SNP (rs2476601) genotyping was performed by TaqMan 5′ allelic discrimination assay and pyrosequencing.

Results

The PTPN22 CT/TT genotype showed significant association with anti–topo I antibody–positive SSc in white patients (odds ratio [OR] 2.21, 95% confidence interval [95% CI] 1.3–3.7) and with ACA‐positive white patients with SSc (OR 1.70, 95% CI 1.1–2.7). Frequency of the PTPN22*T allele also showed significant association with anti–topo I antibody–positive SSc in white patients (OR 2.03, 95% CI 1.3–3.2). When data for patients in the 3 ethnic groups (black, white, and Hispanic) were combined, a significant association with both genotype and allele frequencies was observed, suggesting a trend toward association in ACA‐positive and anti–topo I antibody–positive SSc. Stepwise logistic regression analysis (controlled for the confounding effects of sex and race) showed that the PTPN22 CT/TT genotype was associated with a significantly higher risk of SSc compared with the CC genotype (for patients with SSc, OR 1.64, 95% CI 1.2–2.2; for ACA‐positive patients with SSc, OR 1.63, 95% CI 1.0–2.6; for anti–topo I antibody–positive SSc, OR 2.33, 95% CI 1.5–3.7).

Conclusion

Our results indicate that the PTPN22 R620W polymorphism is associated with ACA‐positive and anti–topo I antibody–positive subsets of SSc and represents a risk factor in both white patients and black patients. The association of subsets of SSc with the PTPN22 R620W polymorphism further strengthens the classification of SSc within the spectrum of autoimmune diseases and strongly suggests the involvement of common susceptibility genes and similarly disordered immunoregulatory pathways.

     

Reproductive factors and the risk of scleroderma: An Italian case–control study

Objective

To investigate the association between scleroderma (systemic sclerosis; SSc) and reproductive factors in a hospital‐based case–control study conducted at the University Hospital of Verona in Northeastern Italy.

Methods

Forty‐six confirmed cases of SSc in women (42 with diffuse SSc and 4 with limited SSc) and 153 female control subjects with orthopedic disorders were recruited at the University Hospital. For each subject, information on age at first pregnancy, number of children and abortions, and use of oral contraceptives was obtained by means of a structured questionnaire, and information on the subject's occupational history and lifestyle factors was also sought.

Results

Parous women had a reduced risk of SSc (age‐adjusted odds ratio [OR] 0.3, 95% confidence interval [95% CI] 0.1–0.8) compared with nulliparous women. The risk decreased with an increasing number of children: the age‐adjusted OR was 0.6 (95% CI 0.2–1.7) for those women who had had 1 child, 0.3 (95% CI 0.1–0.7) for those having had 2 children, and 0.3 (95% CI 0.1–0.8) for those having had 3 or more children. Abortive pregnancies were inversely related to SSc risk: for women who had an abortion, the OR was 0.5 (95% CI 0.2–1.5) compared with women with no history of abortion. The overall history of any pregnancy (abortive or age‐adjusted complete) was associated with a reduced risk of SSc (age‐adjusted OR 0.3, 95% CI 0.1–0.7).

Conclusion

Since the incidence of SSc is higher in women and has its peak after childbearing age, it has been hypothesized that immunobiologic modifications during pregnancy may be associated with SSc development. Our findings showing a reduced risk of SSc among parous women seem to exclude the possibility of pregnancy itself as a risk factor for SSc. The role of HLA compatibility between the mother and the fetus, however, should be evaluated in further research.

     

Association of a KCNA5 gene polymorphism with systemic sclerosis–associated pulmonary arterial hypertension in the European Caucasian population

Objective

Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor β receptors; however, some other candidate genes have also been advocated, including potassium voltage‐gated channel, shaker‐related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH.

Methods

Four KCNA5 single‐nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes.

Results

The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48–0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13–0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21–0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc.

Conclusion

Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

     

Positive association of SLC26A2 gene polymorphisms with susceptibility to systemic‐onset juvenile idiopathic arthritis

Objective

To investigate SLC26A2, the gene that causes diastrophic dysplasia, in juvenile idiopathic arthritis (JIA).

Methods

Nine polymorphisms across the SLC26A2 gene locus were investigated using MassArray genotyping in 826 UK Caucasian JIA cases and 617 ethnically matched healthy controls.

Results

Significant associations between multiple single‐nucleotide polymorphisms (SNPs) across SLC26A2 and systemic‐onset JIA were found. In each case, homozygosity for the minor allele conferred the increased risk of disease susceptibility: rs1541915 (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.4–3.7, P = 0.0003), rs245056 (OR 2.8, 95% CI 1.7–4.6, P = 0.00002), rs245055 (OR 2.5, 95% CI 1.2–5.0, P = 0.004), rs245051 (OR 2.3, 95% CI 1.4–3.7, P = 0.0005), rs245076 (OR 2.7, 95% CI 1.3–5.4, P = 0.0015), and rs8073 (OR 2.3, 95% CI 0.9–5.6, P = 0.04).

Conclusion

These findings show the value of using monogenic disease loci as candidates for investigation in JIA. We identified a subgroup‐specific association between SNPs within the SLC26A2 gene and systemic‐onset JIA. Our findings also highlight systemic‐onset JIA as being a distinctly different disease from that in the other JIA subgroups.

     

Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis

Objective

Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors.

Methods

Cases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single‐nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results

The strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61–0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05–1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02–1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01–1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy‐Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA.

Conclusion

We have demonstrated associations between JIA and variants in the TNFAIP3, STAT4, and C12orf30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors.

     

The association of a nonsynonymous single‐nucleotide polymorphism in TNFAIP3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese population

Objective

Genome‐wide association (GWA) studies in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Caucasian populations have independently identified risk variants in and near the tumor necrosis factor α (TNFα)–induced protein 3 gene (TNFAIP3), which is crucial for the regulation of TNF‐mediated signaling and Toll‐like receptor signaling. The aim of this study was to assess the role of TNFAIP3 in the development of SLE and RA in Japanese subjects.

Methods

We selected 2 single‐nucleotide polymorphisms (SNPs) from previous GWA studies. Rs2230926 is a nonsynonymous SNP in TNFAIP3 and is associated with SLE, while rs10499194 is an intergenic SNP associated with RA. We then performed 2 independent sets of SLE case–control comparisons (717 patients and 1,362 control subjects) and 3 sets of RA case–control comparisons (3,446 patients and 2,344 control subjects) using Japanese subjects. We genotyped SNPs using TaqMan assays.

Results

We observed a significant association between rs2230926 and an increased risk of SLE and RA in the Japanese population (for SLE, odds ratio [OR] 1.92, 95% confidence interval [95% CI] 1.53–2.41, P = 1.9 × 10⁻⁸; for RA, OR 1.35, 95% CI 1.18–1.56, P = 2.6 × 10⁻⁵). The intergenic SNP rs10499194 was also associated with SLE and RA, while the risk allele for RA in Caucasians was protective against the diseases in our population.

Conclusion

We demonstrated a significant association between the nonsynonymous variant in TNFAIP3 and the risk for SLE and RA in the Japanese population. TNFAIP3, similar to STAT4 and IRF5, may be a common genetic risk factor for SLE and RA that is shared between the Caucasian and Japanese populations.

     

Association of the FAM167A–BLK region with systemic sclerosis

Objective

An association of single‐nucleotide polymorphisms (SNPs) in the FAM167A (previously referred to as C8orf13)–BLK region with systemic lupus erythematosus (SLE) has been demonstrated in Caucasians and in Asians. Recent studies have shown that many genes, including IRF5, STAT4, and PTPN22, are shared susceptibility genes in multiple autoimmune diseases. We undertook the current study to examine whether the FAM167A–BLK region is also associated with susceptibility to systemic sclerosis (SSc).

Methods

Japanese patients with SSc (n = 309) and healthy controls (n = 769) were enrolled in a 2‐tiered case–control association study. In tier 1, 124 patients and 412 controls were tested to determine association of 16 tag SNPs encompassing the FAM167A–BLK region with SSc. In tier 2, an additional 185 patients and 357 controls were analyzed for SNP rs13277113.

Results

Two haplotype blocks that correspond approximately to FAM167A and BLK were observed. In tier 1 of the study, the rs13277113A allele in the BLK block exhibited the most significant association with SSc after correction for multiple testing (permutated P = 0.024). Two SNP haplotypes formed by rs13277113 and the most significant SNP in the FAM167A block did not exhibit stronger association. When samples from tier 1 and tier 2 were combined, the rs13277113A allele was significantly associated with SSc (odds ratio 1.45 [95% confidence interval 1.17–1.79], P = 6.1 × 10⁻⁴). Association or a tendency toward association of rs13277113A with SSc was observed regardless of a patient's autoantibody profile or whether a patient had diffuse cutaneous or limited cutaneous SSc.

Conclusion

Our findings indicate that the rs13277113A allele is associated not only with SLE but also with SSc and that the FAM167A–BLK region is a common genetic risk factor for both SLE and SSc.

     

PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population

Objective

Systemic sclerosis (SSc) is an autoimmune disease for which multiple susceptibility genes have been reported. Genome‐wide association studies have shown that large numbers of susceptibility genes are shared among autoimmune diseases. Recently, our group identified 9 novel susceptibility genes associated with rheumatoid arthritis (RA) in a Japanese population. The aim of this study was to elucidate whether the 18 genes that displayed associations or suggestive associations for RA in our previous study are associated with SSc in Japanese.

Methods

We performed an association study that included 415 patients with SSc and 16,891 control subjects, followed by a replication study that included 315 patients and 21,054 control subjects. The 18 markers reported to display association with RA were analyzed for their associations with SSc in the first study, and 5 markers were further analyzed in the replication study. The inverse variance method was used to evaluate the associations of these markers with SSc in a combined study.

Results

In the phospholipase D4 gene (PLD4), rs2841277 displayed a significant association with SSc in Japanese patients (P = 0.00017). We observed that rs2841280 in exon 2 of PLD4 was in strong linkage disequilibrium with rs2841277 and introduced an amino acid alteration. We also observed associations between SSc and rs6932056 in TNFAIP3 and rs2280381 in IRF8 (P = 0.0000095 and P = 0.0030, respectively), both of which displayed associations with SSc in a European population.

Conclusion

We determined that PLD4 is a novel susceptibility gene for SSc in Japanese, thus confirming the involvement of PLD4 in autoimmunity. Associations between SSc and TNFAIP3 or IRF8 were also detected in our Japanese population. SSc and RA appear to share relatively large proportions of their genetic backgrounds.

     

Soluble CD90 as a potential marker of pulmonary involvement in systemic sclerosis

Objective

Vascular injury and endothelial cell (EC) activation are pathogenic hallmarks of systemic sclerosis (SSc; scleroderma). Human CD90 is highly expressed on activated ECs and can be shed from the cell surface. This study was conducted to examine whether soluble CD90 (sCD90) is elevated in the sera of patients with SSc and linked to pulmonary involvement and in particular, pulmonary arterial hypertension (PAH).

Methods

sCD90 serum concentrations were assessed in 76 patients with SSc and related to clinical data, lung function, 6‐minute walk distance, echocardiography, bronchoalveolar lavage fluid, and laboratory parameters. Thirty‐one healthy volunteers and 29 patients with idiopathic retroperitoneal fibrosis (IRF) served as controls.

Results

sCD90 serum concentrations were elevated in patients with SSc compared to healthy volunteers (P = 0.001) and patients with IRF (P = 0.01). SSc patients with pulmonary fibrosis (P = 0.006) and patients with PAH (P < 0.001) had increased sCD90 serum concentrations compared to patients without the respective pulmonary manifestation of SSc. sCD90 levels correlated with diffusing capacity for carbon monoxide (n = 65; r = ?0.348, P = 0.005) and systolic pulmonary artery pressure (n = 53; r = 0.469, P < 0.001). Receiver operating characteristic curve testing determined an optimal cutoff value of ≥626 ng/ml with a sensitivity of 68% and a specificity of 83% for PAH (area under the curve 0.773, 95% confidence interval 0.648–0.898; P < 0.001).

Conclusion

sCD90 concentrations were increased in the sera of SSc patients, particularly in patients with vascular involvement of the lungs. These data suggest that sCD90 should be further evaluated as a marker for diagnosis of PAH in SSc.

     

Association of the IL2RA/CD25 gene with juvenile idiopathic arthritis

Objective

IL2RA/CD25, the gene for interleukin‐2 receptor α, is emerging as a general susceptibility gene for autoimmune diseases because of its role in the development and function of regulatory T cells and the association of single‐nucleotide polymorphisms (SNPs) within this gene with type 1 diabetes mellitus (DM), Graves' disease, rheumatoid arthritis (RA), and multiple sclerosis (MS). The aim of this study was to determine whether SNPs within the IL2RA/CD25 gene are associated with juvenile idiopathic arthritis (JIA).

Methods

Three SNPs within the IL2RA/CD25 gene, that previously showed evidence of an association with either RA, MS, or type 1 DM, were selected for genotyping in UK JIA cases (n = 654) and controls (n = 3,849). Data for 1 SNP (rs2104286) were also available from North American JIA cases (n = 747) and controls (n = 1,161). Association analyses were performed using Plink software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Results

SNP rs2104286 within the IL2RA/CD25 gene was significantly associated with UK JIA cases (OR for the allele 0.76 [95% CI 0.66–0.88], P for trend = 0.0002). A second SNP (rs41295061) also showed modest evidence for association with JIA (OR 0.80 [95% CI 0.63–1.0], P = 0.05). Association with rs2104286 was convincingly replicated in the North American JIA cohort (OR 0.84 [95% CI 0.65–0.99], P for trend = 0.05). Meta‐analysis of the 2 cohorts yielded highly significant evidence of association with JIA (OR 0.76 [95% CI 0.62–0.88], P = 4.9 × 10⁻⁵).

Conclusion

These results provide strong evidence that the IL2RA/CD25 gene represents a JIA susceptibility locus. Further investigation of the gene using both genetic and functional approaches is now required.

     

Association of pruritus with quality of life and disability in systemic sclerosis

Objective

To our knowledge, no studies have investigated the association of pruritus, which is present in almost half of patients with systemic sclerosis (SSc; scleroderma), with quality of life (QOL) and disability. The objective of this study was to investigate the association of pruritus with QOL and disability in SSc.

Methods

We performed a cross‐sectional, multicenter study of 578 SSc patients ≥1 year post–enrollment in the Canadian Scleroderma Research Group Registry. Patients reported whether they experienced pruritus during the past month on most days and underwent clinical histories and medical examinations. QOL was measured using the mental and physical component summary scores of the Short Form 36, and disability was measured with the Health Assessment Questionnaire disability index. The association of pruritus with QOL and disability was estimated using linear regression, controlling for sociodemographic and disease variables.

Results

A total of 248 patients (43%) reported pruritus on most days. Patients with pruritus had significantly worse mental (Hedges's g = ?0.43; 95% confidence interval [95% CI] ?0.59, ?0.26) and physical function (Hedges's g = ?0.51; 95% CI ?0.68, ?0.34) and greater disability (Hedges's g = 0.46; 95% CI 0.29, 0.63) than patients without pruritus. In multivariate analyses, controlling for age, sex, marital status, education, disease duration, skin score, number of tender joints, gastrointestinal symptoms, breathing problems, Raynaud's phenomenon, and finger ulcers, pruritus was independently associated with mental (P = 0.017) and physical function (P = 0.003), but not disability (P = 0.112).

Conclusion

Pruritus is common and associated with QOL in SSc. More attention to pruritus in SSc is needed, including its measurement, etiology, trajectory, and potential methods for intervention.

     

HLA–DRB1*0407 and *1304 are risk factors for scleroderma renal crisis

Objective

To examine the predictive role of HLA genetic markers in scleroderma renal crisis (SRC), beyond the known clinical correlates, in a large population of patients with systemic sclerosis (SSc).

Methods

SSc patients from the Scleroderma Family Registry and DNA Repository, the Genetics versus Environment in Scleroderma Outcomes Study, and the rheumatology division registry at the University of Texas Health Science Center at Houston were included in the study. Relevant clinical data were obtained by chart review, and autoantibodies were detected utilizing commercially available kits. HLA class II genotyping was performed on extracted and purified genomic DNA.

Results

Overall, 1,519 SSc patients were included in the study, of whom 90 (6%) had developed SRC. Among the 90 patients with SRC, the diffuse cutaneous disease subtype was found in 76%, antitopoisomerase antibodies (antitopo) in 9%, anticentromere antibodies (ACAs) in 2%, and anti–RNA polymerase III (anti–RNAP III) in 50% of patients. In multivariate analyses of clinical and demographic parameters, diffuse disease type and anti–RNAP III were strong risk factors for the presence of SRC, whereas ACAs and antitopo were protective. In the final multivariate analysis, which included HLA alleles, HLA–DRB1*0407 (odds ratio [OR] 3.21, 95% confidence interval [95% CI] 1.27–8.08; P = 0.013) and DRB1*1304 (OR 4.51, 95% CI 1.30–15.65; P = 0.018) were identified as independent risk factors for SRC. Only 3 clinical characteristics, diffuse disease type, anti–RNAP III, and ACAs, remained significantly associated with SRC in the final model.

Conclusion

The results of this study suggest that DRB1*0407 and *1304 are independent risk factors, beyond the known clinical correlates, for the development of SRC.

     

Health‐related quality of life in systemic sclerosis: A systematic review

Objective

A number of studies (all n <200) have assessed health‐related quality of life (HRQOL) in patients with systemic sclerosis (SSc), but no systematic review of the effect of SSc on HRQOL has been done. The objective of this study was to systematically review the literature on HRQOL in SSc measured using the Medical Outcomes Trust Short Form 36 (SF‐36).

Methods

A comprehensive search was conducted in August 2007 using Medline, CINAHL, and EMBase to identify original research studies reporting SF‐36 scores of SSc patients. Selected studies were reviewed and characteristics of the study samples and SF‐36 data were extracted. Bayesian meta‐analysis and meta‐regression were performed to obtain pooled estimates of SF‐36 physical component summary (PCS) and mental component summary (MCS) scores for all patients as well as by limited and diffuse disease status.

Results

Twelve data sets with a total of 1,127 SSc patients were included in the systematic review. HRQOL was impaired in patients with SSc, with pooled SF‐36 PCS scores being more than 1 SD below the general population (38.3; 95% credible interval [95% CI] 35.2, 41.5) and pooled SF‐36 MCS scores being ～0.5 SDs below the general population (46.6; 95% CI 44.2, 49.1). SF‐36 PCS scores were 3.5 points (95% CI ?1.0, 8.0) lower in patients with diffuse compared with limited disease.

Conclusion

This study provides robust evidence of the presence and magnitude of impairment in HRQOL in patients with SSc. Although the impairment appears greater in physical health, mental health impairment is also reported.