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.

     

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.

     

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.     

Heritability of vasculopathy,autoimmune disease,and fibrosis in systemic sclerosis: A population‐based study

Objective

To investigate the familiality of systemic sclerosis (SSc) in relation to Raynaud's phenomenon (RP) (a marker of vasculopathy), other autoimmune inflammatory disease, and fibrotic interstitial lung disease (ILD).

Methods

A genealogic resource, the Utah Population Database (UPDB), was used to test heritability of RP, other autoimmune disease, and ILD. Diseases were defined by International Classification of Diseases, Ninth Revision codes and identified from statewide discharge data, the University of Utah Health Science Center Enterprise Data Warehouse, and death certificates and were linked to the UPDB for analysis. Familial standardized incidence ratio (FSIR), relative risks (RRs) to first‐, second‐, third‐, and fourth‐degree relatives for SSc, RP, other autoimmune disease, and ILD (with 95% confidence intervals [95% CIs]), and population attributable risk (PAR) were calculated.

Results

A software kinship analysis tool was used to analyze 1,037 unique SSc patients. Fifty SSc families had significant FSIRs, ranging from 2.07 to 17.60. The adjusted PAR was ∼8%. The RRs were significant for other autoimmune disease in the first‐degree relatives (2.49 [95% CI 1.99–3.41], P = 2.42 × 10⁻¹⁵) and second‐degree relatives (1.48 [95% CI 1.34–2.39], P = 0.002), for RP in first‐degree relatives (6.38 [95% CI 3.44–11.83], P = 4.04 × 10⁻⁹) and second‐degree relatives (2.39 [95% CI 1.21–4.74], P = 0.012), and for ILD in first‐degree relatives (1.53 [95% CI 1.04–2.26], P = 0.03), third‐degree relatives (1.47 [95% CI 1.18–1.82], P = 0.0004), and fourth‐degree relatives (1.2 [95% CI 1.06–1.35], P = 0.004).

Conclusion

These data suggest that SSc pedigrees include more RP, autoimmune inflammatory disease, and ILD than would be expected by chance. In SSc pedigrees, genetic predisposition to vasculopathy is the most frequent risk among first‐degree relatives.

     

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.

     

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.

     

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.

     

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.

     

Determining the Risk Factors and Clinical Features Associated With Severe Gastrointestinal Dysmotility in Systemic Sclerosis

Objective

A subset of patients with systemic sclerosis (SSc) develop severe gastrointestinal (GI) dysmotility. We sought to determine predictors of severe SSc GI dysmotility and to identify distinct features associated with this phenotype.

Methods

Patients with SSc who required supplemental nutrition (enteral or parenteral tube feeding) were compared to SSc patients with mild GI symptoms in a cross‐sectional analysis. The association between severe GI dysmotility and clinical and serologic features was examined using logistic regression. Baseline data were examined to determine predictors of developing severe GI dysfunction using Cox regression.

Results

SSc patients with severe GI dysmotility (n = 66) were more likely than those patients with mild GI symptoms (n = 1,736) to be male (odds ratio [OR] 2.47 [95% confidence interval (95% CI) 1.34–4.56]; P = 0.004), and to have myopathy (OR 5.53 [95% CI 2.82–10.82]; P < 0.001), and sicca symptoms (OR 2.40 [95% CI 1.30–4.42]; P = 0.005), even after adjustment for potential confounders. Baseline features that were associated with the future development of severe GI dysfunction included male sex (hazard ratio [HR] 2.99 [95% CI 1.53–5.84]; P = 0.001) and myopathy (HR 5.08 [95% CI 2.21–11.67]; P < 0.001).

Conclusion

Distinct clinical features are present in SSc patients who are at risk of developing severe GI dysmotility. This finding is not only important clinically but also suggests that a unique pathologic process is at work in these patients.

     

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.

     

BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4

Objective

To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene–gene interactions between BANK1 and IRF5 as well as STAT4.

Methods

BANK1 single‐nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls.

Results

The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64–0.93) and an OR of 0.73 (95% CI 0.61–0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A‐T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57–0.86], P = 3.39 × 10⁻⁴) and the G‐C haplotype to be a risk factor (OR 1.25 [95% CI 1.06–1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43‐fold.

Conclusion

Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects.

     

Increased frequency of DRB1*11:01 in anti–hydroxymethylglutaryl‐coenzyme A reductase–associated autoimmune myopathy

Objective

To investigate the association of anti–hydroxymethylglutaryl‐coenzyme A reductase (anti‐HMGCR) myopathy with HLA class I and II antigens.

Methods

HLA antigens were determined in 1) 20 white and 8 African American anti‐HMGCR patients, 2) 487 white and 167 African American controls, and 3) 51 white subjects with mild self‐limited statin intolerance.

Results

White anti‐HMGCR patients had a higher frequency of the combination HLA–DR11, DQA5, and DQB7 than controls or statin‐intolerant subjects (70% versus 17%; odds ratio [OR] 11.7 [95% confidence interval (95% CI) 4.0–35.3], P = 4.1 × 10^?7 and 70% versus 21%; OR 8.3 [95% CI 2.2–33.9], P = 5.4 × 10^?4, respectively). This combination was not increased in African American anti‐HMGCR subjects compared to controls (13% versus 3%; OR 4.6 [95% CI 0.2–53.3], P = 0.2). However, DR11 was increased in African American anti‐HMGCR patients compared to controls (88% versus 21%; OR 26.4 [95% CI 3.1–590.3], P = 0.0002). High‐resolution mapping showed that 95% with DR11 had DRB1*11:01. DQA1 and DQB6 were less frequent in white anti‐HMGCR–positive patients compared to controls (25% versus 65%; OR 0.2 [95% CI 0.1–0.5], P = 5.5 × 10^?4 and 0% versus 45%; OR 0.0 [95% CI 0.0–0.3], P = 2.1 × 10^?5, respectively). DRB11 was not associated with particular disease features.

Conclusion

DRB1*11:01 is associated with an increased risk of anti‐HMGCR myopathy in whites and African Americans. These findings suggest a mechanistic link between statin exposure, increased HMGCR expression, and the possible presentation of HMGCR‐derived peptide(s) by DRB1*11:01.

     

Combination of Capillaroscopic and Ultrasonographic Evaluations in Systemic Sclerosis: Results of a Cross‐Sectional Study

Objective

To compare microvascular damages on nailfold capillaroscopy (NFC) with macrovascular manifestations evaluated by hand power Doppler ultrasonography (PDUS) in systemic sclerosis (SSc) patients, and to assess the associations of these damages with the main digital manifestations of the disease: digital ulcers, acroosteolysis, and calcinosis.

Methods

NFC, hand radiographs, and PDUS were systematically performed in 64 unselected SSc patients. PDUS evaluation with assessment of ulnar artery occlusion (UAO) and finger pulp blood flow (FPBF) were performed blinded for the results of radiographs and NFC.

Results

UAO and pathologic FPBF were associated with severe capillary loss (<4 capillaries/mm) on NFC (odds ratio [OR] 4.04 [95% confidence interval (95% CI) 1.23–13.29]; P < 0.05, and OR 3.38 [95% CI 1.03–11.05]; P < 0.05, respectively). Digital ulcer history was associated with UAO (OR 10.71 [95% CI 3.36–34.13]; P < 0.0001), pathologic FPBF (OR 7.67 [95% CI 2.52–23.28]; P < 0.0001), late NFC pattern (OR 6.33 [95% CI 2.03–19.68]; P = 0.001), and severe capillary loss (OR 8.52 [95% CI 2.15–33.78]; P = 0.001). Acroosteolysis was also associated with UAO (OR 15.83 [95% CI 3.95–63.54]; P < 0.0001), pathologic FPBF (OR 5.52 [95% CI 1.71–17.90]; P = 0.003), late NFC pattern (OR 6.86 [95% CI 2.18–21.53]; P = 0.001), and severe capillary loss (OR 7.20 [95% CI 2.16–24.02]; P = 0.001). Calcinosis on radiographs was associated with late NFC pattern (OR 5.41 [95% CI 1.82–16.12]; P = 0.002), severe capillary loss (OR 12.69 [95% CI 3.14–51.26]; P < 0.0001), and UAO (OR 3.19 [95% CI 1.14–8.92]; P = 0.025). Combination of UAO and severe capillary loss in the same patient was especially associated with digital ulcer history (OR 18.60 [95% CI 2.24–154.34]; P = 0.001) and acroosteolysis (OR 10.83 [95% CI 2.56–45.88]; P = 0.001).

Conclusion

Microvascular damages evaluated by NFC and macrovascular features like UAO assessed by PDUS show concordant associations with the main digital manifestations of the disease.

     

Nonconcordance between subclinical atherosclerosis and the calculated Framingham risk score in HIV‐infected patients: relationships with serum markers of oxidation and inflammation

Objectives

HIV‐infected patients show an increased cardiovascular disease (CVD) risk resulting, essentially, from metabolic disturbances related to chronic infection and antiretroviral treatments. The aims of this study were: (1) to evaluate the agreement between the CVD risk estimated using the Framingham risk score (FRS) and the observed presence of subclinical atherosclerosis in HIV‐infected patients; (2) to investigate the relationships between CVD and plasma biomarkers of oxidation and inflammation.

Methods

Atherosclerosis was evaluated in 187 HIV‐infected patients by measuring the carotid intima‐media thickness (CIMT). CVD risk was estimated using the FRS. We also measured the circulating levels of interleukin‐6, monocyte chemoattractant protein‐1 (MCP‐1) and oxidized low‐density lipoprotein (LDL), and paraoxonase‐1 activity and concentration.

Results

There was a weak, albeit statistically significant, agreement between FRS and CIMT (κ=0.229, P<0.001). A high proportion of patients with an estimated low risk had subclinical atherosclerosis (n=66; 56.4%). In a multivariate analysis, the presence of subclinical atherosclerosis in this subgroup of patients was associated with age [odds ratio (OR) 1.285; 95% confidence interval (CI) 1.084–1.524; P=0.004], body mass index (OR 0.799; 95% CI 0.642–0.994; P=0.044), MCP‐1 (OR 1.027; 95% CI 1.004–1.050; P=0.020) and oxidized LDL (OR 1.026; 95% CI 1.001–1.051; P=0.041).

Conclusion

FRS underestimated the presence of subclinical atherosclerosis in HIV‐infected patients. The increased CVD risk was related, in part, to the chronic oxidative stress and inflammatory status associated with this patient population.

     

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.

     

Association of the interleukin‐1 gene cluster with radiographic signs of osteoarthritis of the hip

Objective

To study the role of the interleukin‐1β gene (IL1B) and the IL‐1 receptor antagonist gene (IL1RN) in relation to the occurrence of radiographic osteoarthritis (ROA) in the hip, knee, and hand and disc degeneration of the spine.

Methods

The study population consisted of a random sample of 886 subjects (ages 55–65 years) from a population‐based cohort (the Rotterdam study). Two polymorphisms within IL1B (3953C>T and −511C>T) and one within IL1RN (the variable‐number tandem repeat [VNTR]) were analyzed and used in an association study of the occurrence of ROA. Haplotyping and simultaneous logistic regression analysis were performed to investigate whether the associations observed were independent.

Results

Associations with a predisposition for hip ROA were observed for heterozygous and homozygous carriers of the rare IL1B allele −511T (crude odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.0–3.4 and OR 2.9, 95% CI 1.4–6.3, respectively) and of the IL1RN VNTR allele 2 (crude OR 2.0, 95% CI 1.1–3.4 and OR 3.3, 95% CI 1.4–7.8, respectively). An additive effect was observed for carriers of risk alleles of both polymorphisms, with a significant linear‐by‐linear association (P = 0.00022).

Conclusion

Our findings suggest that the IL‐1 gene cluster polymorphisms may play a significant role in the pathogenesis of OA of the hip.

     

Association of the PD‐1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope

Objective

To study the frequency of allele A of polymorphism PD‐1.3 of the PDCD1 gene in patients with rheumatoid arthritis (RA) and its subsets, based on the presence of rheumatoid factor (RF) and the shared epitope (SE) alleles.

Methods

A total of 1,175 patients with RA and 3,404 controls were genotyped for the PD‐1.3 A/G polymorphism, which previously was identified as being involved in susceptibility to systemic lupus erythematosus (SLE) in patients of European descent.

Results

We first detected a trend for association of allele A of the single‐nucleotide polymorphism PD‐1.3 with RA (P = 0.053, odds ratio [OR] 1.18, 95% confidence interval [95% CI] 0.99–1.41). To further clarify the nature of this association, patients with RA were divided into 4 groups according to the presence of RF and the SE alleles. Association was found only in the group of patients negative for both RF and the SE alleles (P = 0.0054 [corrected P = 0.015], OR 1.75, 95% CI 1.15–2.65).

Conclusion

Patients negative for both RF and the SE alleles showed association with the same allele that we previously identified as being involved in susceptibility to SLE. These results provide the first evidence of the involvement of the human PDCD1 gene in arthritis.

     

Atherosclerosis in systemic sclerosis: A systematic review and meta‐analysis

Objective

Systemic sclerosis (SSc) is characterized by calcification, vasculopathy, and endothelial wall damage, all of which can increase the risk of developing atherosclerosis and cardiovascular disease. The aim of this study was to perform a systematic review and meta‐analysis to determine whether the risk of atherosclerosis is increased in SSc patients compared to healthy individuals.

Methods

A systematic search was performed to identify studies published in PubMed and the Cochrane database up to May 2010, and recently published abstracts were also reviewed. Two reviewers independently screened articles to identify studies comparing the rate of atherosclerosis in SSc patients to that in healthy controls. The studies utilized one of the following methods: angiography, Doppler ultrasound to assess plaque and carotid intima‐media thickness (IMT), computed tomography, magnetic resonance imaging, flow‐mediated vasodilation (assessed as the FMD%), the ankle–brachial index, or autopsy. For carotid IMT and FMD% values, we computed a pooled estimate of the summary mean difference and explored predictors of carotid IMT using random‐effects meta‐regression.

Results

Of the 3,156 articles initially identified, 31 were selected for systematic review. The meta‐analysis included 14 studies assessing carotid IMT and 7 assessing brachial artery FMD%. Compared to healthy controls, SSc patients had a higher prevalence of coronary atherosclerosis, peripheral vascular disease, and cerebrovascular calcification. Meta‐analysis showed that SSc patients had increased carotid IMT (summary mean difference 0.11 mm, 95% confidence interval [95% CI] 0.05 mm, 0.17 mm; P = 0.0006) and lower FMD% (summary mean difference −3.07%, 95% CI −5.44%, −0.69%; P = 0.01) compared to controls. There was marked heterogeneity between the studies, which was mainly attributable to variations in disease duration and differences in the mean/median age between SSc patients and controls.

Conclusion

Patients with SSc have an increased risk of atherosclerosis compared to healthy subjects. Further studies should elucidate the mechanism of this increased risk.

     

Association of a transmembrane polymorphism of Fcγ receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients

Objective

To investigate the possible association of the Fcγ receptor IIb (FcγRIIb) Ile/Thr187 transmembrane domain polymorphism, which significantly affects receptor signaling, with susceptibility to systemic lupus erythematosus (SLE) in Taiwanese patients.

Methods

We used matrix‐assisted laser desorption ionization−time‐of‐flight mass spectrometry to genotype 351 Taiwanese SLE patients and 372 age‐ and sex‐matched healthy individuals from the same geographic area. Allele frequencies and genotype distributions were compared between the patients and controls, both as an aggregate and as stratified by sex, autoantibody profile, and clinical parameters. A combined analysis was conducted to assess the FCGR2B Thr187 allele as a common risk factor in different ethnic populations.

Results

The minor Thr187 allele was significantly associated with SLE in Taiwanese subjects (P = 0.017, odds ratio [OR] 1.989 [95% confidence interval (95% CI) 1.119–3.553]). Interestingly, male SLE patients showed enrichment of the Thr/Thr187 genotype (24%; 7 of 29) as compared with female SLE patients (10%; 32 of 322) (P = 0.043, OR 2.884 [95% CI 1.028–7.839]). Additionally, SLE patients with Thr/Thr187 and Ile/Thr187 genotypes were more likely to have pleural effusions (P = 0.038, OR 1.874 [95% CI 1.033–3.411]) and anti‐SSA/Ro antibody production (P = 0.046, OR 2.221 [95% CI 1.013–4.897]). Combined analysis of 4 groups of Asian patients strongly supported the association of the FCGR2B Thr187 allele with the lupus phenotype (P = 0.000159).

Conclusion

The FcγRIIb transmembrane polymorphism is a strong disease susceptibility candidate in epistasis with other genetic effects in Taiwanese and other Asian populations. It may also play a more prominent role in male patients with SLE.