A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc

Early- versus late-onset systemic sclerosis. Differences in clinical presentation and outcome in 1037 patients

Peak age at onset of systemic sclerosis (SSc) is between 20 and 50 years, although SSc is also described in both young and elderly patients. We conducted the present study to determine if age at disease onset modulates the clinical characteristics and outcome of SSc patients. The Spanish Scleroderma Study Group recruited 1037 patients with a mean follow-up of 5.2 ± 6.8 years. Based on the mean ± 1 standard deviation (SD) of age at disease onset (45 ± 15 yr) of the whole series, patients were classified into 3 groups: age ≤ 30 years (early onset), age between 31 and 59 years (standard onset), and age ≥ 60 years (late onset). We compared initial and cumulative manifestations, immunologic features, and death rates. The early-onset group included 195 patients; standard-onset group, 651; and late-onset, 191 patients. The early-onset group had a higher prevalence of esophageal involvement (72% in early-onset compared with 67% in standard-onset and 56% in late-onset; p = 0.004), and myositis (11%, 7.2%, and 2.9%, respectively; p = 0.009), but a lower prevalence of centromere antibodies (33%, 46%, and 47%, respectively; p = 0.007). In contrast, late-onset SSc was characterized by a lower prevalence of digital ulcers (54%, 41%, and 34%, respectively; p < 0.001) but higher rates of heart conduction system abnormalities (9%, 13%, and 21%, respectively; p = 0.004). Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients (p = 0.010). After correction for the population effects of age and sex, standardized mortality ratio was shown to be higher in younger patients. The results of the present study confirm that age at disease onset is associated with differences in clinical presentation and outcome in SSc patients

Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE)

Aim: Patients with systemic sclerosis (SSc) are at increased risk of cancer, a growing cause of non-SSc-related death among these patients. We analyzed the increased cancer risk among Spanish patients with SSc using standardized incidence ratios (SIRs) and identified independent cancer risk factors in this population. Material and methods: Spanish Scleroderma Registry data were analyzed to determine the demographic characteristics of patients with SSc, and logistic regression was used to identify cancer risk factors. SIRs with 95% confidence intervals (CIs) relative to the general Spanish population were calculated. Results: Of 1930 patients with SSc, 206 had cancer, most commonly breast, lung, hematological, and colorectal cancers. Patients with SSc had increased risks of overall cancer (SIR 1.48, 95% CI 1.36-1.60; P < 0.001), and of lung (SIR 2.22, 95% CI 1.77-2.73; P < 0.001), breast (SIR 1.31, 95% CI 1.10-1.54; P = 0.003), and hematological (SIR 2.03, 95% CI 1.52-2.62; P < 0.001) cancers. Cancer was associated with older age at SSc onset (odds ratio [OR] 1.22, 95% CI 1.01-1.03; P < 0.001), the presence of primary biliary cholangitis (OR 2.35, 95% CI 1.18-4.68; P = 0.015) and forced vital capacity <70% (OR 1.8, 95% CI 1.24-2.70; P = 0.002). The presence of anticentromere antibodies lowered the risk of cancer (OR 0.66, 95% CI 0.45-0.97; P = 0.036). Conclusions: Spanish patients with SSc had an increased cancer risk compared with the general population. Some characteristics, including specific autoantibodies, may be related to this increased risk

Cross-disease Meta-analysis of Genome-wide Association Studies for Systemic Sclerosis and Rheumatoid Arthritis Reveals IRF4 as a New Common Susceptibility Locus

Objectives: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that share clinical and immunological characteristics. To date, several shared SSc- RA loci have been identified independently. In this study, we aimed to systematically search for new common SSc-RA loci through an inter-disease meta-GWAS strategy. Methods: We performed a meta-analysis combining GWAS datasets of SSc and RA using a strategy that allowed identification of loci with both same-direction and opposingdirection allelic effects. The top single-nucleotide polymorphisms (SNPs) were followed-up in independent SSc and RA case-control cohorts. This allowed us to increase the sample size to a total of 8,830 SSc patients, 16,870 RA patients and 43,393 controls. Results: The cross-disease meta-analysis of the GWAS datasets identified several loci with nominal association signals (P-value < 5 x 10-6), which also showed evidence of association in the disease-specific GWAS scan. These loci included several genomic regions not previously reported as shared loci, besides risk factors associated with both diseases in previous studies. The follow-up of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these two diseases (Pcombined = 3.29 x 10-12). In addition, the analysis of the biological relevance of the known SSc-RA shared loci pointed to the type I interferon and the interleukin 12 signaling pathways as the main common etiopathogenic factors. Conclusions: Our study has identified a novel shared locus, IRF4, for SSc and RA and highlighted the usefulness of cross-disease GWAS meta-analysis in the identification of common risk loci

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 +/- 20.6% vs 93.6 +/- 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 +/- 5.2 mm vs 19.9 +/- 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P &lt; 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 ± 5.2 mm vs 19.9 ± 6.7 mm, P &lt; 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P &lt; 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P &lt; 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals

Registry of the Spanish network for systemic sclerosis: survival, prognostic factors, and causes of death

Systemic sclerosis (SSc) is a rare, multisystem disease showing a large individual variability in disease progression and prognosis. In the present study, we assess survival, causes of death, and risk factors of mortality in a large series of Spanish SSc patients. Consecutive SSc patients fulfilling criteria of the classification by LeRoy were recruited in the survey. Kaplan-Meier and Cox proportional-hazards models were used to analyze survival and to identify predictors of mortality. Among 879 consecutive patients, 138 (15.7%) deaths were registered. Seventy-six out of 138 (55%) deceased patients were due to causes attributed to SSc, and pulmonary hypertension (PH) was the leading cause in 23 (16.6%) patients. Survival rates were 96%, 93%, 83%, and 73% at 5, 10, 20, and 30 years after the first symptom, respectively. Survival rates for diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc were 91%, 86%, 64%, and 39%; and 97%, 95%, 85%, and 81% at 5, 10, 20, and 30 years, respectively (log-rank: 67.63, P < 0.0001). The dcSSc subset, male sex, age at disease onset older than 65 years, digital ulcers, interstitial lung disease (ILD), PH, heart involvement, scleroderma renal crisis (SRC), presence of antitopoisomerase I and absence of anticentromere antibodies, and active capillaroscopic pattern showed reduced survival rate. In a multivariate analysis, older age at disease onset, dcSSc, ILD, PH, and SRC were independent risk factors for mortality. In the present study involving a large cohort of SSc patients, a high prevalence of disease-related causes of death was demonstrated. Older age at disease onset, dcSSc, ILD, PH, and SRC were identified as independent prognostic factors