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Although previous studies have suggested a relationship between telomere shortening and systemic sclerosis (SSc), the association between these two traits remains poorly understood. The objective of this study was to assess the causal relationship between telomere length in leukocytes (LTL) and SSc using the two-sample Mendelian randomization approach, with the genome-wide association study data for both LTL and SSc. The results of inverse-variance weighted regression (OR = 0.716 [95% CI 0.528–0.970], p = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563–0.911], p = 0.035) indicate an association between telomere length and SSc. Specifically, longer genetically predicted LTL is associated with a reduced risk of SSc. Sensitivity tests highlight the significant roles of the variants rs10936599 and rs2736100 annotated to the TERC and TERT genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc.

OBJECTIVES: Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA. METHODS: Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls. CONCLUSIONS: Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway.

CD40, BLK and BANK1 genes involved in the development and signaling of B-cells are identified as susceptibility loci for numerous inflammatory diseases. Accordingly, we assessed the potential influence of CD40, BLK and BANK1 on the pathogenesis of immunoglobulin-A vasculitis (IgAV), predominantly a B-lymphocyte inflammatory condition. Three genetic variants within CD40 (rs1883832, rs1535045, rs4813003) and BLK (rs2254546, rs2736340, rs2618476) as well as two BANK1 polymorphisms (rs10516487, rs3733197), previously associated with inflammatory diseases, were genotyped in 382 Caucasian patients with IgAV and 955 sex- and ethnically matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of CD40, BLK and BANK1 when IgAV patients and healthy controls were compared. Similar results were found when CD40, BLK and BANK1 genotypes or alleles frequencies were compared between patients with IgAV stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. Moreover, no CD40, BLK and BANK1 haplotype differences were disclosed between patients with IgAV and healthy controls and between patients with IgAV stratified according to the clinical characteristics mentioned above. Our findings indicate that CD40, BLK and BANK1 do not contribute to the genetic background of IgAV.

Objectives: To determine if patients with the predominant extracranial large-vessel-vasculitis (LVV) pattern of giant cell arteritis (GCA) have a distinctive HLA-B association, different from that reported in biopsy-proven cranial GCA patients. In a further step we assessed if the combination of HLA-B and HLA-DRB1 alleles confers an increased risk for GCA susceptibility, either for the cranial and extracranial LVV phenotypes. Methods: A total of 184 patients with biopsy-proven cranial GCA, 105 with LVV-GCA and 486 healthy controls were included in our study. We compared HLA-B phenotype frequencies between the three groups. Results: HLA-B*15 phenotype was significantly increased in patients with classic cranial GCA compared to controls (14.7% versus 5.8%, respectively; p<0.01; OR [95% CI] =2.81 [1.54-5.11]). It was mainly due to the HLA-B*15:01 allele (12.5% versus 4.0%, respectively; p<0.01; OR [95% CI] =3.51 [1.77-6.99]) and remained statistically significant after Bonferroni correction. Similar HLA-B*15 association was observed in patients with the LVV-GCA (11.4% versus 5.8%, p=0.04, OR [95% CI] =2.11 [1.04-4.30]). This association was also mainly due to the HLA-B*15:01 allele (10.5% versus 4.0%, respectively; p=0.0054; OR [95% CI] =2.88 [1.19-6.59]). Noteworthy, the presence of HLA-B*15:01 together with HLA-DRB1*04:01 led to an increased risk of developing both cranial and extracranial LVV-GCA. Conclusions: Susceptibility to GCA is strongly related to the HLA region, regardless of the clinical phenotype of expression of the disease.

Objective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation. Conclusions This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression.

Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that the IL33-IL1RL1 signalling pathway does not contribute to the genetic network underlying IgAV.

BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immune-mediated conditions, being BAFF GCTGT>A a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGT>A, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV.

Introduction/Background: The purpose of this study was to evaluate the association between Fracture Risk Assessment Tool (FRAX) and serum fibroblast grow factor-23 (FGF-23) levels in SSc women patients compared with healthy controls. Methodology: This cross-sectional study was performed in San Cecilio Hospital, Granada (Spain) from November 2017 to May 2019. Sixty-two women with SSc and 62 age and sex matched healthy controls were included in this study. FGF-23 serum concentration was evaluated by indirect enzyme-linked immunosorbent assay. The FRAX scoring tool was applied using the on-line calculator (www.shef.ac.uk/FRAX). Results: Even though there was no significant difference in FGF-23 levels between SSc women patients and healthy controls (78.2 ± 60.5 vs 80.3 ± 56.3 pg/mL, p = 0.662). FGF-23 levels were positively associated with FRAX index within the study group. Conclusions: This study shows that FGF-23 status is associated with FRAX index in women with SSc. FGF-23 could be a promising biomarker for detecting risk fracture in SSc women patients.

Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn’s disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.

OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a major regulator of type I interferon induction and is also critical to produce pro-inflammatory cytokines. An influence of IRF5 genetic variants on the increased risk of immune-mediated diseases has been described. Accordingly, we aimed to evaluate the implication of IRF5 in the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. METHODS: Three tag genetic variants (rs2004640, rs2070197 and rs10954213), representative of 3 different haplotype blocks within IRF5, were genotyped in 372 Caucasian patients with IgAV and 876 sex and ethnically matched healthy controls by TaqMan assays. RESULTS: No significant differences in the genotype and allele frequencies between patients with IgAV and healthy controls were observed when each IRF5 polymorphism was evaluated independently. Likewise, no significant differences between patients with IgAV and healthy controls were found when we assessed the three IRF5 polymorphisms combined, conforming haplotypes. In addition, there were no significant differences in genotype, allele and haplotype frequencies of IRF5 when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IRF5 on the pathogenesis of IgAV.

OBJECTIVES: We aimed to compare serum Klotho and fibroblast growth factor-23 (FGF-23) levels between rheumatoid arthritis (RA) patients and healthy controls. Possible association between FGF-23 and soluble Klotho with different characteristic of the disease as well as their potential role as surrogate markers of cardiovascular disease (CVD) were studied. METHODS: Sixty-three patients with RA recruited at Vega-Baja Hospital, Orihuela (Spain) from November 2016 to May 2018 and sixty-five age- and sex-matched healthy controls were included in this study. Serum Klotho and FGF-23 were analysed using ELISA. RESULTS: Patients had higher serum levels of Klotho than healthy controls (p˂0.0001). They were positively associated with the presence of anticitrullinated peptide antibody and rheumatic factor (p<0.05). Klotho serum levels were higher in RA patients treated with biologic agents than in those undergoing conventional therapy (p=0.008). However, no association with carotid intima media thickness was found. Although no significant differences in serum FGF-23 levels between patients and controls were found (p=0.43), FGF-23 levels were positively associated with low-density lipoprotein (LDL-c) level (p<0.05) and smoking (p=0.008) in patients with RA. CONCLUSIONS: The increased serum Klotho levels in RA patients, especially in those undergoing biologic therapy, may indicate a potential implication in the pathogenesis of the disease. Although levels of FGF-23 were related to LDL-c levels, the FGF-23-Klotho axis does not seem to be related to subclinical arteriosclerosis in RA.

OBJECTIVES: Cytokines signaling pathway genes represent a key component of the genetic network implicated in the pathogenesis of immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. Interleukin (IL)17A is described as a genetic risk locus for some autoimmune diseases, such as giant cell arteritis and spondyloarthritis. Accordingly, we aimed to determine the potential influence of IL17A on the pathogenesis of IgAV. METHODS: Five IL17A tag polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909), which cover the major variability of this gene, were genotyped in 360 Caucasian patients with IgAV and 1,003 sex and ethnically matched healthy controls using TaqMan probes. RESULTS: No statistically significant differences between patients with IgAV and healthy controls were observed when each IL17A genetic variant was analysed independently. Similarly, no statistically significant differences between patients with IgAV and healthy controls were found when the five IL17A polymorphisms were evaluated combined conforming haplotypes. In addition, there were no statistically significant differences in genotype, allele and haplotype frequencies of IL17A when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IL17A on the pathogenesis of IgAV.