KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor.

INTRODUCTION: Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicentre Caucasian SSc cohort.METHODS:2,343 SSc cases (179 PAH positive, confirmed by right heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single nucleotide polymorphism (SNP) was genotyped using a TaqMan SNP genotyping assay.RESULTS:Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (e.g. limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled-analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH positive group. The comparison of PAH positive patients versus PAH negative patients showed no significant differences among patients.CONCLUSIONS:Our data do not support an important role of KCNA5 as a SSc susceptibility factor or as a PAH development genetic marker for SSc patients

Confirmation of association of the macrophage migration inhibitory factor gene with systemic sclerosis in a large European population.

OBJECTIVES The aim of this study was to confirm the implication of macrophage migration inhibitory factor (MIF) gene in SSc susceptibility or clinical phenotypes in a large European population. METHODS: A total of 3800 SSc patients and 4282 healthy controls of white Caucasian ancestry from eight different European countries were included in the study. The MIF -173 single nucleotide polymorphism (SNP) was selected as genetic marker and genotyped using Taqman 5' allelic discrimination assay. RESULTS: The MIF -173 SNP showed association with SSc [P\u2009=\u20090.04, odds ratio (OR)\u2009=\u20091.10, 95% CI 1.00, 1.19]. Analysis of the MIF -173 polymorphism according to SSc clinical phenotype revealed that the frequency of the -173*C allele was significantly higher in the dcSSc group compared with controls (P\u2009=\u20095.30E-03, OR\u2009=\u20091.21, 95% CI 1.07, 1.38). Conversely, the frequency of the MIF -173*C allele was significantly underrepresented in the lcSSc group compared with dcSSc patients, supporting previous findings [(P\u2009=\u20090.04, OR\u2009=\u20090.86, 95% CI 0.75, 0.99); meta-analysis including previous results (P\u2009=\u20090.005, OR\u2009=\u20090.83, 95% CI 0.73, 0.94)]. CONCLUSION: Our results confirm the role of MIF -173 promoter polymorphism in SSc, and provide evidence of a strong association with the dcSSc subgroup of patients. Hence, the MIF -173 variant is confirmed as a promising clinical phenotype genetic marker

Functional impairment of systemic scleroderma patients with digital ulcerations: results from the DUO Registry

Objective. Digital ulcers (DUs) are frequent manifestations of systemic scleroderma (SSc). This study assessed functional limitations due to DUs among patients enrolled in the Digital Ulcer Outcome (DUO) Registry, an international, multicentre, observational registry of SSc patients with DU disease. Methods. Patients completed at enrolment a DU-specific functional assessment questionnaire with a 1-month recall period, measuring impairment in work and daily activities, and hours of help needed from others. Physician-reported clinical parameters were used to describe the population. For patients who completed at least part of the questionnaire, descriptive analyses were performed for overall results, and stratified by number of DUs at enrolment. Results. This study included 2327 patients who completed at least part of the questionnaire. For patients with 0, 1-2, and DUs at enrolment, mean overall work impairment during the prior month among employed/self-employed patients was 28\%, 42\%, and 48\%, respectively. Across all included patients, ability to perform daily activities was impaired on average by 35\%, 54\%, and 63\%, respectively. Patients required a mean of 2.0, 8.7, and 8.8 hours of paid help and 17.0, 35.9, and 63.7 hours of unpaid help, respectively, due to DUs in the prior month. Patients with DUs had more complications and medication use than patients with no DUs. Conclusion. With increasing number of DUs, SSc patients reported more impairment in work and daily activities and required more support from others