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

Lara Bossini‐Castillo ,Carlos Tolosa,Carmen Fonseca,Lorenzo Beretta,Jasper Broen,Rosa García-Portales,Roger Hesselstrand,Claudio Lunardi,Jacob M Van Laar,Jane Worthington,Luis Rodríguez‐Rodríguez ,Esther F Vicente-Rabaneda ,Christopher P Denton ,Miguel A González‐Gay ,Timothy R D J Radstake ,Madelon C Vonk ,María Teresa Camps ,Iván Castellví ,Ariane L Herrick ,Paul G Shiels ,José Luis Callejas ,María Victoria Egurbide ,Carmen P Simeón ,Annemie J Schuerwegh ,Patrícia Carreira ,Javier Martín

doi:10.1186/ar4124

Abstract

IntroductionPotassium 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 multicenter Caucasian SSc cohort.MethodsThe 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 by using a TaqMan SNP genotyping assay.ResultsIndividual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, 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 with PAH-negative patients showed no significant differences among patients.ConclusionsOur data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients.

Highlights

Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction
We emphasize that the size of our pooled pulmonary arterial hypertension (PAH)+ patient subgroup represents the largest systemic sclerosis (SSc)-related PAH+ cohort analyzed to date (n = 179)
The power of the study of this clinical feature in our population to detect an association equivalent to that previously reported by Wipff et al is 95%, at the 5% significance level

Summary

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. Two of the four new SSc genetic-susceptibility markers identified in the previously mentioned study might play a relevant role in the SSc-related fibrotic process, SOX5 and NOTCH4 [4]. No such strategy has yet been considered for pulmonary involvement, and only some studies have reported significant genetic association with SScrelated lung involvement [5,6,7,8,9]. Wipff et al [11] recently described the association of potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) with SSc-related pulmonary arterial hypertension (PAH)

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