KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor
Arthritis Research & Therapy volume 14, Article number: R273 (2012)
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 multicenter Caucasian SSc cohort.
The 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.
Individual 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.
Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients.
Systemic sclerosis (SSc) is a life-threatening fibrotic connective tissue disorder that affects the skin and different internal organs . The 10-year survival of SSc patients reaches only 63%, with pulmonary involvement the leading cause of death . SSc is a complex disorder in which the environmental triggers and genetic susceptibility factors co-act in the development and maintenance of the disease . As a clearer picture of the genetic component of this disease is being revealed, interest in genetic markers for specific clinical features, especially lung involvement, is increasing. An SSc phenotype-restricted genome-wide analysis was carried out recently . Remarkably, 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 . However, no such strategy has yet been considered for pulmonary involvement, and only some studies have reported significant genetic association with SSc-related lung involvement [5–9]. Furthermore, only the association of CD226 with pulmonary fibrosis has been independently replicated . Wipff et al.  recently described the association of potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) with SSc-related pulmonary arterial hypertension (PAH).
Potassium voltage-gated channels (Kv channels) are homo- or heterotetramers of structural α-subunits and regulatory β-subunits, which control potassium (K) flux. K balance is known to regulate the apoptotic cell shrinkage, a main event in the apoptotic process . Specifically, KCNA5 participates in pulmonary artery smooth muscle cell (PASMC) apoptosis control . It has been reported that overexpression of the KCNA5 gene induces accelerated K efflux and increases caspase-3 proteolytic activity, promoting apoptosis .
KCNA5 is also involved in membrane-potential maintenance and vascular-tone regulation . Hypoxic conditions produce a specific inhibition of KCNA5 in the PASMCs, causing pulmonary vasoconstriction [15–17]. Moreover, it has been reported that primary pulmonary hypertension patients have an intrinsic reduced level of KCNA5 mRNA in their PASMCs, and this characteristic might play an important role in the pathogenesis of the disease .
The role of KCNA5 genetic polymorphisms in pulmonary disease also was explored. Remillard et al.  analyzed the influence of KCNA5 genetic variants in IPAH, and showed that different single-nucleotide polymorphisms (SNPs) were related to abnormal function or drug responsiveness. Recently, the importance of KCNA5 variants in SSc-related PAH was analyzed . In the previously mentioned study, the association of KCNA5 with SSc and specifically with PAH-positive (PAH+) patients was described . Moreover, the rs10744676 polymorphism was reported as the variant underlying the observed association .
In light of the previous evidence, the main goal of this report is to replicate the association of KCNA5 rs10744676 polymorphism with SSc and SSc-related PAH in an independent European population of Caucasian ancestry.
Materials and methods
Our study comprised 2,343 SSc cases and 2,690 controls from Spain, The Netherlands, Italy, Sweden, and The United Kingdom. All the individuals included in this report were of Caucasian ancestry. Patients were classified as having limited (lcSSc) or diffuse SSc (dcSSc), according to their skin involvement, as defined by LeRoy et al. . The serologic subgroup stratification of the patients was based on the presence of SSc-associated autoantibodies (anti-centromere antibodies (ACAs) and anti-topoisomerase (ATA)). Pulmonary fibrosis was diagnosed by the presence of interstitial abnormalities in high-resolution computed tomography (HRCT). Patients defined as PAH+ showed a mean resting pulmonary artery pressure > 25 mm Hg and a pulmonary capillary wedge pressure ≤15 mm Hg, at the time of a right-heart catheterization . The control population consisted of unrelated healthy individuals recruited in the same geographic regions as the SSc patients and matched by age, sex, and ethnicity with the SSc-patient groups. Approval of local ethical committees was obtained from all the participating centers (Comité de Bioética del Consejo Superior de Investigaciones Científicas, Comitato Etico Azienda Ospedaliera Universitaria Integrata di Verona, Local Ethics Committee of the Radboud University Nijmegen Medical Centre, Medische Ethische Commissie Leids Universitair Medisch Centrum, The regional Ethical Review Board in Lund, Local Research Ethics Committee at Glasgow Royal Infirmary, U.O. Comitato di Etica e Sperimentazione Farmaci Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico di Milano, Local Research Ethics Committee at Glasgow Royal Infirmary, Royal Free Hospital and Medical School Research Ethics Committee, Manchester University Research Ethics Committee). Written informed consent was required for both patients and controls to be included in the study.
Genotyping and statistical analysis
The rs10744676 KCNA5 biallelic variant was analyzed with TaqMan SNP genotyping assay in a 7900HT Real-Time polymerase chain reaction (PCR) system from Applied Biosystems by following the manufacturer's suggestions (Foster City, CA, USA).
None of the included cohorts showed significant deviation from Hardy-Weinberg equilibrium (HWE) (P value significance threshold, 0.05). Significance for the allelic model in the individual cohort analyses was calculated by 2 × 2 contingency tables and the Fisher Exact test or χ2 when necessary. Odds ratios (ORs) were calculated according to the Woolf method. A Breslow-Day test (BD test) was performed to assess the homogeneity of the association among populations, and pooled analysis under a Cochran-Mantel-Haenszel fixed-effect model was used to analyze jointly all the included cohorts. Statistical analyses were performed as implemented in PLINK (v1. 07) software package . Power was calculated by using the software Power Calculator for Genetic Studies 2006 and assuming an additive model and previously reported minor allele frequency (MAF) and ORs .
The power of our replication study in each stratified analysis is summarized in Table 1. We emphasize that the size of our pooled PAH+ patient subgroup represents the largest 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.
Table 2 shows the results of the comparison of the complete set of SSc and each of the previously defined subgroups with the healthy control group. As observed in the table, the analyzed polymorphism showed no significant association with either the disease or any of the subsets, not even the PAH-positive group. Furthermore, no significant association was observed in the individual population analyses, either in the whole disease comparison or in the different subphenotypes (see Additional file 1, Table S1). The different cohorts showed a high interpopulation combinability, as can be observed in the Breslow-Day test results (Table 2).
The minor allele in the Spanish and Italian control populations included in this study was less frequent than that in the pooled population described by the Wipff et al. (rs10744676*C FrequencySpain = 10.48%; rs10744676*C FrequencyItaly = 10.00%; rs10744676*C Frequencypooled_Wipff = 14.7%). However, these frequencies are in concordance with those reported for the HapMap CEU population (MAFHapMap_CEU = 10.00%). Moreover, MAF differences have been reported in different European populations (MAF1000Genomes_CEU = 17.64%, MAF1000Genomes_GBR = 15.73%, MAF1000Genomes_FIN = 13.98%, MAF1000Genomes_TSI = 8.16%).
In addition, the analysis of PAH+ versus PAH- patients revealed no phenotype-restricted association in this subgroup (PMH = 0.59; OR, 0.91; 95% CI, 0.64 to 1.28).
Despite the previous findings of an association of the rs10744676 KCNA5 genetic variant with PAH+ SSc patients, our data do not corroborate the reported protective effect of the minor allele of this polymorphism on SSc-related PAH.
It is worth mentioning that the prevalence of right-heart catheterization-confirmed PAH in our pooled population (7.64%) is consistent with previous reports . However, SSc is a chronic progressive disease, and some patients classified as PAH- might develop PAH in the future. Therefore, we consider this issue a limitation of our study and similar reports. In this context, we point out that the mean disease duration for the patient group included in this study (mean disease duration, 13.9 ± 14.4 years, as reported in Bossini-Castillo et al. ) was higher than that in Wipff et al.  (11.9 ± 9.4 years in the discovery cohort and 13.9 ± 14.4 years in the replication), which might influence the observed differences.
The PAH+ cohort studied in this report reached a 95% estimated statistical power to detect an association equivalent to that observed by Wipff et al. within this subgroup (OR, 0.47, in the comparison between PAH+ SSc patients and controls of the discovery phase and two replication steps ). Hence, we consider that the lack of replication observed in our study is unlikely to be caused by a type II error (false negative) because of a reduced statistical power. However, autoimmune-associated variants usually show modest degrees of risk, especially in the case of non-HLA loci . Wipff et al. reported an OR for KCNA5 rs10744676 polymorphism that was remarkably more protective than the SSc genetic-association standards for non-HLA loci (that is, modest ORs between 0.70 and 1). Thus, we reflect that if the influence of rs10744676 in the SSc-patient genetic predisposition to PAH is modest, the statistical power to detect a possible association in the PAH+ cohort analyzed in the present article might be insufficient, and a possible modest effect of KCNA5 rs10744676 might be overlooked (Table 1).
In addition, it is established that PAH is more frequent in ACA+ patients , and despite the suggestive association with PAH+ patients, no significant association with the ACA+ subphenotype was identified in the previous SSc study  or in this report. This fact is also consistent with a lack of association of the selected polymorphism with PAH development.
Although rs10744676 might have a functional role in KCNA5 expression because of its location in its putative promoter, no evidence confirms a functional role for this variant. Therefore, we speculate that the previously mentioned association with SSc could be the consequence of a tagged causal variant yet to be discovered. Moreover, because PAH onset time has not been considered for the analyses, it might act as a confounding factor in the discrepant results.
In summary, our data do not support an important role of rs10744676 as a PAH genetic marker in SSc patients.
- BD test:
- CD226 :
cluster of differentiation 226
Utah residents with ancestry from northern and western Europe
diffuse cutaneous systemic sclerosis
High-resolution computed tomography
- KCNA5 :
potassium voltage-gated channel shaker-related subfamily member 5
- Kv channels:
potassium voltage-gated channels
limited cutaneous systemic sclerosis
minor allele frequency
- NOTCH4 Notch (Drosophila:
) homologue 4
pulmonary arterial hypertension
pulmonary artery smooth muscle cell
polymerase chain reaction
- SOX5 :
SRY (sex-determining region Y)-box 5
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We thank Sofia Vargas, Sonia García, and Gema Robledo for excellent technical assistance and all the patients and control donors for their essential collaboration. We thank Banco Nacional de ADN (University of Salamanca, Spain), who supplied part of the control DNA samples. We are also thankful to EUSTAR (The EULAR Scleroderma Trials and Research group for the facilitation of this project. We thank the following Spanish Scleroderma Group members for their contribution in this study: Norberto Ortego-Centeno and Raquel Ríos, Unidad de Enfermedades Sistémicas Autoinmunes, Servicio de Medicina Interna, Hospital Clínico Universitario San Cecilio, Granada; Nuria Navarrete, Servicio de Medicina Interna, Hospital Virgen de las Nieves, Granada; Antonio Fernández-Nebro, Servicio de Medicina Reumatología, Hospital Carlos Haya, Málaga; María F. González-Escribano, Servicio de Inmunología, Hospital Virgen del Rocío, Sevilla; Julio Sánchez-Román, Mª Jesús Castillo and Francisco José García-Hernández, Servicio de Medicina Interna, Hospital Virgen del Rocío, Sevilla; Mª Ángeles Aguirre and Inmaculada Gómez-Gracia, Servicio de Reumatología, Hospital Reina Sofía, Córdoba; Benjamín Fernández-Gutiérrez, Servicio de Reumatología, Hospital Clínico San Carlos, Madrid; José Luis Andreu and Mónica Fernández de Castro, Servicio de Reumatología, Hospital Puerta del Hierro, Madrid; Paloma García de la Peña, Servicio de Reumatología, Hospital Madrid Norte Sanchinarro, Madrid; Francisco Javier López-Longo and Lina Martínez, Servicio de Reumatología, Hospital General Universitario Gregorio Marañón, Madrid; Vicente Fonollosa, Servicio de Medicina Interna, Hospital Valle de Hebrón, Barcelona; Gerard Espinosa, Servicio de Medicina Interna, Hospital Clinic, Barcelona; Anna Pros, Servicio de Reumatología, Hospital Del Mar, Barcelona; Mónica Rodríguez Carballeira, Servicio de Medicina Interna, Hospital Universitari Mútua Terrasa, Barcelona; Francisco Javier Narváez, Servicio de Reumatología, Hospital Universitari de Bellvitge, Barcelona; Bernardino Díaz, Luis Trapiella and María Gallego, Servicio de Medicina Interna, Hospital Central de Asturias, Oviedo; María del Carmen Freire and Inés Vaqueiro, Unidad de Trombosis y Vasculitis, Servicio de Medicina Interna, Hospital Xeral-Complexo Hospitalario Universitario de Vigo, Vigo; Luis Sáez-Comet, Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitario Miguel Servet, Zaragoza; Federico Díaz and Vanesa Hernández, Servicio de Reumatología, Hospital Universitario de Canarias, Tenerife; Juan José Alegre, Servicio de Reumatología, Hospital del Doctor Peset Aleixandre, Valencia; José Andrés Román-Ivorra, Servicio de Reumatología, Hospital Universitari i Politecnic La Fe, Valencia. Francisco J. Blanco-García and Natividad Oreiro, Servicio de Reumatología, INIBIC-Hospital Universitario A Coruña, La Coruña.
This work was supported by the following grants: JM was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain, in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain, and by Fondo Europeo de Desarrollo Regional (FEDER). TRDJR was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). JM and TRDJR were sponsored by the Orphan Disease Program grant from the European League Against Rheumatism (EULAR). BPCK is supported by the Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). This study was also funded by PI-0590-2010, Consejería de Salud, Junta de Andalucía, Spain.
The authors declare that they have no competing interests.
LBC contributed to the analysis and interpretation of data and to the drafting of the manuscript. CPS, LB, and JB participated in the acquisition of data and the drafting of the manuscript. CF, TRDJR, and JM contributed to the conception and design of the study and critically revised the manuscript. MCV, JLC, PC, LRR, RGP, MAGG, IC, MTC, CT, EVR, MVE, AJS, RH, CL, JMvL, PS, AH, JW, CD, and the Spanish Scleroderma Group were involved in the acquisition of data and the revision of the manuscript. All authors read and approved the final manuscript.
Carmen Fonseca and Javier Martin contributed equally to this work.
Electronic supplementary material
Additional file 1: Genotype and minor allele frequencies of KCNA5 rs10744676 genetic variant in five European cohorts. This file contains Table S1, showing the genotype and allele distributions of KCNA5 rs10744676 genetic variant in five European cohorts (2,343 SSc cases and 2,690 controls). (DOC 71 KB)
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Bossini-Castillo, L., Simeon, C.P., Beretta, L. et al. KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor. Arthritis Res Ther 14, R273 (2012). https://doi.org/10.1186/ar4124