A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility
- Elena López-Isac1,
- Lara Bossini-Castillo1,
- Carmen P Simeon2,
- María Victoria Egurbide3,
- Juan José Alegre-Sancho4,
- Jose Luis Callejas5,
- José Andrés Roman-Ivorra6,
- Mayka Freire7,
- Lorenzo Beretta8,
- Alessandro Santaniello8,
- Paolo Airó9,
- Claudio Lunardi10,
- Nicolas Hunzelmann11,
- Gabriela Riemekasten12,
- Torsten Witte13,
- Alexander Kreuter14,
- Jörg H W Distler15,
- Annemie J Schuerwegh16,
- Madelon C Vonk17,
- Alexandre E Voskuyl18,
- Paul G Shiels19,
- Jacob M van Laar20,
- Carmen Fonseca21,
- Christopher Denton21,
- Ariane Herrick22,
- Jane Worthington22,
- Shervin Assassi23,
- Bobby P Koeleman24,
- Maureen D Mayes23,
- Timothy RDJ Radstake25,
- Javier Martin1Email author and
- Spanish Scleroderma Group
© López-Isac et al.; licensee BioMed Central Ltd. 2014
Received: 12 July 2013
Accepted: 18 December 2013
Published: 9 January 2014
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.
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.
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.
Our results suggest a role of PPARG gene in the development of SSc.
Systemic sclerosis (SSc) is a complex autoimmune disease with heterogeneous clinical manifestations characterized by extensive fibrosis in the skin and multiple internal organs, vascular damage, and immune imbalance with autoantibody production . SSc patients are commonly classified in two major subtypes: limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc), the latter with more progressive fibrosis of the skin, lungs, and other internal organs and, ultimately, with worse prognosis .
The etiology of this disorder is still unclear. However, epidemiologic and genetic studies clearly reflect the existence of a complex genetic component together with the influence of environmental factors . During recent years, great advances have been made in our knowledge of the genetic basis of SSc [3, 4], in part, thanks to the two independent genome-wide associations studies (GWASs) conducted in Caucasian populations that have been recently published [5, 6], and several consequent follow-up studies [7–10].
However, despite these advances, the number of currently known loci explaining the genetic component of SSc is limited. To date, 13 loci have been identified as genetic risk factors for SSc at the genome-wide significance level. In other autoimmune diseases with multifactorial inheritance, such as Crohn disease, ulcerative colitis, or systemic lupus erythematosus, individual GWAS scans and follow-up meta-analyses have identified more than 71, 47, and 35 susceptibility loci, respectively [11–13]. Therefore, it is expected that additional risk factors for SSc remain to be discovered, and further meta-analyses and large replication studies are needed to identify part of the missing heritability of this disease.
Follow-up studies focused on the so-called grey zone of the GWASs, where SNPs with tier 2 associations (P values between 5 × 10-8 and 5 × 10-3) are located, constitute one of the most useful GWAS data-mining methods, because possible real association signals could be masked in that area because of a lack of statistical power. On this basis, we aimed to perform a follow-up study of the SNPs located in the grey zone of the GWAS by Allanore et al. , taking advantage of our GWAS data sets. We hypothesize that using a larger cohort would increase the statistical power and might lead to the identification of new suitable SSc genetic risk factors.
In the first step of this study, we focused on the 90 GWAS-genotyped SNPs that reached a P value < 10-4 in the discovery phase of the GWAS carried out by Allanore et al. . Then, we analyzed the SNPs overlapping with those included in Radstake et al. . After excluding those SNPs located within MHC genes or in previously associated loci, data for 66 SNPs were selected. A meta-analysis including these 66 SNPs was performed on the combined data set from the two SSc GWASs, showing only two SNPs (rs310746 PPARG and rs6832151 CHRNA9 genetic variants) with a P value < 10-5 (see later). These two genetic variants were genotyped in independent replication cohorts. Finally, we performed a meta-analysis for these two selected SNPs combining genotype data from both first and replication steps.
The first step of the study comprised a total of 2,921 SSc patients and 6,963 healthy controls of Caucasian ancestry from two previously published GWASs (European, USA, and French) [5, 6]. The replication cohort was composed of 1,068 SSc patients and 1,490 healthy controls from two case–control sets of European ancestry (Italy and United Kingdom). We also included 5,272 extra English controls from The Wellcome Trust Case Control Consortium for the replication step comprising a total of 6,762 controls for this stage.
All SSc patients fulfilled the classification criteria by LeRoy et al. . Approval from the local ethical committees (Comité de Bioética del Consejo Superior de Investigaciones Científicas, U.O. Comitato di Etica e Sperimentazione Farmaci Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico di Milano, Comitato Etico Azienda Ospedaliera Universitaria Integrata di Verona, The Ethics Committee of the Spedali Civili, Brescia, Royal Free Hospital and Medical School Research Ethics Committee, Manchester University Research Ethics Committee, Local Research Ethics Committee at Glasgow Royal Infirmary, Newcastle University Ethics Committee, Ethical Committee of the University Erlangen-Nuremberg, Local Ethics Committee of the Radboud University Nijmegen Medical Centre, Medical Ethics Review Committee of the VU University, Medische Ethische Commissie Leids Universitair Medisch Centrum, Ethics Review Board of the Ruhr University Bochum, Ethics Committee of the University of Cologne, Ethical Committee from the Charité University Hospital, Ethik-Kommission der MHH, Internal Review Board of Texas University), and written informed consents from all participants were obtained in accordance with the tenets of the Declaration of Helsinki.
In the first stage, genotype data for the 66 selected SNPs were obtained from both published SSc GWASs [5, 6]. QC filters and principal component analysis were applied to the GWASs data, as described in Radstake et al.  and Allanore et al..
In the replication phase, DNA from patients and controls was obtained by using standard methods. Genotyping was performed by using TaqMan 5′ allele discrimination predesigned assays from Applied Biosystems (rs310746 ID: C___8756618_10; rs6832151 ID: C__29224385_10, Foster City, CA, USA) in both 7900HT Fast Real-Time PCR System (Applied Biosystems, Foster City, C A, USA), and LightCycler 480 Real-Time PCR System (Roche Applied Science, Mannheim, Germany). Genotyping call rate was > 98% for both genotyped SNPs.
Association analyses of the genotype data was carried out with StatsDirect V.2.6.6 (StatsDirect, Altrincham, UK) and PLINK V.1.07  software. Statistical significance was calculated by 2 × 2 contingency tables and χ2 or Fisher Exact test, when necessary, to obtain P values, odds ratios (ORs), and 95% confidence intervals (CIs) in the population-specific analyses. Mantel-Haenszel tests under fixed effects or random effects, when appropriate, were performed to meta-analyze the combined data. Breslow–Day method (BD) was used to assess the homogeneity of the associations among the different populations (Breslow–Day P values <0.05 were considered statistically significant). Hardy-Weinberg equilibrium (HWE) was tested for all cohorts (HWE P values lower than 0.01 were considered to show significant deviation from the equilibrium). None of the included cohorts showed significant deviation from HWE for the two genotyped SNPs. Since the analyses were performed by using GWAS data, the statistical threshold for considering a P value as a significant P value in the allelic association analyses was set at 5 × 10-8.
The statistical power of the combined analysis was 70% for the PPARG rs310746 and 100% for the CHRNA9 rs6832151 to detect associations with OR = 1.3 and a statistical significance of 5 × 10-8, according to Power Calculator for Genetic Studies 2006 software .
Meta-analysis of 66 GWAS-genotyped SNPs in scleroderma (SSc) patients and healthy controls of Caucasian origin
OR (CI 95%)a
CHRNA9 | RHOH
Analysis of rs310746 and rs6832151 minor allele frequencies in the GWASs, replication, and combined cohorts
OR (CI 95%)a
In this study we conducted a meta-analysis combining previously published SSc GWASs data for 66 SNPs and analyzed the possible role of two selected SNPs, PPARG rs310746 and CHRNA9 rs6832151, in SSc risk by using independent replication cohorts.
Meta-analyses are a useful tool to increase the statistical power of genetic studies, thus improving the accuracy of the estimations of statistical significance. Of note, associations identified from a single GWAS often tend to have inflated effect sizes . On this basis, our data suggest that most signals from the grey zone observed in the discovery phase of the GWAS by Allanore et al.  presented inflated effect sizes, also called the winner’s curse. In fact, this effect was already observed in the replication study conducted by our group for the novel SSc genetic risk factors identified by Allanore et al. , in which we could not replicate the association described for RHOB.
Our overall combined meta-analysis showed that the association of the PPARG rs310746 genetic variant with SSc remained with a nominal but non-genome-wide significant P value. This SNP is located upstream of PPARG, which encodes the peroxisome proliferator-activated receptor gamma (PPARG). PPARG was initially identified in adipose tissue, where this nuclear receptor plays important roles in adipogenesis, insulin sensitivity, and homeostasis . Interestingly, during recent years, several studies have identified a novel role of PPARG as an antifibrotic effector. Thus, it has been reported that fibroblasts exposure to pharmacologic PPARG ligands give rise to suppression of collagen synthesis, myofibroblast differentiation, and other TGF-β-induced fibrotic responses in vitro[19–21]. Moreover, functional studies showed that PPARG agonist attenuated dermal fibrosis in mice with bleomycin-induced scleroderma [22, 23].
These findings are remarkable in SSc, in which fibrosis is one of the main hallmarks of the disease. In this regard, Wei et al.  demonstrated that PPARG expression and function are impaired in SSc patients. Therefore, defects in PPARG expression may influence the uncontrolled progression of fibrosis in SSc. In addition, PPARG has been associated with other autoimmune diseases, such as inflammatory bowel disease [25, 26] and psoriatic arthritis , and it is also a confirmed susceptibility locus in type 2 diabetes mellitus .
Although PPARG was the most likely biologic candidate gene for the reported suggestive association signal, we could not rule out TIMP4 as another possible gene for this signal. Further analyses are required to elucidate the functional implication of the reported signal.
Regarding the CHRNA9 genetic variant, despite the suggestive association found in the first step of the present study, the overall combined meta-analysis did not show evidence of association with SSc. Moreover, the effect size of the analyzed genetic variant was heterogeneous between the different populations. Although our data showed heterogeneity and lack of association in this locus, a slight or modest effect of CHRNA9 cannot be ruled out, and further studies will be required to determine whether this region is associated with SSc.
It is worth mentioning that the analyzed CHRNA9 SNP has been previously associated with Graves disease (first, through a GWAS performed in the Chinese Han population , and subsequently, in a replication study performed in a Polish Caucasian population ), but this is the only reported association between this gene and an autoimmune disease.
In conclusion, we report a suggestive association between PPARG rs310746 and SSc. However, further studies are needed to establish this locus firmly as a new susceptibility SSc genetic risk factor.
- BD test:
cholinergic receptor nicotinic, Alpha 9
diffuse cutaneous systemic sclerosis
genome-wide association study
Human leukocyte antigen
limited cutaneous systemic sclerosis
minor allele frequency
major histocompatibility complex
polymerase chain reaction
peroxisome proliferator-activated receptor gamma
single nucleotide polymorphism
transforming growth factor.
We thank Sofia Vargas, Sonia García, and Gema Robledo for their 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.
This work was supported by the following grants: JM was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 and SAF2012-34435 from the Spanish Ministry of Economy and Competitiveness, CTS-4977, and CTS-180 from Junta de Andalucía, and is sponsored by the Orphan Disease Program grant from the European League Against Rheumatism (EULAR). This study was also funded by PI-0590-2010, from Consejería de Salud y Bienestar Social, Junta de Andalucía, Spain. JLCR and JM are funded by Consejería de Salud, Junta de Andalucía, through PI-0590-2010. ELI was supported by Ministerio de Educación, Cultura y Deporte through the program FPU. TRDJR was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). TW was granted by DFG WI 1031/6.1. Study on USA samples were supported by US National Institutes of Health and National Institute of Arthritis and Musculoskeletal Diseases (NIH-NIAMS) R01-AR-055258, Two-Stage Genome Wide Association Study in Systemic Sclerosis (MDM) and by the NIH-NIAMS Center of Research Translation (CORT) in SSc (P50AR054144) (MDM, FCA, FKT), the NIH-NIAMS SSc Family Registry and DNA Repository (N01-AR-0-2251) (MDM), NIH-KL2RR024149 (SA), K23AR061436 (SA), and the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-07-01-0111) (MDM).
Spanish Scleroderma Group
Spanish Scleroderma Group: Norberto Ortego-Centeno and Raquel Ríos, Unidad de Enfermedades Sistémicas Autoinmunes, Department of Internal Medicine, Hospital Clínico Universitario San Cecilio, Granada; Nuria Navarrete, Department of Internal Medicine, Hospital Virgen de las Nieves, Granada; Rosa García Portales, Department of Rheumatology, Hospital Virgen de la Victoria, Málaga; María Teresa Camps, Department of Internal Medicine, Hospital Carlos Haya, Málaga; Antonio Fernández-Nebro, Department of Rheumatology, Hospital Carlos Haya, Málaga; María F. González-Escribano, Department of Immunology, Hospital Virgen del Rocío, Sevilla; Julio Sánchez-Román, Francisco José García-Hernández and Mª Jesús Castillo, Department of Internal Medicine, Hospital Virgen del Rocío, Sevilla; Mª Ángeles Aguirre and Inmaculada Gómez-Gracia, Department of Rheumatology, Hospital Reina Sofía/IMIBIC, Córdoba; Patricia Carreira, Department of Rheumatology. Hospital Universitario 12 de Octubre, Madrid; Benjamín Fernández-Gutiérrez and Luis Rodríguez-Rodríguez, Department of Rheumatology, Hospital Clínico San Carlos, Madrid; Esther Vicente, Department of Rheumatology, Hospital La Princesa, Madrid; José Luis Andreu and Mónica Fernández de Castro, Department of Rheumatology, Hospital Puerta de Hierro Majadahonda, Madrid; Paloma García de la Peña, Department of Rheumatology, Hospital Madrid Norte Sanchinarro, Madrid; Francisco Javier López-Longo and Lina Martínez, Department of Rheumatology, Hospital General Universitario Gregorio Marañón, Madrid; Vicente Fonollosa and Carmen Pilar Simeón, Department of Internal Medicine, Hospital Valle de Hebrón, Barcelona; Gerard Espinosa, Department of Internal Medicine, Hospital Clinic, Barcelona; Iván Castellví, Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, Barcelona; Carlos Tolosa, Department of Internal Medicine, Hospital Parc Tauli, Sabadell; Anna Pros, Department of Rheumatology, Hospital Del Mar, Barcelona; Mónica Rodríguez Carballeira, Department of Internal Medicine, Hospital Universitari Mútua Terrasa, Barcelona; Francisco Javier Narváez, Department of Rheumatology, Hospital Universitari de Bellvitge, Barcelona; Manel Rubio Rivas, Department of Internal Medicine, Hospital Universitari de Bellvitge, Barcelona; Vera Ortiz Santamaría, Department of Rheumatology, Hospital General de Granollers, Granollers; Miguel Ángel González-Gay, Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander; Bernardino Díaz and Luis Trapiella, Department of Internal Medicine, Hospital Central de Asturias, Oviedo; Adrián Sousa, Unidad de Trombosis y Vasculitis, Department of Internal Medicine, Hospital Xeral-Complexo Hospitalario Universitario de Vigo, Vigo; Patricia Fanlo Mateo, Department of Internal Medicine Hospital Virgen del Camino, Pamplona; Luis Sáez-Comet, Unidad de Enfermedades Autoinmunes Sistémicas, Department of Internal Medicine, Hospital Universitario Miguel Servet, Zaragoza; Federico Díaz and Vanesa Hernández, Department of Rheumatology, Hospital Universitario de Canarias, Tenerife; Emma Beltrán, Department of Rheumatology, Hospital General Universitario de Valencia, Valencia; and Francisco J. Blanco García and Natividad Oreiro, Department of Rheumatology, INIBIC-Hospital Universitario A Coruña, La Coruña.
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