Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Olga Y Gorlova ,Monique Hinchcliff,J Lee Nelson,Nicolas Hunzelmann,Shervin Assassi,Annette T Lee,Blanca Rueda,Marie Vanthuyne,Peter K Gregersen,Filip De Keyser,Benedicte A Lie,Øyvind Palm,J Hummers,Paul G Shiels,Annet Italiaander,Meng May Chee,Roger Hesselstrand,Carmen Fonseca,Leonid Padyukov,Christopher P Denton,Rajan Madhok,Maureen D Mayes,Annemie J Schuerwegh,Alexander Kreuter,Jane Worthington,Christopher I Amos,Madelon C Vonk,Bobby P C Koeleman,John Varga,Torsten Witte,Frank C Arnett,Vanessa Smith,Pravitt Gourh,Filemon K Tan,Laura K Hummers,Roel A Ophoff,Elfride De Baere,Frederick M Wigley,Claudio Lunardi,Timothy R D J Radstake,Raffaella Scorza,Paloma García De La Peña,Alexandre E Voskuyl,Lorenzo Beretta,Behrooz Z Alizadeh,Ruben Van ’T Slot ,Marieke J.h Coenen ,Ariane L Herrick ,Jasper Broen ,Miguel A González‐Gay ,María Teruel ,Ying Jin ,Norbérto Ortego-Centeno ,Lina‐Marcela Diaz‐Gallo ,V Fonollosa ,Annica Nordin ,F Houssiau ,José-Ezequiel Martín ,Sandeep K Agarwal ,René Westhovens ,Carmen P Simeón ,Jacob M Van Laar ,Francisco J García–Hernández ,Anna‐Maria Hoffmann‐Vold ,G Riemekasten ,Paolo Airò ,María Francisca González‐Escribano ,Patrícia Carreira ,P.l.c.m Van Riel ,Javier Martı́n

doi:10.1371/journal.pgen.1002178

Abstract

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10−12, OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10−6, OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10−7, OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10−61, OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10−76, OR = 8.84), and in NOTCH4 with ACA P = 8.84×10−21, OR = 0.55) and ATA (P = 1.14×10−8, OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

Highlights

Genetic factors play an essential role in scleroderma or systemic sclerosis (SSc) etiology as in most complex autoimmune diseases [1]
The discovery of genetic variants associated with specific clinical manifestations of the disease will lead to new insights regarding pathogenesis and may open novel avenues of therapy that can be targeted to specific subsets
The aim of this study was to assess the genetic component involved in four different SSc clinical and auto-antibody subphenotypes through an analysis of our previous genome-wide association study (GWAS) data stratified for these disease subphenotypes, together with a large, new replication study

Summary

Introduction

Genetic factors play an essential role in scleroderma or systemic sclerosis (SSc) etiology as in most complex autoimmune diseases [1]. SSc patients are classified into two clinical subgroups based on the extent of skin involvement, limited SSc (lcSSc) and diffuse SSc (dcSSc) that are associated with different clinical complications and prognoses [17] Another SSc hallmark is the presence of disease specific and usually mutually exclusive auto-antibodies that correlate both with the extent of skin involvement and the various disease manifestations, such as pulmonary fibrosis and renal crisis [18]. The most common are DNA topoisomerase I (ATA), and anti-centromere antibodies (CENP A and/or B proteins) [19] Each of these auto-antibodies is a marker for relatively distinct clinical subgroups of SSc, with anticentromere typically associated with limited cutaneous disease, uncommon pulmonary fibrosis, late-onset pulmonary hypertension but generally an overall good prognosis, while ATA is a marker for diffuse skin disease and clinically significant pulmonary fibrosis with a resultant poorer prognosis

Objectives

Methods

Results

Conclusion