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Lina-Marcela Diaz-Gallo,
Carmen P Simeon, Jasper C Broen,
Norberto Ortego-Centeno,
Lorenzo Beretta,
Madelon C Vonk,
Patricia E Carreira,
Sofia Vargas,
José Andrés Román-Ivorra,
Miguel A González-Gay, [......],
Jane Worthington,
Christopher P Denton,
Xiaodong Zhou,
Frank C Arnett,
Carmen Fonseca,
Bobby Pc Koeleman,
Shervin Assasi,
Timothy R D J Radstake,
Maureen D Mayes,
Javier Martín
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). PATIENTS AND METHODS: The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. RESULTS: We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (p(c)=6.6E-4 and p(c)=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (p(c)=1.7E-03 and p(c)=8E-4, respectively). CONCLUSIONS: These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.
Annals of the rheumatic diseases 11/2012; · 8.11 Impact Factor
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Jose-Ezequiel Martin, Jasper C Broen,
F David Carmona,
Maria Teruel,
Carmen P Simeon,
Madelon C Vonk,
Ruben van 't Slot,
Luis Rodriguez-Rodriguez,
Esther Vicente,
Vicente Fonollosa, [......],
Ariane Herrick,
Christopher Denton,
Filemon K Tan,
Frank C Arnett,
Shervin Assassi,
Carmen Fonseca,
Maureen D Mayes,
Timothy R D J Radstake,
Bobby P C Koeleman,
Javier Martin
[show abstract]
[hide abstract]
ABSTRACT: Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value = 5.04 × 10(-12), odds ratio (OR) = 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value = 3.18 × 10(-7), OR = 1.36) and NFKB1 (P-value = 1.03 × 10(-6), OR = 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones.
Human Molecular Genetics 03/2012; 21(12):2825-35. · 7.64 Impact Factor
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Olga Gorlova,
Jose-Ezequiel Martin,
Blanca Rueda,
Bobby P C Koeleman,
Jun Ying,
Maria Teruel,
Lina-Marcela Diaz-Gallo, Jasper C Broen,
Madelon C Vonk,
Carmen P Simeon, [......],
Carmen Fonseca,
Christopher P Denton,
Peter K Gregersen,
Sandeep Agarwal,
Shervin Assassi,
Filemon K Tan,
Frank C Arnett,
Timothy R D J Radstake,
Maureen D Mayes,
Javier Martin
PLoS Genetics 08/2011; 7(8). · 8.69 Impact Factor
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Olga Gorlova,
Jose-Ezequiel Martin,
Blanca Rueda,
Bobby P C Koeleman,
Jun Ying,
Maria Teruel,
Lina-Marcela Diaz-Gallo, Jasper C Broen,
Madelon C Vonk,
Carmen P Simeon, [......],
Carmen Fonseca,
Christopher P Denton,
Peter K Gregersen,
Sandeep Agarwal,
Shervin Assassi,
Filemon K Tan,
Frank C Arnett,
Timothy R D J Radstake,
Maureen D Mayes,
Javier Martin
[show abstract]
[hide abstract]
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.
PLoS Genetics 07/2011; 7(7):e1002178. · 8.69 Impact Factor
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Timothy R D J Radstake,
Olga Gorlova,
Blanca Rueda,
Jose-Ezequiel Martin,
Behrooz Z Alizadeh,
Rogelio Palomino-Morales,
Marieke J Coenen,
Madelon C Vonk,
Alexandre E Voskuyl,
Annemie J Schuerwegh, [......],
Laura Hummers,
J Lee Nelson,
Sandeep K Agarwal,
Shervin Assassi,
Pravitt Gourh,
Filemon K Tan,
Bobby P C Koeleman,
Frank C Arnett,
Javier Martin,
Maureen D Mayes
[show abstract]
[hide abstract]
ABSTRACT: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.
Nature Genetics 04/2010; 42(5):426-9. · 35.53 Impact Factor
