1. New insight on the Xq28 association with systemic sclerosis
- Author
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Maureen D. Mayes, Gabriela Riemekasten, Alexandre E. Voskuyl, V. Fonollosa, Jane Worthington, Madelon C. Vonk, Miguel A. González-Gay, Christopher P. Denton, José Luis Callejas-Rubio, Alexander Kreuter, Javier Martin, F. David Carmona, Annemie J. Schuerwegh, Jasper C A Broen, Patricia Carreira, Rajan Madhok, Timothy R D J Radstake, Paul G. Shiels, Lina-Marcela Diaz-Gallo, Frank C. Arnett, Jörg H W Distler, Carmen P. Simeon, Nicolas Hunzelmann, Jacob M van Laar, Torsten Witte, Filemon K. Tan, M. Carmen Cénit, Carmen Fonseca, Shervin Assassi, Ariane L. Herrick, Francisco Javier López-Longo, Rheumatology, and CCA - Disease profiling
- Subjects
medicine.medical_specialty ,Linkage disequilibrium ,Methyl-CpG-Binding Protein 2 ,Pulmonary Fibrosis ,Immunology ,Genome-wide association study ,Polymorphism, Single Nucleotide ,Gastroenterology ,Article ,Linkage Disequilibrium ,General Biochemistry, Genetics and Molecular Biology ,Gene Frequency ,Rheumatology ,Medizinische Fakultät ,Polymorphism (computer science) ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Genetic Predisposition to Disease ,ddc:610 ,Chromosomes, Human, X ,Scleroderma, Systemic ,Lupus erythematosus ,business.industry ,Haplotype ,Case-control study ,Genetic Diseases, X-Linked ,medicine.disease ,Connective tissue disease ,Interleukin-1 Receptor-Associated Kinases ,Haplotypes ,Case-Control Studies ,Scleroderma, Diffuse ,Evaluation of complex medical interventions Auto-immunity, transplantation and immunotherapy [NCEBP 2] ,Female ,Gene polymorphism ,business - Abstract
ObjectiveTo evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2).MethodsWe analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc.ResultsIRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10−3, OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10−4, OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF− (p=0.025, OR=1.26, 95% CI 1.03 to 1.55).ConclusionsOur data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.
- Published
- 2013
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