title: New insight on the Xq28 association with systemic sclerosis.
abstract: OBJECTIVE
  To 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).
  
  
  METHODS
  We 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.
  
  
  RESULTS
  IRAK1 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).
  
  
  CONCLUSIONS
  Our 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.
authors: Instituto de Parasitología y Biomedicina 'López-Neyra', CSIC, , Granada, Spain.
authors: F David
authors: FD
authors: Carmona
authors: M Carmen
authors: MC
authors: Cénit
authors: Lina-Marcela
authors: LM
authors: Diaz-Gallo
authors: Jasper C A
authors: JC
authors: Broen
authors: Carmen P
authors: CP
authors: Simeón
authors: Patricia E
authors: PE
authors: Carreira
authors: José-Luis
authors: JL
authors: Callejas-Rubio
authors: Vicente
authors: V
authors: Fonollosa
authors: Francisco J
authors: FJ
authors: López-Longo
authors: Miguel A
authors: MA
authors: González-Gay
authors: Nicolas
authors: N
authors: Hunzelmann
authors: Gabriela
authors: G
authors: Riemekasten
authors: Torsten
authors: T
authors: Witte
authors: Alexander
authors: A
authors: Kreuter
authors: Jörg H W
authors: JH
authors: Distler
authors: Rajan
authors: R
authors: Madhok
authors: Paul
authors: P
authors: Shiels
authors: Jacob M
authors: JM
authors: van Laar
authors: Annemie J
authors: AJ
authors: Schuerwegh
authors: Madelon C
authors: MC
authors: Vonk
authors: Alexandre E
authors: AE
authors: Voskuyl
authors: Carmen
authors: C
authors: Fonseca
authors: Christopher P
authors: CP
authors: Denton
authors: Ariane
authors: A
authors: Herrick
authors: Jane
authors: J
authors: Worthington
authors: Frank C
authors: FC
authors: Arnett
authors: Filemon K
authors: FK
authors: Tan
authors: Shervin
authors: S
authors: Assassi
authors: Timothy R D J
authors: TR
authors: Radstake
authors: Maureen D
authors: MD
authors: Mayes
authors: Javier
authors: J
authors: Martín
mesh_terms: D016022:Case-Control Studies; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D015810:Linkage Disequilibrium; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000235:genetics; D045743:Scleroderma, Diffuse / Q000235:genetics; D012595:Scleroderma, Systemic / Q000150:complications / Q000235:genetics*
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: Autoimmune Diseases; Gene Polymorphism; Systemic Sclerosis