OBJECTIVE: Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. To date, it is not known whether genes on the sex chromosomes influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Phe functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). This study was undertaken to test for an association between SSc and the IRAK1 SLE risk haplotype. METHODS: We tested for an association with the IRAK1 SLE risk haplotype in a discovery set of 849 SSc patients and 625 controls. IRAK1 rs1059702 was further genotyped in a replication set, which included Caucasian women from Italy (493 SSc patients and 509 controls) and Germany (466 SSc patients and 1,083 controls). RESULTS: An association between the IRAK1 haplotype and SSc was detected in the discovery set. In both the discovery and replication sets, the rs1059702 TT genotype was found to be associated with specific SSc subsets, highlighting a potential contribution to disease severity. A meta-analysis provided evidence of an association of both the T allele and TT genotype with the overall disease, with an odds ratio (OR) of 1.20 and 95% confidence interval (95% CI) of 1.06-1.35 for the T allele (P = 0.003) and an OR of 1.49 and 95% CI of 1.06-2.10 for the TT genotype (P = 0.023). However, the most notable associations were observed with the diffuse cutaneous, anti-topoisomerase I antibody positive, and SSc-related fibrosing alveolitis subsets (OR 2.35 [95% CI 1.51-3.66], P = 1.56 × 10(-4), OR 2.84 [95% CI 1.87-4.32], P = 1.07 × 10(-6), and OR 2.09 [95% CI 1.35-3.24], P = 9.05 × 10(-4), respectively). CONCLUSION: Our study provides the first evidence of an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.
OBJECTIVE: Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. To date, it is not known whether genes on the sex chromosomes influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Phe functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). This study was undertaken to test for an association between SSc and the IRAK1SLE risk haplotype. METHODS: We tested for an association with the IRAK1SLE risk haplotype in a discovery set of 849 SSc patients and 625 controls. IRAK1rs1059702 was further genotyped in a replication set, which included Caucasian women from Italy (493 SSc patients and 509 controls) and Germany (466 SSc patients and 1,083 controls). RESULTS: An association between the IRAK1 haplotype and SSc was detected in the discovery set. In both the discovery and replication sets, the rs1059702 TT genotype was found to be associated with specific SSc subsets, highlighting a potential contribution to disease severity. A meta-analysis provided evidence of an association of both the T allele and TT genotype with the overall disease, with an odds ratio (OR) of 1.20 and 95% confidence interval (95% CI) of 1.06-1.35 for the T allele (P = 0.003) and an OR of 1.49 and 95% CI of 1.06-2.10 for the TT genotype (P = 0.023). However, the most notable associations were observed with the diffuse cutaneous, anti-topoisomerase I antibody positive, and SSc-related fibrosing alveolitis subsets (OR 2.35 [95% CI 1.51-3.66], P = 1.56 × 10(-4), OR 2.84 [95% CI 1.87-4.32], P = 1.07 × 10(-6), and OR 2.09 [95% CI 1.35-3.24], P = 9.05 × 10(-4), respectively). CONCLUSION: Our study provides the first evidence of an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.
Authors: Yu Zhai; Ke Xu; Rui-Xue Leng; Han Cen; Wei Wang; Yan Zhu; Mo Zhou; Chen-Chen Feng; Dong-Qing Ye Journal: Inflamm Res Date: 2013-02-23 Impact factor: 4.575
Authors: Debendra Pattanaik; Monica Brown; Bradley C Postlethwaite; Arnold E Postlethwaite Journal: Front Immunol Date: 2015-06-08 Impact factor: 7.561
Authors: Kenneth M Kaufman; Jian Zhao; Jennifer A Kelly; Travis Hughes; Adam Adler; Elena Sanchez; Joshua O Ojwang; Carl D Langefeld; Julie T Ziegler; Adrienne H Williams; Mary E Comeau; Miranda C Marion; Stuart B Glenn; Rita M Cantor; Jennifer M Grossman; Bevra H Hahn; Yeong Wook Song; Chack-Yung Yu; Judith A James; Joel M Guthridge; Elizabeth E Brown; Graciela S Alarcón; Robert P Kimberly; Jeffrey C Edberg; Rosalind Ramsey-Goldman; Michelle A Petri; John D Reveille; Luis M Vilá; Juan-Manuel Anaya; Susan A Boackle; Anne M Stevens; Barry I Freedman; Lindsey A Criswell; Bernardo A Pons Estel; Joo-Hyun Lee; Ji-Seon Lee; Deh-Ming Chang; R Hal A Scofield; Gary S Gilkeson; Joan T Merrill; Timothy B Niewold; Timothy James Vyse; Sang-Cheol Bae; Marta E Alarcón-Riquelme; Chaim O Jacob; Kathy Moser Sivils; Patrick M Gaffney; John B Harley; Amr H Sawalha; Betty P Tsao Journal: Ann Rheum Dis Date: 2012-08-17 Impact factor: 19.103
Authors: F David Carmona; M Carmen Cénit; Lina-Marcela Diaz-Gallo; Jasper C A Broen; Carmen P Simeón; Patricia E Carreira; José-Luis Callejas-Rubio; Vicente Fonollosa; Francisco J López-Longo; Miguel A González-Gay; Nicolas Hunzelmann; Gabriela Riemekasten; Torsten Witte; Alexander Kreuter; Jörg H W Distler; Rajan Madhok; Paul Shiels; Jacob M van Laar; Annemie J Schuerwegh; Madelon C Vonk; Alexandre E Voskuyl; Carmen Fonseca; Christopher P Denton; Ariane Herrick; Jane Worthington; Frank C Arnett; Filemon K Tan; Shervin Assassi; Timothy R D J Radstake; Maureen D Mayes; Javier Martín Journal: Ann Rheum Dis Date: 2013-02-26 Impact factor: 19.103