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.

Susceptibility of autoimmune diseases in three polymorphisms of infection-associated gene IRAK1

“…Three SNPs of IRAK1 have been found to be related to ADs risk: rs3027898 for RA [15,22], rs1059702 for SSc [23,24] and rs1059703 for SLE [14,25]. However, the results remain in conflict.…”

“…Four races were included: Caucasian, Asian, African, and Latin-American. Four studies were not in HWE in control groups [14,15,23,24]. …”

Roles of Methyl-CpG Binding Protein 2 in Immune Function

“…However, evidence suggests that MeCP2 is not only related to Rett syndrome and MeCP2 duplication syndrome, but may also contribute to primary immunologic disorders, such as systemic lupus erythematosus (SLE) (Kaufman et al, 2013;Koelsch et al, 2013;Sawalha et al, 2008;Webb et al, 2009), primary Sjogren's syndrome (Cobb et al, 2010), systemic sclerosis (Carmona et al, 2013), and rheumatoid arthritis (Han et al, 2013).…”

“…However, studies using mice that specifically overexpress only MeCP2, and not IRAK1, have demonstrated that MeCP2 significantly influences immune function on its own (Koelsch et al, 2013;Yang et al, 2012 (Koelsch et al, 2013;Yang et al, 2012), but also MeCP2 loss-of-function / Rett syndrome (Cronk et al, 2015a;Cronk et al, 2015b;Derecki et al, 2012;Horiuchi et al, 2016;Jiang et al, 2014;Jin et al, 2015;Li et al, 2014;Maezawa and Jin, 2010;O'Driscoll et al, 2013b;O'Driscoll et al, 2015), and potentially even other immunologic disorders outside of either Rett or MeCP2 duplication (Carmona et al, 2013;Cobb et al, 2010;Han et al, 2013;Kaufman et al, 2013;Koelsch et al, 2013;Sawalha et al, 2008;Webb et al, 2009). …”

“…The functional comparison between MeCP2 alleles associated with autoimmune disease (Carmona et al, 2013;Cobb et al, 2010;Han et al, 2013;Kaufman et al, 2013;Koelsch et al, 2013;Sawalha et al, 2008;Webb et al, 2009), MeCP2 mutations resulting in Rett syndrome (Christodoulou et al, 2003), and Xq28 duplication in MeCP2 duplication syndrome (Ramocki et al, 2010) …”