This may in part explain the familial co-segregation seen between some of these diseases, for example between T1D and autoimmune thyroid disease [26,43]

This may in part explain the familial co-segregation seen between some of these diseases, for example between T1D and autoimmune thyroid disease [26,43]. whereas the minor allele (A) of em PTPN22 /em rs2476601 confers susceptibility (odds ratio = 1.40). These results confirmed previously described associations with AAV. After meta-analysis, the em PTPN22 /em rs2476601 association was further strengthened (combined em P /em = 4.2 10-7, odds ratio of 1 1.48 for the A allele). The other 9 SNPs, including rs763361 in em CD226 /em , showed no association with AAV. Conclusion Our study of T1D associated SNPs in AAV has confirmed em CTLA4 /em and em PTPN22 /em as susceptibility loci in AAV. These genes encode two key regulators of the immune response and are associated with many autoimmune diseases, including T1D, autoimmune thyroid disease, celiac disease, rheumatoid arthritis, and now AAV. Background Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterised by small vessel inflammation and necrosis, and autoantibodies against specific neutrophil components (ANCA). The anatomical context of the inflamed vessels determines the signs and symptoms of disease. Renal and lung manifestations are common but any organ or system can be affected. AAV includes the clinical syndromes Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss Syndrome (CSS). AAV is a complex disease with both genetic and environmental factors involved in pathogenesis [1]. The magnitude of the increased familial risk is moderate; it is lower than that seen in systemic lupus erythematosus (SLE) or multiple sclerosis, but similar to that observed in rheumatoid arthritis [2]. The genes responsible for most of this risk are unknown [3]. The only consistent HLA association is with em DPB1*0401 /em [4], however many HLA class I and class II molecules have been associated with disease in small non-replicated studies [3]. There is increasing evidence that susceptibility loci are shared Umbralisib R-enantiomer between autoimmune diseases [5]. Therefore, we tested ten candidate loci on the basis of prior replicated associations with T1D [6,7]. The candidate loci tested were em Rabbit Polyclonal to Trk B (phospho-Tyr515) PTPN22 /em , em IFIH1 /em , em CTLA4 /em , em IL2 /em , em CYP27B1 /em , em ERBB3 /em , em SH2B3 /em , Umbralisib R-enantiomer em CLEC16A /em , em PTPN2 /em and em CD226 /em . We have previously reported an association between em IL2RA /em and AAV [8]. Prior evidence supporting association exists for em CTLA4 /em , em PTPN22 /em and em CD226 /em [9-12]. CTLA-4 protein expression on CD4 T cells is increased in WG [13]. Several studies tested em CTLA4 /em for association with WG or AAV. The results of Umbralisib R-enantiomer these studies are conflicting. Giscombe em et al. /em found an association with a SNP at position -318 (rs5742909) using 32 WG patients and 122 controls [9]. Zhou em et al. /em found an association Umbralisib R-enantiomer between WG and shorter (AT)n microsatellite length in the 3’UTR of em CTLA4 /em in a cohort of 117 WG Umbralisib R-enantiomer patients and 123 controls [14]. Slot em et al. /em reported an association with a different SNP at position +49 using 102 AAV patients and 192 controls, and no effect at position -318 or the (AT)n microsatellite [10]. Finally, Spriewald em et al. /em reported no association with either of the SNPs -318 or +49, or the (AT)n microsatellite in the 3’UTR of em CTLA4 /em , using 32 WG patients and 91 controls [15]. The prior em PTPN22 /em report used 199 WG cases and 399 healthy controls and rs2476601 [11]. The em CD226 /em report used 642 German WG patients and 1226 controls, but, in a parallel analysis, did not find an association in a cohort of 105 UK WG patients [12]. We sought to confirm these prior associations, and test the other T1D susceptibility loci, using a collection of 641 AAV cases and 9115 controls. Methods Patients and controls The AAV cohort comprises subjects from four sources, all meeting the Chapel Hill diagnostic criteria [16]: 1. The MRC/Kidney Research UK (KRUK) National DNA Bank for Glomerulonephritis. Individuals were between the ages of 18 and 70 years, were ANCA seropositive, and had biopsy-proven necrotizing glomerulonephritis. 2. The UK vasculitis cohort 2 was recruited from 9 centres in the UK and comprised patients seropositive for ANCA and/or with histological evidence of small vessel vasculitis. 3. Patients recruited from the University of Birmingham. All individuals were ANCA seropositive with firm clinical and/or histological evidence of vasculitis. 4. The Lupus and Vasculitis Service, Addenbrooke’s Hospital, Cambridge. All individuals were ANCA seropositive with firm clinical and/or histological evidence of vasculitis. Genotyping was performed using TaqMan genotyping kits (Applied Biosystems) for each SNP, with fluorescence data captured using an ABI 7900 HT Fast Real-Time PCR System (Applied.