Presentation: PTPN22 and IRF5 Alleles in Wegener’s Granulomatosis (WG) (2007)

2000 PTPN22 and IRF5 Alleles in Wegener’s Granulomatosis (WG)

BACKGROUND: There is increasing evidence for an autoimmune diathesis in WG. Recently, two non-MHC loci have been conclusively shown to associate with other systemic autoimmune diseases; PTPN22 with RA and IRF5 with SLE. Indeed, the minor allele of the PTPN22 R620W (rs2476601) polymorphism has been associated with susceptibility to multiple autoimmune diseases including Type 1Diabetes, RA, SLE and Autoimmune Thyroid Disease in Caucasian populations.
PURPOSE: We have examined the distribution of these autoimmune susceptibility loci in a large cohort of Caucasian patients with WG and healthy Caucasian controls.
METHODS: Caucasian patients with WG (n=456) met ACR criteria for the diagnosis of WG. Caucasian controls (n=687) were recruited from each of the contributing institutions. Genotyping was performed using either TaqMan allelic discrimination assays or an Illumina Golden-Gate SNP array.
RESULTS: Association between the genotype distribution of the PTPN22 R620W variant (rs2476601) and disease was observed (p=0.029). More striking was the strong association under a recessive genetic model (p=0.0078, OR=0.24, 95% CI: 0.07-0.75). 11 additional PTPN22 haplotype-tagging SNPs were examined but none were associated with disease. Five haplotype tagging SNPs in the IRF5 locus were also examined. No association with WG was observed with the intronic donor splice site in the alternate exon 1 of IRF5, rs2004640, a site which that strongly associates with the SLE phenotype. However, suggestive association was observed at the intronic SNP (rs7808907, p=0.028) and at a 3’-UTR SNP (rs2280714, p=0.029). Strongest association between the IRF5 SNPs and WG was observed under an additive model at the intronic SNP rs7808907 (p=0.0085, OR=1.25, 95% CI: 1.06-1.49).
CONCLUSION: These data support a role for genetic factors in the development of WG. The association with disease in individuals homozygous for the PTPN22 W620 variant in patients with WG suggests that T cell dysregulation may be important in the development of disease. Association of WG with alleles of IRF5 suggests that altered transcription of genes for inflammatory cytokines may also be important in WG. While the IRF5 intronic SNP rs7808907 has no known function, rs2280714 is strongly associated with IRF5 expression. Together, these results support a role for genetic variants in immunologically important genes in the development of WG.

 J.C. Edberg, None; J. Kelley, None; G.S. Hoffman, None; P.A. Merkel, None; E.W. St. Clair, None; U. Specks, None; P.F. Dellarippa, None; R.F. Spiera, None; M.C. Marion, None; C.D. Langefeld, None; A.B. Begovich, Celera, 1; Applied Biosystems, 1; Celera, 3; J.H. Stone, None.

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