OBJECTIVE: Wegener's granulomatosis (WG) and Churg-Strauss syndrome (CSS) belong to the heterogeneous group of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Current understanding of their pathogenesis and genetic background is limited. Expression levels of interleukin-10 (IL-10), a potent and pleiotropic cytokine, are largely determined by variations in the gene encoding the IL-10 precursor. This study was undertaken to determine the impact of IL10 polymorphisms on the pathogenesis of both WG and CSS in large cohorts. METHODS: Three single-nucleotide polymorphisms (SNPs) tagging the promoter haplotypes of the IL10 gene (IL10 -3575, IL10 -1082, and IL10 -592) were analyzed in 403 patients with WG and 103 patients with CSS as well as 507 matched control subjects from Germany. In addition, 3 informative SNPs in other parts of IL10 were genotyped. RESULTS: None of the markers or their haplotypes was associated with WG or any of its subgroups classified according to ANCA status, sex, or presence of further WG genetic risk factors. In contrast, the IL10 -3575/-1082/-592 TAC haplotype, part of the extended ancient haplotype IL10.2, was highly significantly associated with ANCA-negative CSS (chi2 = 19.14, P = 0.000012, corrected P = 0.0003, odds ratio 2.16, 95% confidence interval 1.52-3.06). CONCLUSION: These findings challenge those from previous studies of IL10 in WG and provide further evidence that CSS and WG have distinct genetic backgrounds. Because the IL10.2 haplotype has been correlated reproducibly with increased IL10 expression, the possible role of IL-10 in the pathogenesis of ANCA-negative CSS needs to be further elucidated.
OBJECTIVE:Wegener's granulomatosis (WG) and Churg-Strauss syndrome (CSS) belong to the heterogeneous group of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Current understanding of their pathogenesis and genetic background is limited. Expression levels of interleukin-10 (IL-10), a potent and pleiotropic cytokine, are largely determined by variations in the gene encoding the IL-10 precursor. This study was undertaken to determine the impact of IL10 polymorphisms on the pathogenesis of both WG and CSS in large cohorts. METHODS: Three single-nucleotide polymorphisms (SNPs) tagging the promoter haplotypes of the IL10 gene (IL10 -3575, IL10 -1082, and IL10 -592) were analyzed in 403 patients with WG and 103 patients with CSS as well as 507 matched control subjects from Germany. In addition, 3 informative SNPs in other parts of IL10 were genotyped. RESULTS: None of the markers or their haplotypes was associated with WG or any of its subgroups classified according to ANCA status, sex, or presence of further WG genetic risk factors. In contrast, the IL10 -3575/-1082/-592 TAC haplotype, part of the extended ancient haplotype IL10.2, was highly significantly associated with ANCA-negative CSS (chi2 = 19.14, P = 0.000012, corrected P = 0.0003, odds ratio 2.16, 95% confidence interval 1.52-3.06). CONCLUSION: These findings challenge those from previous studies of IL10 in WG and provide further evidence that CSS and WG have distinct genetic backgrounds. Because the IL10.2 haplotype has been correlated reproducibly with increased IL10 expression, the possible role of IL-10 in the pathogenesis of ANCA-negative CSS needs to be further elucidated.
Authors: Zachary M Dong; Edwin Lin; Michael E Wechsler; Peter F Weller; Amy D Klion; Bruce S Bochner; Don A Delker; Mark W Hazel; Keke Fairfax; Paneez Khoury; Praveen Akuthota; Peter A Merkel; Anne-Marie Dyer; Carol Langford; Ulrich Specks; Gerald J Gleich; Vernon M Chinchilli; Benjamin Raby; Mark Yandell; Frederic Clayton Journal: Am J Pathol Date: 2020-04-03 Impact factor: 4.307