OP0238 Fcgr2b and Multiple Hla Loci Are Associated with Susceptibility To IGG4-Related Disease
Authors: C. Terao, M. Ota, M. Shiokawa, K. Kuriyama, Y. Kodama, K. Uchida, I. Yamaguchi, T. Kawaguchi, S. Kawaguchi, K. Higasa, T. Mimori, K. Okazaki, T. Chiba, S. Kawa, F. Matsuda
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> IgG4-related disease (IgG4RD) is an emerging concept of an autoimmune disease entity including autoimmune pancreatitis, IgG4-related sialadenitis and IgG-related kidney disease (Ref 1–3). Comprehensive genetic landscape of IgG4RD is unknown. <h3>Objectives</h3> To perform a genome-wide association study of IgG4RD to detect susceptibility loci and uncover the pathophysiology underlying IgG4RD. <h3>Methods</h3> We conducted a two-staged genome-wide association study composed of a total of 850 cases and 2,082 controls by genotyping 2,310,564 single nucleotide polymorphisms (SNPs). Allele frequencies were compared between cases and controls by logistic regression analysis and followed by meta-analysis with use of inverse-variance method. Comprehensive analysis in the <i>HLA</i> region using imputation of amino acid residues of classical <i>HLA</i> alleles in combination with direct sequencing was also performed. The associations between clinical manifestations and correlates especially genetic components were analyzed. <h3>Results</h3> We identified <i>FCGR2B</i> and the <i>HLA</i> region as susceptibility loci to IgG4RD (<i>p</i>≤1.2x10<sup>–11</sup>). We also found evidence that the <i>HLA</i> region contained at least two independent associations in <i>HLA-DRB1</i> and <i>HLA-A</i> regions. The amino acid position 11 in the HLA-DRB1 peptide-binding groove, the strongest susceptibility position to other autoimmune diseases, was strongly associated with IgG4RD (<i>p</i>=1.3x10<sup>–22</sup>). We also found a significant synergistic effect in combination of the two SNPs in <i>FCGR2B</i> and <i>HLA-DRB1</i> loci (<i>p</i>≤0.024). The susceptibility SNP in <i>FCGR2B</i> was in linkage disequilibrium with a functional missense variant of <i>FCGR2B</i> and showed an association with the decreased gene expression (<i>p</i>≤<i>1</i>.0x10<sup>–10</sup>). None of rare or coding variants found by direct sequencing in the <i>FCGR2B</i> region and copy number variations could explain the association. The SNP in <i>FCGR2B</i> and age at diagnosis were independently associated with recurrence of IgG4RD (<i>p</i>≤0.013). When we assessed common genetic architectures between IgG4RD and other autoimmune diseases, SLE-susceptibility loci showed a trend of opposite directions in IgG4RD susceptibility in contrast to RA, which showed a trend of common directions with IgG4RD (<i>p</i>=0.027). <h3>Conclusions</h3> A total of three susceptibility markers to IgG4RD were identified. <i>FCGR2B</i> may play critical roles in developing and the progression of IgG4RD. HLA-DRB1 amino acid position 11 is important for IgG4RD. Common molecular pathways are suggested to underlie IgG4RD and other autoimmune diseases. <h3>References</h3> Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Modern rheumatology/the Japan Rheumatism Association 2012;22:1–14. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001;344:732–8. Stone JH, Khosroshahi A, Deshpande V, et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum 2012;64:3061–7. <h3>Disclosure of Interest</h3> None declared