Background 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.
Objectives To perform a genome-wide association study of IgG4RD to detect susceptibility loci and uncover the pathophysiology underlying IgG4RD.
Methods 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 HLA region using imputation of amino acid residues of classical HLA alleles in combination with direct sequencing was also performed. The associations between clinical manifestations and correlates especially genetic components were analyzed.
Results We identified FCGR2B and the HLA region as susceptibility loci to IgG4RD (p≤1.2x10–11). We also found evidence that the HLA region contained at least two independent associations in HLA-DRB1 and HLA-A 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 (p=1.3x10–22). We also found a significant synergistic effect in combination of the two SNPs in FCGR2B and HLA-DRB1 loci (p≤0.024). The susceptibility SNP in FCGR2B was in linkage disequilibrium with a functional missense variant of FCGR2B and showed an association with the decreased gene expression (p≤1.0x10–10). None of rare or coding variants found by direct sequencing in the FCGR2B region and copy number variations could explain the association. The SNP in FCGR2B and age at diagnosis were independently associated with recurrence of IgG4RD (p≤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 (p=0.027).
Conclusions A total of three susceptibility markers to IgG4RD were identified. FCGR2B 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.
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.
Disclosure of Interest None declared