Autoimmune pancreatitis is characterised by irregular narrowing of the main pancreatic duct, swelling of the pancreas, histological evidence of lymphoplasmacytic inflammation, and high serum immunoglobulin G4 (IgG4) concentration.1,2,3,4 Although the human leucocyte antigen DRB1*0405‐DQB1*0401 haplotype has been associated with autoimmune pancreatitis,5 the role of genetic factors has not yet been fully defined. A new family of genes called Fc receptor‐like genes (FCRLs), which have high structural homology with classical Fcγ receptor genes, has recently been identified.6,7FCRL3 polymorphisms have been shown to be associated with various autoimmune diseases, such as rheumatoid arthritis, autoimmune thyroid disease, and systemic lupus erythematosus, in Japanese populations.8,9 These polymorphisms alter the binding affinity of nuclear factor κB and regulate FCRL3 expression. FCRL3 expression on B cells has been observed in significant amounts and is known to augment autoantibody production in individuals with disease susceptible genotypes.8 We therefore investigated the association of disease susceptibility to autoimmune pancreatitis with FCRL3 polymorphisms in a Japanese population. Furthermore, we sought to determine whether serum IgG4 concentration was associated with FCRL3 polymorphisms in patients with autoimmune pancreatitis.
Patients and controls were recruited from Shinshu University Hospital and affiliated hospitals in Japan. The test group consisted of 59 patients with autoimmune pancreatitis, 62 patients with chronic calcifying pancreatitis, and 97 unrelated Japanese controls. The diagnosis of autoimmune pancreatitis was based on clinical, imaging tests, and/or histopathological findings in accordance with the criteria of the Japan Pancreas Society,10 and all patients fulfilled these criteria. Serum IgG4 concentration was measured as reported previously.3 We found high serum IgG4 concentrations (median 730.0 mg/dl (interquartile range 265.0–1037.5)) in 55 of 59 patients with autoimmune pancreatitis but not in patients with chronic calcifying pancreatitis or controls. We treated 52 of 59 patients with prednisolone, and all patients responded favourably to corticosteroid therapy. DNA was extracted by standard techniques from EDTA blood. All subjects were genotyped for FCRL3 −169, −110, +358, and +1381 by TaqMan assay. The significance of allele distribution between patients with autoimmune pancreatitis and those with chronic calcifying pancreatitis or healthy subjects was tested using the χ2 method with continuity correction. Serum IgG4 concentrations were regressed on the number of susceptible alleles.
The observed genotype frequencies of patients and controls were in Hardy‐Weinberg equilibrium. Analysis of genotype distribution frequencies for FCRL3‐110 polymorphisms revealed a significant difference between autoimmune pancreatitis patients and control subjects (χ2 = 8.12, p = 0.017). Positivity for the −110G allele was significantly decreased in autoimmune pancreatitis patients (p = 0.012, odds ratio 0.13; table 1), indicating a significant association of the −110A/A genotype with autoimmune pancreatitis. The frequency of −110A/A alleles was significantly increased in patients with autoimmune pancreatitis compared with controls (p = 0.012, odds ratio = 7.45; table 1). There are two possible explanations for these findings: FCRL3−110 may be functionally linked with susceptibility to autoimmune pancreatitis, or this allele may be a linkage marker for a neighbouring unidentified susceptibility gene on chromosome 1q 21. No other alleles were found to be significantly associated with autoimmune pancreatitis.
Table 1 FCRL3−110 polymorphisms in 59 patients with autoimmune pancreatitis, 62 patients with chronic calcifying pancreatitis, and 97 healthy subjects.
| Frequency (%) | Autoimmune pancreatitis v chronic calcifying pancreatitis (p value) | Autoimmune pancreatitis v healthy subjects p value (OR (95% CI)) | |||
|---|---|---|---|---|---|
| Autoimmune pancreatitis (n = 59) | Chronic calcifying pancreatitis (n = 62) | Healthy subjects (n = 97) | |||
| Genotype frequency | |||||
| A/A | 13.6 | 6.5 | 2.1 | 0.32 | 0.012 (7.45: 1.53–36.41) |
| A/G | 30.5 | 32.3 | 36.1 | 0.99 | 0.59 |
| G/G | 55.9 | 61.3 | 61.9 | 0.68 | 0.57 |
| Allele positivity | |||||
| A present | 44.1 | 38.7 | 38.1 | 0.68 | 0.57 |
| G present | 86.4 | 93.5 | 97.9 | 0.32 | 0.012 (0.13: 0.027–0.66) |
| Allele genotype | |||||
| A present | 28.8 | 22.6 | 20.1 | 0.34 | 0.10 |
| G present | 71.2 | 77.4 | 79.9 | ||
OR, odds ratio; CI, confidence interval.
Mean (SEM) serum IgG4 concentrations in patients with FCRL3−110A/A, −110A/G, and −110G/G were 1279.4 (404.8) mg/dl, 794.8 (149.4) mg/dl, and 669.2 (78.5) mg/dl, respectively. Serum IgG4 concentrations in patients with autoimmune pancreatitis were found to be significantly positively correlated with the number of susceptible alleles (r2 = 0.094, p = 0.014). However, no association between the HLA DRB1*0405‐DQB1*0401 haplotype and FCRL3−110 alleles was found in this study (data not shown). These results suggest that both the HLA DRB1*0405‐DQB1*0401 haplotype and FCRL3−110 alleles are related to susceptibility for autoimmune pancreatitis but play different roles in the mechanisms inducing autoimmune pancreatitis.
Footnotes
This work was supported in part by Grants‐in‐Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (12670471, 13557047, 15659167 and 16390205) and from the Japan Health Sciences Foundation (KH21022), and by a Research of Specific Diseases, Health and Labour Sciences Research Grant, Japan
Conflict of interest: None declared.
References
- 1.Yoshida K, Toki F, Takeuchi T.et al Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci 1995401561–1568. [DOI] [PubMed] [Google Scholar]
- 2.Okazaki K, Chiba T. Autoimmune related pancreatitis. Gut 2002511–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Hamano H, Kawa S, Horiuchi A.et al High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001344732–738. [DOI] [PubMed] [Google Scholar]
- 4.Aparisi L, Farre A, Gomez‐Cambronero L.et al Antibodies to carbonic anhydrase and IgG4 levels in idiopathic chronic pancreatitis: relevance for diagnosis of autoimmune pancreatitis. Gut 200554703–709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kawa S, Ota M, Yoshizawa K.et al HLA DRB10405‐DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology 20021221264–1269. [DOI] [PubMed] [Google Scholar]
- 6.Davis R S, Wang Y H, Kubagawa H.et al Identification of a family of Fc receptor homologs with preferential B cell expression. Proc Natl Acad Sci U S A 2001989772–9777. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hatzivassiliou G, Miller I, Takizawa J.et al IRTA1 and IRTA2, novel immunoglobulin superfamily receptors expressed in B cells and involved in chromosome 1q21 abnormalities in B cell malignancy. Immunity 200114277–289. [DOI] [PubMed] [Google Scholar]
- 8.Kochi Y, Yamada R, Suzuki A.et al A functional variant in FCRL3, encoding Fc receptor‐like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 200537478–485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ikari K, Momohara S, Nakamura T.et al Supportive evidence for a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis. Ann Rheum Dis 200665671–673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Steinberg W M, Barkin J, Bradley E L., 3rdet al ontroversies in clinical pancreatology: autoimmune pancreatitis: does it exist? Pancreas 2003271–13. [DOI] [PubMed] [Google Scholar]