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Clinical Chemistry 53: 1700-1705, 2007; 10.1373/clinchem.2007.085951
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(Clinical Chemistry. 2007;53:1700-1705.)
© 2007 American Association for Clinical Chemistry, Inc.

Clinical Immunology

T-Cell Regulatory Gene CTLA-4 Polymorphism/Haplotype Association with Autoimmune Pancreatitis

Ming-Chu Chang1, Yu-Ting Chang1, Yu-Wen Tien2, Po-Chin Liang3, I-Shiow Jan4, Shu-Chen Wei1 and Jau-Min Wong1,a

Departments of1 Internal Medicine, 2 Surgery, 3 Radiology, and 4 Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.

aAddress correspondence to this author at: Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chung Shan South Rd., Taipei, Taiwan. Fax 886-2-23947927; e-mail jmwong{at}ha.mc.ntu.edu.tw.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Autoimmune pancreatitis (AIP) is a distinct disease entity of chronic pancreatitis. Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is a key negative regulator of the T-cell immune response, and its gene is highly polymorphic. Many positive associations between cytotoxic T-lymphocyte–associated protein 4 (CTLA4) single-nucleotide polymorphisms and various autoimmune diseases have been identified. We investigated possible genetic associations of CTLA4 in a Chinese population with AIP.

Methods: We performed genotyping for CTLA4 (49 A/G, –318 C/T, and CT60 A/G) and tumor necrosis factor (TNF)-{alpha} promoter (–857 C/T, –863 C/A, and –1031 C/T) by use of PCR sequence-specific primers and direct sequencing, respectively, in 46 patients with AIP, 78 patients with chronic calcifying pancreatitis (CCP), and 200 healthy individuals.

Results: We found a significant increase in CTLA4 49A carriers in patients with AIP compared with healthy individuals (78.3% vs 48%; P <0.0001). The frequency of CTLA4 49A was also significantly higher in patients with AIP compared with CCP (78.3% vs 37.1%; P <0.0001). CTLA4 49A conferred a higher risk of AIP [with CCP, odds ratio (OR) 7.20; P <0.0001]. The –318C/+49A/CT60G haplotype was associated with a higher susceptibility to AIP (OR 8.53; P = 0.001). The TNF-{alpha} promoter –863A was associated with extrapancreatic involvement in patients with AIP.

Conclusion: CTLA-4 49A polymorphism and –318C/+49A/CT60G haplotype are associated with AIP in a Chinese population.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Autoimmune pancreatitis (AIP), 1 first reported in 1995 (1), is now an established etiological agent of chronic pancreatitis (2). Reports from around the world have described cases of AIP (3)(4)(5)(6) and reflect growing concern about its incidence.

AIP can be defined as a chronic inflammation of the pancreas and is characterized serologically by increases of serum gamma globulin, IgG, and/or IgG4, and the presence of autoantibodies (7). Histopathological investigation of AIP typically reveals dense periductal lymphoplasmacytic inflammation, periductal and parenchymal fibrosis, and obliterative venulitis (8). Diagnosis is important, because the disease is characterized by a remarkable response to steroid therapy. Diagnostic criteria are evolving and combine histology, imaging, serology, other organ involvement, and response to steroid therapy (5) along with recently modified proposals (9)(10).

Understanding of the pathogenesis of AIP is immature. Previous studies have shown that CD8+ and CD4+ T cells abundantly infiltrate the pancreatic tissue (11), and carbonic anhydrase II might be one of the target antigens (12). Activated CD4+ T cells specific for pancreatic amylase can induce pancreatitis in the rat that is similar to human AIP (13). Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), which is expressed on activated CD8+ and CD4+ T cells, is important in the regulation of T-cell stimulation. Distinct functions of CTLA-4 include setting the threshold for T-cell activation, thereby contributing to the maintenance of peripheral tolerance (14), suppression of T-cell proliferation and inflammatory cytokine production, and induction of apoptosis in activated T cells (15). The inhibitory role of CTLA-4 in maintaining homeostasis of inflammatory reactions makes it a potential candidate gene in determining genetic predisposition of autoimmune diseases.

Many single-nucleotide polymorphisms (SNPs) have been identified in the cytotoxic T-lymphocyte–associated protein 4 (CTLA4) 2 region (16). Autoimmune disease associations with different CTLA4 polymorphisms have yielded mixed results in different ethnic groups (17)(18). Among them, the +49A>G polymorphism in exon 1, resulting in a threonine-to-alanine conversion at codon 17, has been identified as a functional polymorphism of CTLA4 with lower mRNA levels of the soluble alternative splice form of CTLA-4 (16)(19)(20). An A-to-G base exchange polymorphism in exon 1 of CTLA4 at position 49 has been associated with susceptibility to autoimmune hepatitis (21). A recent study that screened all known SNPs in the CTLA4 region demonstrated that the linkage with Graves disease, autoimmune hypothyroidism, and type 1 diabetes was strongest with the G allele of the noncoding CT60 A/G polymorphism, which correlates with decreased mRNA for the soluble alternative splice form of CTLA-4 (16).

The occurrence of extrapancreatic lesions in AIP suggests that it might be a systemic disorder. Kawa et al. (22) have shown that the HLA DRB10405-DQB10401 haplotype is associated with AIP in a Japanese population. We undertook the current study to investigate associations of the CTLA4 (–318, +49 G/A, and CT60) polymorphisms and haplotypes with susceptibility to AIP in Chinese patients as well as their associations with extrapancreatic manifestations.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study participants
Between September 1990 and September 2005, we obtained consecutive DNA samples from 46 patients with AIP (34 men and 12 women), ages 32 to 78 years [mean (SD) 55.5 (15.6) years], at National Taiwan University Hospital. We also obtained consecutive DNA samples from 78 patients with chronic calcifying pancreatitis (CCP; 40 alcoholic and 38 idiopathic; 58 men and 20 women), ages 23 to 76 years [45.0 (14.3) years], during the same period. CTLA4 genotypes from 200 ethnically matched healthy individuals were obtained in a previous study (23). The healthy controls were unrelated apheresis blood donors living in the northern region of Taiwan; their age and sex were not significantly different from those of the patients.

All patients with AIP were diagnosed on the basis of the characteristic findings of imaging tests; histologic examination of pancreatic tissues obtained at surgery; persistence of high serum concentrations of IgG4, IgG, or antinuclear antibodies (ANAs); other organ involvement; and steroid response (9)(10)(24)(25). Serum IgG4 concentrations were measured in 26 of 46 patients, and all were increased [median (SD) 4.36 (3.7) g/L]. Twenty-six patients were treated with prednisolone, resulting in the improvement of clinical and imaging findings. Twelve patients were not initially treated with prednisolone at their local hospital, and their obstructive jaundice was treated with endoscopic drainage. Their symptoms and findings subsided gradually after steroid therapy. Twenty patients underwent a choledocojejunostomy as palliative surgery or Whipple procedure for obstructive jaundice under the impression of pancreatic cancer in the 1990s. Patients rarely complained of the typical severe abdominal pain of pancreatitis, and the major presenting symptom of many patients (56.7%) was painless jaundice. Other symptoms of AIP included nonspecific mild abdominal pain (36.7%) and weight loss (40.0%). None of the patients had a history of alcohol abuse or other predisposing factors of chronic pancreatitis. The high proportion of the elderly male population and frequent presence of obstructive jaundice were consistent with previous reports. In 70% (32 of 46) of the patients with AIP, the referring physician initially suspected a diagnosis of pancreaticobiliary malignancies. Diabetes was diagnosed in 43.4% (20 of 46), and half of these cases (10 of 20) were new-onset diabetes (within a year of the diagnosis of AIP).

The 78 patients with CCP had calcification of the pancreas and marked irregular dilation of the main pancreatic duct, features not found in patients with AIP.

All participants who were prospectively recruited provided written informed consent for the tests. We collected serum samples from the healthy individuals after we obtained informed consent (23). The institutional ethics committee approved this study.

ctla4 genotyping
We purified genomic DNA from whole blood collected preoperatively by use of the QIAamp blood reagent set (Qiagen) and assessed quantity and purity on the basis of spectroscopic absorbance at 260 and 280 nm. We performed polymorphism analyses for CTLA4 (–318 C/T, 49 A/G, and CT60 A/G) according to modified protocols from reported assays (26). We performed PCR amplification of the promoter or coding regions of the genes using specifically designed pairs of oligonucleotide primers. We then identified polymorphisms by restriction enzyme length polymorphism for CTLA4. We confirmed individual genotype by use of PCR with subsequent direct sequencing (ABI Prism 377 DNA sequencer; PE Biosystems). Primer sequences, annealing temperatures for PCR, and detection methods have been described (26). All laboratory assays were conducted and interpreted blindly, without the knowledge of case or control status. We determined the presence of the tumor necrosis factor (TNF)-{alpha} promoter polymorphisms (–1031, –863, –857) by use of direct sequencing as reported (23).

statistical analysis
We estimated genotype frequencies by direct counting for each CTLA4 allele. We compared between-group demographic data by the Student unpaired t-test for continuous data and by the {chi}2 test for categorical data. We performed statistical analysis of genotype distribution and allele frequencies by {chi}2 test (SPSS for Windows 11.5; SPSS). We tested Hardy–Weinberg equilibrium among the controls and AIP patients to confirm the controls as suitable. We applied multiple stepwise logistic regressions to determine the independent risk factor related with the presence of AIP, with enrolling age and sex as adjustment to prevent confounding bias. We estimated strength of association by calculating the odds ratio (OR). All tests were 2-tailed, with statistical significance set at P <0.05.

We performed expectation maximization-based haplotype frequency estimations and permutation-based hypothesis testing on the basis of previous work in our institution (27)(28). The significance level was P <0.05 for the omnibus test and 1 x 10–3 (0.05/8) for individual haplotype analyses (8 haplotypes for 3 loci).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
genotype and allele distribution
The distribution of CTLA4 genotypes and allele frequencies in patients with AIP and CCP and healthy controls is shown in Table 1 . The distribution of allele and genotype frequencies in healthy individuals was similar to previous reports in Chinese (26). The individual –318, +49, and CT60 polymorphisms and their haplotypes were in Hardy–Weinberg equilibrium in patients with AIP and CCP and healthy controls. The CTLA4 +49 and CT60 polymorphisms were in strong linkage disequilibrium, and only 3 haplotypes were identified in both patients with AIP/CCP and healthy controls, which were similar in Australian whites (29).


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  		Table 1. Distribution of CTLA4 genotype and allele frequencies in patients with AIP and CCP and healthy controls.

patients with aip
Among CTLA4 polymorphisms, the frequency of 49A was increased in patients with AIP compared with healthy individuals (78% vs 48%; corrected P <0.0001; Table 2 ). CTLA-4 49A conferred an increased risk of AIP compared with healthy individuals (OR 3.90; 95% CI 1.84–8.28; P <0.0001; Table 2 ). The distribution of –318 and 60CT allele frequencies and genotypes was not significantly different in AIP patients compared with healthy individuals (Table 1Up ).


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  		Table 2. Allele frequency and 3-locus haplotype (–318/49/60) frequency estimates of CTLA-4 in patients with AIP and CCP and healthy controls and significance levels of comparison from permutation tests.

patients with ccp
No CTLA-4 allele/genotype was significantly associated with CCP patients compared with healthy individuals.

patients with aip vs ccp
We found a significant increase in the frequencies of CTLA-4 49A in patients with AIP compared with CCP (OR 7.20; 95% CI 3.09–16.74; P <0.0001; Table 2Up ).

ctla-4 haplotype distribution
There were significant differences in the frequency of the CTLA4 haplotype between patients with AIP and CCP and healthy controls (P = 0.002; Table 2Up ). Relative to the 318C/49G/CT60G haplotype, the frequency of the haplotype 318C/49A/CT60G (OR 2.90; 95% CI 1.49–5.64) was increased in patients with AIP compared with controls. Relative to the 318C/49G/CT60G haplotype, the frequency of the haplotype 318C/49A/CT60G (OR 8.53, 95% CI 3.67–19.85) was increased in patients with AIP compared with CCP (Table 3 ).


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  		Table 3. Allele frequency and 3-locus haplotype (–318/49/60) frequency of CTLA-4 and TNF-{alpha} promoter polymorphisms in patients with AIP with and without extrapancreatic manifestations (EM).

patients with aip with vs without extrapancreatic manifestations
In our series, 19 of 46 patients (41.3%) with AIP had associated extrapancreatic lesions (5 women and 14 men). The age of these patients was 57.0 (16.2) years, which was not significantly different from those without such lesions [55.00 (14.4) years]. The extrapancreatic lesions included tubulointerstitial nephritis (6 of 46), abdominal lymphadenopathy (9 of 46), neck lymphadenopathy (4 of 46), hepatic inflammatory pseudotumors (4 of 46), sialadenitis (3 of 46), autoimmune thyroiditis (5 of 46), autoimmune hepatitis (7 of 46), and orbital pseudotumors (1 of 46). Of the laboratory measurements examined—including aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, amylase, lipase, bilirubin, carcinoembryonic antigen, carbohydrate antigen 19-9, and IgG4—only aspartate aminotransferase, alanine aminotransferase, ANA, and IgG4 showed statistical significance between groups with and without extrapancreatic lesions (P = 0.003, 0.001, 0.035, and 0.006, respectively. Only TNF-{alpha} promoter –863A and CTLA-4 49A showed a significant difference between AIP patients with extrapancreatic manifestation and controls.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We believe this is the first study to investigate the association of CTLA4 polymorphisms in AIP. Our findings indicate a significantly higher frequency of the CTLA4 49A allele in these patients than in geographically and ethnically matched controls and patients with CCP. Genetic associations with polymorphisms of exon 1 of the CTLA4 gene have been widely reported in other autoimmune diseases (21)(30)(31)(32). Strong linkage disequilibrium has been found between CTLA4 SNPs in whites (33) and Chinese (26). CTLA-4 49A and CT60G polymorphisms and 49A/60G haplotypes were associated with susceptibility to extraglandular manifestations in primary Sjögren syndrome (29). The 49A allele was also found significantly more frequently in patients with celiac disease (34) and lymphoma(35). In this study, we found that the CTLA-4 49A variant and CTLA-4 318C/49A/CT60G haplotype were associated with increased risk in patients with AIP. The findings suggest a role of CTLA4 polymorphisms/haplotypes in predisposition to AIP in Chinese.

The CTLA-4 haplotypes associated with AIP are probably different from the haplotypes associated with other organ-specific autoimmune diseases, especially in the CTLA-4 49 G/A polymorphism. In Graves disease, autoimmune hypothyroidism, and type 1 diabetes, associations with both CT60G and 49G SNPs have been observed, the association with CT60G being strongest (16). Unlike these organ-specific autoimmune diseases, both primary Sjögren syndrome and systemic lupus erythematosus (SLE) are associated with systemic B cell activation, polyclonal hypergammaglobulinemia, ANA, and multisystem involvement. AIP is often considered a systemic disorder rather than an organ-specific autoimmune disease with the presence of autoantibodies, increased IgG and/or IgG4, and extrapancreatic manifestations (10). From this point of view, it is very similar to the primary Sjögren syndrome or SLE, and interestingly, both primary Sjögren syndrome and SLE carry the +49A allele. Therefore, our finding of association of CTLA4 polymorphisms with AIP has biologic plausibility.

The CTLA-4 exon 1 gene polymorphism may be functionally linked with susceptibility to AIP. The role for CTLA-4 might be to maintain peripheral self-tolerance by modulating T-cell immune response (36)(37). Indeed, the functional importance of this molecule is emphasized by the development of lethal self-reactive lymphoproliferative disease in CTLA-4–deficient mice (38). Blockade of CTLA-4/B7 interaction promotes disease onset and accelerates disease progression in murine models of autoimmunity (39). The end-stage phenotype of a specific autoimmune disease may be clinically distinct and/or organ specific, with fundamental shared immunoregulatory processes affecting cytokine production, pro/antiinflammatory cytokine ratios, apoptosis, effector T-cell regulation, and antibody production.

In our previous study, we found that TNF-{alpha} haplotype–containing promoter –863A increased the risk of chronic pancreatitis (alcoholic and idiopathic) in Chinese (23). Interestingly, in this cohort, the promoter –863A polymorphism is associated with extrapancreatic manifestations of AIP, and those patients also had significantly higher IgG4 concentrations than patients without extrapancreatic involvement. Moreover, we found that the CTLA4 +49 polymorphism is associated with AIP but not subtypes of CCP in our Chinese population. The influence of TNF-{alpha} promoter –863A and CTLA4 +49 in the susceptibility of AIP (OR 11.97; 95% CI 4.18–34.22) suggests a possible gene–gene interaction.

This population-based, case–control study investigated CTLA4 gene polymorphisms/haplotypes in AIP. Case–control candidate gene studies are frequently criticized, and they do indeed have a number of recognized problems. However, large family groupings with AIP are not available for genetic studies, and our investigation is based on a uniquely characterized and systemically evaluated homogeneous group of patients and ethnically similar healthy controls and patients with CCP. Ethnic differences and disease heterogeneity may account for variation in host susceptibility. Knowledge of other risk-conferring alleles and investigation in other ethnic groups are needed in future studies to provide a better understanding.

Additional studies enrolling more patients and in different ethnic populations will offer additional information about the general contribution of the CTLA4 gene to the development of AIP. Functional studies of polymorphisms and their interaction with other susceptibility genes are needed to facilitate understanding of the mechanisms of AIP.


   Acknowledgments
 
Grant/funding support: National Science Council, Taiwan (NSC 94-2314-B-002-272); National Taiwan University Hospital (NTUH-95-M-22); and Liver Disease Prevention and Treatment Foundation.

Financial disclosures: None declared.

Acknowledgments: We express our deep gratitude to all of the patients and controls who participated in the study.


   Footnotes
 
1 Nonstandard abbreviations: AIP, autoimmune pancreatitis; CTLA-4, cytotoxic T lymphocyte–associated antigen 4; SNP, single-nucleotide polymorphism; CCP, chronic calcifying pancreatitis; ANA, antinuclear antibody; TNF, tumor necrosis factor; OR, odds ratio; SLE, systemic lupus erythematosus.

2 Human gene: CTLA4, cytotoxic T-lymphocyte–associated protein 4.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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