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Clinical Chemistry 54: 131-138, 2008. First published November 2, 2007; 10.1373/clinchem.2007.093492
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Right arrow Lipids, Lipoproteins, and Cardiovascular Risk Factors
(Clinical Chemistry. 2008;54:131-138.)
© 2008 American Association for Clinical Chemistry, Inc.

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Association of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutation/Variant/Haplotype and Tumor Necrosis Factor (TNF) Promoter Polymorphism in Hyperlipidemic Pancreatitis

Yu-Ting Chang1, Ming-Chu Chang1, Ta-Chen Su1,2, Po-Chin Liang3, Yi-Ning Su4, Chun-Hung Kuo1, Shu-Chen Wei1 and Jau-Min Wong1,a

1 Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei Taiwan; 2 Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan; 3 Department of Radiology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; 4 Department of Medical Genetics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.

aAddress correspondence to this author at: Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chung Shan South Road, Taipei, Taiwan. Fax 886-2-23633658; e-mail jmwong{at}ntu.edu.tw.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: The mechanism by which hypertriglyceridemia (HTG) leads to pancreatitis is not clear. We sought to determine whether the genes involved in pancreatic ductal or acinar cell injury, including the cationic trypsinogen gene [protease, serine, 1 (trypsin 1) (PRSS1)], the pancreatic secretory trypsin inhibitor gene [serine peptidase inhibitor, Kazal type 1 (SPINK1)], the cystic fibrosis transmembrane conductance regulator gene [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette subfamily C, member 7) (CFTR)], and inflammation genes such as tumor necrosis factor [tumor necrosis factor, TNF superfamily, member 2 (TNF)] are associated with hyperlipidemic pancreatitis (HLP) in patients with HTG.

Methods: We performed genetic analysis of 126 HTG patients in Taiwan (46 with HLP and 80 without HLP). The entire coding and intronic regions of the PRSS1, SPINK1, and CFTR genes were identified by heteroduplex analysis techniques and were confirmed by sequencing analysis. The presence of 125G/C, 1001 + 11C>T, 1540A>G (Met470Val), 2694T>G, and 4521G>A in CFTR, the presence of 272C>T in SPINK1, and TNF promoter polymorphisms (nucleotide positions 1031, 863, 857, 308, and 308) were measured by direct sequencing.

Results: Of the 126 HTG patients, 13 (10.3%) carried a CFTR mutation. No PRSS1 or SPINK1 mutations were detected in our patients or in HTG controls. The CFTR gene mutation rates in HTG with and without HLP were 26.1% (12 of 46) and 1.3% (1 of 80), respectively (P <0.0001). The CFTR gene mutations were all Ile556Val. A multivariate analysis of HTG patients indicated that triglycerides, CFTR 470Val, and TNF promoter 863A were independent risk markers for HLP.

Conclusions: This genetic study is the first one to address the association of HLP with the CFTR mutation/variant/haplotype and TNF promoter polymorphism in a Chinese HTG population. The results suggest that the occurrence of HLP is multifactorial and polygenic.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Hypertriglyceridemia (HTG)1 is associated with acute pancreatitis and is found in 3%–38% of patients with acute pancreatitis (1)(2)(3)(4)(5). HTG is the 3rd most frequent etiology of acute pancreatitis in Taiwan (6), accounting for about 10%–15% of patients with acute pancreatitis. In the absence of other etiologic factors and in the presence of high serum triglyceride (TG) concentrations (>11.3 mmol/L), acute pancreatitis is considered to be secondary to HTG, (5)(7). Patients who present with significant HTG and pancreatitis usually have a preexisting abnormality in lipoprotein metabolism, such as lipoprotein lipase deficiency or apolipoprotein C deficiency (8). Mutations, such as in genes for lipoprotein lipase and apolipoprotein, have been reported to be associated with HTG, but their occurrence does not explain why some patients develop acute pancreatitis and others do not. Previous studies have been inconclusive regarding which HTG patients will develop pancreatitis (9)(10)(11) and in explaining why some HTG patients seldom develop pancreatitis. The mechanism by which HTG leads to pancreatitis is not clear. Unbound free fatty acids are toxic and may cause trypsinogen activation, which could then lead to injury of acinar cells or capillaries and thereby initiate acute pancreatitis (12)(13). Some HTG patients, however, seldom develop pancreatitis, even with marked increases in TG concentrations (2).

Genetic factors may play important roles in susceptibility to pancreatic injury, as well as in the severity and evolution of the inflammatory process (8). In humans, the genes PRSS12 [protease, serine, 1 (trypsin 1)], SPINK1 (serine peptidase inhibitor, Kazal type 1) (14), and CFTR [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)] (15)(16)(17) and genes encoding factors that modulate the inflammatory response to pancreatic injury, such as TNF [tumor necrosis factor (TNF superfamily, member 2)] (18), are reportedly associated with acute recurrent pancreatitis (19) and chronic pancreatitis (20). In addition, mutations in these genes have enhanced the pancreatic inflammatory response in animal models. A transgenic mouse model expressing the Arg122His mutation in mouse trypsinogen displayed early-onset acinar injury, inflammatory cell infiltration, and enhanced response to cerulein-induced pancreatitis (21). Similarly, cftr(–/–) mice showed constitutive expression of proinflammatory cytokines and developed more severe pancreatitis episodes after cerulein stimulation (22). We evaluated the hypotheses that sensitization of ductal or acinar pancreas cells or cofactors is involved in the HTG process to induce acute pancreatitis and high serum TG concentrations and that mutations and functional variations of PRSS1, SPINK1, and CFTR, and TNF promoter polymorphisms are associated with hyperlipidemic pancreatitis (HLP).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
cases (htg with hlp) and controls (htg without hlp)
Patients and control individuals were recruited at a tertiary referral center (National Taiwan University Hospital) from September 2004 through December 2006. All patients and control individuals were Taiwanese or Taiwan Chinese from the same narrowly confined area in Taiwan (18). Most study participants were not aboriginal Taiwanese, i.e., individuals with ancestors who had moved to Taiwan from southeastern China about 500 years ago. The control HTG patients without HLP were from the same areas as the HLP patients, were recruited from the hospital during the same time period, and had no history of acute pancreatitis, chronic pancreatitis, pancreatic adenocarcinoma, or any apparent biliary or pancreatic diseases. The control individuals also had no family history of pancreatitis or pancreatic adenocarcinoma. A diagnosis of HLP was based on the presence of a typical history (upper-abdominal pain with radiation to the back that was relieved by leaning forward or sitting upright and was increased after eating) and the following: suggestive radiologic findings and/or a 3-fold increase in amylase and/or lipase concentrations. Excluded from the study were patients who reported any other known risk factors for pancreatitis (either singly or in combination), including the following: a history of alcohol consumption of more than 2 drinks/day (20 g); biliary, metabolic (such as increased calcium), or autoimmune factors; medication with known pancreatic toxicity; pancreatic or periampullary tumors; a pancreatic duct anomaly or endocrine disorders; or a family history of pancreatitis.

Demographic and laboratory data were collected from medical chart records by means of a questionnaire that included information regarding clinical and family history. The clinical histories, which included the age of onset of symptoms, smoking history, and episodes of acute pancreatitis, were collected and reviewed.

anthropometrics and biomedical measurements
We measured fasting concentrations of glucose, total cholesterol, and TGs. Diabetes mellitus was diagnosed on the basis of a fasting plasma glucose value of >6.99 mmol/L and a postprandial 2-h plasma glucose value of >11.10 mmol/L, or by requirements for insulin or oral hypoglycemic drugs. Dyslipidemia was measured as a fasting TG concentration ≥2.25 mmol/L; hypercholesterolemia was indicated by a total-cholesterol concentration ≥6.0 mmol/L. We obtained weight and height measurements and calculated the body mass index.

We studied 126 patients (46 HLP patients and 80 HTG patients without HLP). Blood samples were drawn into EDTA anticoagulant after patients had provided written informed consent. The institutional ethics committee approved the study.

dna extraction
We used the Viogene Blood & Tissue Genomic DNA Extraction System reagent set according to the manufacturer’s instructions to extract genomic DNA from leukocytes and stored the extracts at –20 °C until analysis (15).

mutation/variant screening of the prss1, spink1, and cftr genes
We amplified the coding and flanking noncoding regions of these 3 genes with primers (14)(23) and protocols (24) that have previously been described.

pcr amplification and denaturing hplc heteroduplex analysis
Mutations in the PRSS1, SPINK1, and CFTR genes were examined by PCR analysis and then analyzed with denaturing HPLC, according to procedures modified from those described in previous reports (15)(25). Denaturing HPLC was performed on a WAVE DNA fragment analysis system equipped with a DNASep column and an ultraviolet-C scanner to detect eluted DNA (Transgenomic) (26). Before loading onto the column, we denatured the PCR product by heating to 94 °C for 5 min and reannealing slowly by decreasing the temperature 1 °C/min until the temperature reached 25 °C (70 min total). The resolution temperature for each sequencing analysis was determined with DHPLC Melt software (http://insertion.stanford.edu/melt.html). PCR products displaying abnormal elution profiles were sequenced.

sequence analysis
We sequenced purified PCR products with BigDye Terminator sequencing chemistry (Applied Biosystems) and primers used in the initial amplification step and analyzed the sequencing reaction products with an ABI 3100 automated DNA sequencer (Applied Biosystems). Sequences were compared with the published sequence database (updates at http://www.uni-leipzig.de/pancreasmutation/db.html and http://www.genet.sickkids.on.ca/cftr/app).

variants, polymorphisms, and genotyping for cftr, spink1, and the tnf promoter
We evaluated the presence of 125G/C, 1001 + 11>CT, 1540A>G (Met470Val), 2694T>G, and 4521G>A variants in CFTR and the 272C>T polymorphism in SPINK1 by direct sequencing. TNF promoter polymorphisms (nucleotide positions 1031, 863, 857, 308, 308) were evaluated via direct sequencing.

haplotype analysis
We used a haplotype-based analytical approach to enhance investigation of disease-associated CFTR variants and studied 5 CFTR diallelic polymorphic loci to determine which haplotypes were associated with HLP risk. Expectation-maximization–based estimations of haplotype frequency and permutation-based hypothesis-testing procedures were based on previous work at our institution (18). The level of statistical significance was set at P <0.05 for the omnibus test and 1 x 10–3 (0.05/32) for individual haplotype analyses (32 haplotypes for 5 loci).

statistical analysis
To compare the between-group demographic data, we used the Student unpaired t-test for continuous data and the {chi}2 test for categorical data. Statistical analysis of genotype distribution and allele frequencies was performed with the {chi}2 test or the Fisher exact test. We applied multiple stepwise logistic regression analysis to determine the independent risk factors related to the presence of HLP, with adjustments made for age at study enrollment, sex, and anthropometric and biomedical characteristics to prevent confounding bias. All tests were 2-tailed with statistical significance set at P <0.05 and were performed with SPSS software (SPSS for Windows 11.5).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We studied 126 unrelated HTG patients, 90 of whom were men [mean (SD) age 45.1 (9.9) years]; 46 of the patients had HLP (36 men and 10 women) and 80 patients did not (54 men and 26 women).

The mean age of the HLP patients was younger than that of patients without HLP (P = 0.006). The difference in sex distribution between these 2 groups was not statistically significant. The clinical characteristics of the patients are summarized in Table 1 . TG concentrations, ever-measured maximum TG concentrations, fasting glucose concentrations, hemoglobin A1c concentrations, and body mass indices were higher in HLP patients than in HTG patients without HLP.


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  		Table 1. Clinical characteristics of HTG patients with with and without HLP.1

prss1, spink1, and cftr gene mutations in htg patients with and without hlp
For the patient cohort in this study, we analyzed all exons, including flanking intronic regions of PRSS1, SPINK1, and CFTR, by denaturing HPLC and confirmed the sequences by direct sequencing if heteroduplexing occurred.

Thirteen HTG patients (10.3%) had CFTR mutations. The only CFTR mutation hot spot was in codon 556 (Ile556Val), and of the 13 patients with this substitution, 12 had HLP. The spectrum and distribution of the mutations are presented in Table 1Up . The frequency of CFTR mutation was much higher in HLP patients than in patients without HLP (26.1% and 1.3%, respectively, P <0.001). All of the mutations were present in the heterozygous state. No PRSS1 or SPINK1 mutations were detected in these 2 groups.

association of the cftr met470val polymorphism with hlp
Our results showed a significant difference in the frequency of the 470Val variant between HLP patients (78.3%) and HTG patients without HLP (35.0%, P <0.0001) (Table 1Up ).

cftr haplotype analysis and association of cftr haplotype with hlp
Haplotypes were assembled with the genotype data obtained from the 126 tested samples and with the permutation test–based haplotype program that we used in our previous studies (15)(18). We analyzed 5 loci, consisting of 125G/C, 1001 + 11>CT, 1540A>G (Met470Val), 2694T>G, and 4521G>A variants. Table 2 displays the results of our analyses of the estimated frequencies for 5-locus haplotypes for the CFTR polymorphic sites for patients and control individuals in the entire population. With 5 loci, there should be 32 (i.e., 25) haplotypes. Because of linkage disequilibrium in this small region, however, some haplotypes did not exist or were present at very low frequencies, so we have listed only haplotypes with frequencies >0.001. The results of the omnibus haplotype profile test (27) were statistically significant ({chi}2 = 38.74909; P = 0.001), indicating that the difference in the overall haplotype frequency profile between the patients and control individuals was significant and that some disease-predisposing haplotypes may occur in HTG patients with HLP. The 125G/1001 + 11C/470Met/2694T/4521G haplotype was a dominant haplotype in HTG patients. The 125C/1001 + 11C/470Val/2694T/4521G haplotype was associated with highest risk of HLP, with a large association effect [P = 0.001; odds ratio (OR), 21.94; 95% confidence interval (CI), 2.7–177.9] (Table 2 ).


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  		Table 2. CFTR haplotype analysis in HTG patients with and without HLP and P values for permutation test comparisons.

tnf promoter polymorphism associated with hlp
Of the 1031, 863, 857, 308, and 238 variable nucleotide positions in the TNF promoter, only the 863A variant was associated with HLP among the 126 HTG patients (71.7% vs 31.3%, P <0.001) (Table 1Up ).

gene-gene interaction: cftr met470val and tnf promoter 863c/a
Out result demonstrated that the functional CFTR variant 470Val and the TNF promoter 863A variant were both associated with HLP, with ORs of 3.70 (95% CI, 2.90–15.50) and 4.71 (95% CI, 2.14–10.38), respectively. In patients with CFTR 470Val and TNF 863A, the OR was higher (OR, 5.18; 95% CI, 2.21–12.16) (Table 3 ).


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  		Table 3. Multivariate analysis of predictors of HLP among HTG patients.

anthropometrics and biomedical variables associated with hlp among htg patients
Higher fasting glucose concentrations, hemoglobin A1c concentrations, ever-measured maximum TG concentrations, TG concentrations and body mass indices were associated with the occurrence of HLP in univariate analyses (Table 4 ). According to a multivariate analysis adjusted for age and sex, however, only fasting glucose concentration, ever-measured maximum TG concentration, and TG concentration were independent risk factors for the occurrence of HLP in HTG patients (Table 3Up ).


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  		Table 4. Univariate analyses of predictors of HLP among HTG patients.

genotype-phenotype association
Within the HLP group, patients with CFTR mutations, patients without CFTR mutations, and patients with CFTR Met470Val and TNF promoter variants demonstrated no significant differences with respect to the values for demographic, anthropometric, and biomedical variables.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
It is important and difficult to predict which hyperlipidemic patient is likely to develop an episode of pancreatitis. Comparative profiling of anthropometric and biomedical variables, coupled with a genetic host-susceptibility approach may revolutionize medical practice. We compared the clinical and genetic characteristics of HLP patients and HTG patients without HLP to identify the susceptibility to HLP within a small geographic area. This study is the first to address the role of genetic factors (other than genes involved in lipid metabolism) in HLP and is the first to demonstrate an association of CFTR mutation with HLP. It is the largest study to investigate HLP patients with patients with HTG alone as a control group; other studies have been case reports or case series (9)(10)(11). Our results revealed that the TG concentration, the fasting glucose concentration, and genetic factors (including CFTR mutation/variant/haplotype and TNF promoter polymorphism) may contribute to the development of HLP in HTG patients. Our results suggest that the occurrence of HLP in HTG patients is a multifactorial and polygenic event.

Our previous studies demonstrated that the spectrum of SPINK1, PRSS1 (unpublished data), and CFTR mutations/variants in our study patients with idiopathic chronic pancreatitis is very different from the spectrums in our healthy controls and pancreatitis patients from Western countries (15). In our current study, we detected no PRSS1 or SPINK1 gene mutations in HLP patients and in HTG control individuals. In contrast, the Ile556Val CFTR missense mutation was the most common mutation in our HLP patients. The Ile556Val mutation has a mild effect among CFTR mutations and appears to be associated with the pancreatitis phenotype (28). It was originally identified in patients with moderate pulmonary disease and insufficient pancreatic function (29). Ile556Val was also reported to be associated with chronic pulmonary disease in Singapore (30). The frequency of the Ile556Val mutation in our HLP patients was 26.1% (12 of 46). Interestingly, Ile556Val was also the most frequent CFTR mutation in our patients with idiopathic chronic pancreatitis (15). The frequency of the Ile556Val CFTR mutation in our healthy control population was about 1% (1 in 200) (15), similar to the frequency in our HTG patients without HLP (1.3%, 1 of 80). Because the TG concentrations in our chronic pancreatitis cohort were within the TG reference interval, HTG is not likely associated with the CFTR Ile556Val mutation. Furthermore, the mean TG concentration in our HLP patients with the Ile556Val mutation was not significantly different from that of patients without the Ile556Val mutation.

CFTR is a human gene with many mutations and variants; it is thus advisable to use a comprehensive method to analyze genetic alterations and to use a haplotype-based approach to address the role of CFTR variants in assessing the risks for distinct phenotypes of CFTR-related disease in different populations. Functional CFTR polymorphisms may also affect the expression of the CFTR protein. Met470Val, a common functional polymorphism in CFTR exon 10, affects intrinsic chloride channel activity (31). The cDNA single-nucleotide polymorphisms 2694T>G and 4521G>A may affect pre-mRNA splicing by changing regulatory-sequence motifs of exonic splice enhancers, leading to increased skipping of exons 9 and 12 and lower amounts of normal transcripts (32). The 125G/C polymorphism is associated with susceptibility to pancreatitis in Chinese individuals (15). Our study has shown that 470Val is associated with HLP among patients with HTG. In contrast, the 470Val variant is not associated with susceptibility to idiopathic chronic pancreatitis in Chinese individuals. Lee et al., however, reported that CFTR mutation with a 470Val background was associated with a pancreatic phenotype (pancreatitis) in the Korean population (33). Our haplotype analysis demonstrated a distinct haplotype (125C/1001 + 11C/470Val/2694T/4521G) that conferred a high risk for HLP among HTG patients and the haplotype differed from the one in the risk for idiopathic chronic pancreatitis in the Chinese population (15). These observations suggest that the role of a polymorphism such as Met470Val might be different in different disease subsets and in different ethnic populations.

Proinflammatory cytokines also play an important role in the development of pancreatitis. Different mutations in different genes may lead to different phenotypic presentations of pancreatitis, and even the same mutation may have different consequences depending on the interaction of the genetic background with environmental factors (20). TNF promoter polymorphism has been reported to be associated with the manifestation of hereditary pancreatitis (21) in Caucasians and of chronic pancreatitis in Chinese (18). Our study also has demonstrated that TNF promoter polymorphism (i.e., the 863A variant) is associated with the development of HLP in HTG patients. In an animal model, multiple proinflammatory cytokine genes were constitutively overexpressed in the pancreas of cftr(–/–) mice compared with wild-type mice (22). Furthermore, more severe pancreatitis attacks were observed after cerulein stimulation in cftr(–/–) mice (22). These findings may partially explain the susceptibility to acute pancreatitis in HTG patients with the CFTR variant. Our study has shown that gene-gene interaction between CFTR and TNF increased the risk of HLP development in HTG patients, in addition to producing high serum TG concentrations. Further studies including larger sample sizes and evidence from different ethnic groups are needed, along with investigations of the roles of these genes in the pathogenesis of HLP.

In conclusion, CFTR mutations are associated with a broad spectrum of pancreatic phenotypes. Identification of the association of CFTR and other genes with HLP have provided evidence that HTG patients with CFTR mutations/variants are more susceptible to developing HLP. This susceptibility increased after CFTR mutation/variant interaction with proinflammatory cytokines such as TNF. The development of HLP in HTG patients appears to be a multifactorial and polygenic event.


   Acknowledgments
 
Grant/funding Support: This work was supported by grants from the National Science Council, Taiwan (NSC 94-2314-B-002–272) and NTUH (National Taiwan University Hospital)-95-M-22; Liver Disease Prevention & Treatment Research Foundation.

Financial Disclosures: None declared.

Acknowledgments: The authors express their gratitude to all of the patients and control individuals who participated in the study.


   Footnotes
 
1 Nonstandard abbreviations: HTG, hypertriglyceridemia; TG, triglyceride; OR, odds ratio; CI, confidence interval; HLP, hyperlipidemic pancreatitis.

2 Human genes: PRSS1, protease, serine, 1 (trypsin 1); SPINK1, serine peptidase inhibitor, Kazal type 1; CFTR, cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7); and TNF, tumor necrosis factor (TNF superfamily, member 2).


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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