Gastroenterology

Gastroenterology

Volume 121, Issue 6, December 2001, Pages 1310-1319
Gastroenterology

Clinical Science
Cystic fibrosis gene mutations and pancreatitis risk: Relation to epithelial ion transport and trypsin inhibitor gene mutationsā˜†,ā˜†ā˜†,ā˜…

https://doi.org/10.1053/gast.2001.29673Get rights and content

Abstract

Background & Aims: Nonalcoholic chronic pancreatitis is usually idiopathic and often associated with cystic fibrosis gene (CFTR) mutations. It is unknown whether pancreatitis risk correlates with having 1 or 2 CFTR mutations, abnormal epithelial ion transport, or mutations of other genes. Methods: We tested 39 patients with idiopathic chronic pancreatitis (mean age at diagnosis, 33 years) for common mutations of CFTR and of genes encoding a trypsin inhibitor (PSTI) and trypsinogen (PRSS1). To exclude hereditary pancreatitis, we initially relied on family history and subsequently tested for PRSS1 mutations. Twenty subjects were tested for rare CFTR mutations (DNA sequencing) and 11 were tested for extrapancreatic CFTR function (clinical and physiologic evaluation). Results: Mutations were identified in 24 of 39 subjects. Nine patients had cystic fibrosisā€“causing mutations, 8 of whom also had mild-variable mutations. Eight others had only mild-variable mutations. Nine subjects had the N34S PSTI mutation and 1 had hereditary pancreatitis (R122H, PRSS1). Pancreatitis risk was increased approximately 40-fold by having 2 CFTR mutations (P < 0.0001), 20-fold by having N34S (P < 0.0001), and 900-fold by having both (P < 0.0001). Subjects with 2 CFTR mutations had abnormal nasal epithelial ion transport and clinical findings suggesting residual CFTR function between that in cystic fibrosis and in carriers. By contrast, subjects with only PSTI mutations had normal CFTR function. Conclusions: CFTR-related pancreatitis risk correlates with having 2 CFTR mutations and reduced extrapancreatic CFTR function. The N34S PSTI mutation increased risk separately. Testing for pancreatitis-associated CFTR and PSTI genotypes may be useful in nonalcoholic pancreatitis.

GASTROENTEROLOGY 2001;121:1310-1319

Section snippets

Study subjects

Our prior study examined 27 subjects who were identified by reviewing charts of patients referred to Duke University Medical Center from 1991 to 1996, as described.4 Briefly, each subject was white and had multiple episodes of abdominal pain with objective evidence of pancreatitis; we excluded patients with moderate alcohol use (over 15 drinks/week at any time), hereditary pancreatitis by family history, or CF lung disease.4 When subsequent genetic testing diagnosed hereditary pancreatitis15 in

CFTR mutations in individual subjects

Twenty-six CFTR mutations were detected in 17 subjects (Table 2).There were 21 common mutations; 9 were severe (CFsev: Ī”F508, N1303K, 621+1G>T) and 12 were mild-variable (CFm-v: 5T, R117H). Among the 9 subjects with severe mutations (nominal CF carriers), 3 had common milder CFTR mutations (nos. 1ā€“3), 5 had rare mutations that were detected by DNA sequencing (nos. 4ā€“8), and 1 had a normal second CFTR allele based on DNA sequencing (no. 10). Each of the rare mutations detected in subjects 4ā€“8 is

Discussion

This study shows that idiopathic chronic pancreatitis is often associated with having 2 CFTR mutations or 1 PSTI mutation. These genotypes occurred in many cases diagnosed by age 50 years (16/32 after excluding hereditary pancreatitis) and in most diagnosed by 21 years old (7/10). Pancreatitis risk was highest in those with 2 CFTR mutations plus N34S.

For CFTR, the greatest risk of pancreatitis is associated with compound heterozygote genotypes containing 1 severe mutation plus 1 mild-variable

Acknowledgements

The authors thank R. Pace and C. Foy for technical assistance, S. Minnix for assistance recruiting subjects, Dr. S. Schmidt for assistance with statistics, and the following physicians for providing clinical data about their patients: J. D. Bornstein, J. Baillie, M. S. Branch, and W. R. Treem (Duke University Medical Center), T. Desai (Beaumont Hospital, Royal Oaks, MI), S. Shutz (Wilford Hall Medical Center, Lackland AFB, TX), T. H. Baron (University of Alabama Medical Center, Birmingham, AL),

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    ā˜†

    Supported in part by grants from the Department of Veterans Affairs, the Cystic Fibrosis Foundation, and the National Institutes of Health.

    ā˜†ā˜†

    Address requests for reprints to: Jonathan A. Cohn, M.D., Box 3378, Duke University Medical Center, Durham, North Carolina 27710. e-mail: [email protected]; fax: (919) 684-4983.

    ā˜…

    Drs. Noone and Zhou contributed equally to this work.

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