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Evaluation of the role of CFTR in alcohol related pancreatic disease
  1. J OCKENGA
  1. Department of Gastroenterology
  2. Medical School Jannover
  3. 30625 Hannover, Germany
  4. Department of Human Genetics
  5. Medical School Hannover
  6. 30625 Hannover,Germany
  7. Department of Gastroenterology
  8. Medical School Hannover
  9. 30625 Hannover,Germany
  1. Dr J Ockenga. Ockenga.Johann{at}mh-hannover.de
  1. M STUHRMANN
  1. Department of Gastroenterology
  2. Medical School Jannover
  3. 30625 Hannover, Germany
  4. Department of Human Genetics
  5. Medical School Hannover
  6. 30625 Hannover,Germany
  7. Department of Gastroenterology
  8. Medical School Hannover
  9. 30625 Hannover,Germany
  1. Dr J Ockenga. Ockenga.Johann{at}mh-hannover.de
  1. M P MANNS
  1. Department of Gastroenterology
  2. Medical School Jannover
  3. 30625 Hannover, Germany
  4. Department of Human Genetics
  5. Medical School Hannover
  6. 30625 Hannover,Germany
  7. Department of Gastroenterology
  8. Medical School Hannover
  9. 30625 Hannover,Germany
  1. Dr J Ockenga. Ockenga.Johann{at}mh-hannover.de
  1. X ESTIVILL,
  2. T CASALS
  1. Centre de Genètica Mèdica i Molecular-IRO
  2. L'Hospitalet de Llobregat, Barcelona, Spain
  3. Grup de Recerca d'Epidemiologia Clínica i Molecular del Càncer
  4. Institut Municipal d'Investigació Mèdica
  5. Universitat Pompeu Fabra, Barcelona
  6. Universitat Autònoma de Barcelona, Spain
  7. Servei de Digestiu, Hospital Vall d'Hebron
  8. Barcelona, Spain
  9. Unitat de Biologia Cel.lular i Molecular
  10. Institut Municipal d'Investigació Mèdica
  11. Universitat Pompeu Fabra, Barcelona, Spain
  1. Dr Malats. nuria{at}imim.es
  1. N MALATS,
  2. M PORTA
  1. Centre de Genètica Mèdica i Molecular-IRO
  2. L'Hospitalet de Llobregat, Barcelona, Spain
  3. Grup de Recerca d'Epidemiologia Clínica i Molecular del Càncer
  4. Institut Municipal d'Investigació Mèdica
  5. Universitat Pompeu Fabra, Barcelona
  6. Universitat Autònoma de Barcelona, Spain
  7. Servei de Digestiu, Hospital Vall d'Hebron
  8. Barcelona, Spain
  9. Unitat de Biologia Cel.lular i Molecular
  10. Institut Municipal d'Investigació Mèdica
  11. Universitat Pompeu Fabra, Barcelona, Spain
  1. Dr Malats. nuria{at}imim.es
  1. L GUARNER
  1. Centre de Genètica Mèdica i Molecular-IRO
  2. L'Hospitalet de Llobregat, Barcelona, Spain
  3. Grup de Recerca d'Epidemiologia Clínica i Molecular del Càncer
  4. Institut Municipal d'Investigació Mèdica
  5. Universitat Pompeu Fabra, Barcelona
  6. Universitat Autònoma de Barcelona, Spain
  7. Servei de Digestiu, Hospital Vall d'Hebron
  8. Barcelona, Spain
  9. Unitat de Biologia Cel.lular i Molecular
  10. Institut Municipal d'Investigació Mèdica
  11. Universitat Pompeu Fabra, Barcelona, Spain
  1. Dr Malats. nuria{at}imim.es
  1. F X REAL
  1. Centre de Genètica Mèdica i Molecular-IRO
  2. L'Hospitalet de Llobregat, Barcelona, Spain
  3. Grup de Recerca d'Epidemiologia Clínica i Molecular del Càncer
  4. Institut Municipal d'Investigació Mèdica
  5. Universitat Pompeu Fabra, Barcelona
  6. Universitat Autònoma de Barcelona, Spain
  7. Servei de Digestiu, Hospital Vall d'Hebron
  8. Barcelona, Spain
  9. Unitat de Biologia Cel.lular i Molecular
  10. Institut Municipal d'Investigació Mèdica
  11. Universitat Pompeu Fabra, Barcelona, Spain
  1. Dr Malats. nuria{at}imim.es

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Editor,—In up to 30% of patients with idiopathic pancreatitis (IP) a mutation of at least one or both alleles of the cystic fibrosis transmembrane conductance regulator (CFTR) gene can be identified.1-3 The study by Malats et al (

) addressed the question of whether CFTR mutations, possibly together with environmental factors such as alcohol, may be associated with chronic pancreatitis or pancreatic cancer. The vast majority of the pancreatic patients (86.4%) investigated by Malats et al were diagnosed as having alcoholic pancreatitis (AP), and 75.4% of the cancer patients were daily drinkers. The authors found no statistically significant difference in the prevalence of delta-F508 (0%; 2.4%) and the 5T allele (10.5%; 5.5%) in the AP or cancer groups compared with the expected prevalence in the general population. The lack of a positive association of both delta-F508 and the 5T allele with AP is neither surprising nor argues against involvement of CFTR variations in the development of AP, considering the following.

In cystic fibrosis (CF), the degree of correlation between CFTR genotype and CF phenotype varies between clinical components but is highest for pancreatic involvement.4 CFTR mutations can simplify be divided into “severe” and “mild” with respect to the degree to which mutations impair CFTR function.5Approximately 85% of CF patients suffer from pancreatic insufficiency (PI) while ∼15% are pancreatic sufficient (PS). Generally patients with PI carry two “severe” mutations whereas PS is associated with at least one “mild” mutation (fig 1). In CF, pancreatitis is seen rather frequently in PS patients but not in PI patients. Today, more than 850 CF mutations have been reported to the CF Consortium (http://www.genet.sickkids.on.ca/cftr). The deletion delta-F508, accounting for about 70% of mutant CF alleles worldwide and approximately 53% in Spain, studied by Malats et al, is responsible for severe functional loss of CFTR function. Three additional studies on the prevalence of an abnormal CFTR allele in AP have been published as full papers.3 6 7 Pooling these four studies, one or two mutant CFTR alleles were detected in 9/217 (4.1%) patients with AP. But the detection rate varies between 0% and 8.5% depending on the sensitivity of the screening method to detect an abnormal CF allele in the corresponding population (53–94%). None of the studies revealed a positive association of the 5T allele with IP or AP. Compared with the general population, delta-F508 was significantly more frequent in British and US Caucasian, but not in Australian or Spanish AP patients.

Figure 1

Disease manifestation according to residual cystic fibrosis transmembrane conductance regulator (CFTR) function as a result of the combination of severe or mild CFTR genotype. CF, cystic fibrosis; PS, pancreatic sufficiency; PI, pancreatic insufficiency; CBAVD, congenital absence of the vas deferens.

Up to now no environmental or genetic cofactor was identified in patients with mutant CFTR alleles associated IP, suggesting that impairment of CFTR function alone may be enough to induce pancreatitis.1 2 3 8 9 On the other hand it may be speculated that patients with an abnormal CFTR allele, who develop pancreatitis in conjunction with alcohol abuse, may be characterised by a higher residual CFTR function, which by itself is not capable of inducing pancreatitis.

Therefore, to delineate the genetic background of pancreatic disease in AP it seems to be more appropriate to investigate the prevalence of uncommon mild variants (“atypical mutations”) in large cohorts of AP patients than to test for the more common (“severe, typical”) mutations of the CFTR gene in small patient groups. It has to be considered that the test kits for CFTR mutations often used in routine screening are usually designed to detect the more severe CF mutations. This would result in missing a substantial number of patients with milder CFTR mutations, as suggested by preliminary data on more comprehensive genetic testing in patients with ICP.8

References

Reply

Editor,—We agree with the view of Ockengaet al that from an ideal research perspective a complete analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene should be performed for cases of pancreatitis before a definitive statement on the role of this gene in chronic pancreatitis can be made. However, it is well known that 18–30% of patients with CFTR related disorders (congenital bilateral absence of the vas deferens and bronchiectasis) have only oneCFTR mutated allele.1-1-1-3 Thus despite our study being based on only the two most commonCFTR mutations (F508del and 5T), these two alterations should suffice to rule out or confirm a potential role of CFTR in patients with chronic pancreatic diseases. Furthermore, complete analysis of CFTR in the general population has led to the identification of amino acid variants of yet unknown functional significance in about 10% of subjects.1-4 It is highly likely that complete analysis ofCFTR would render a large number of amino acid changes of uncertain clinical and functional consequences, as it has been shown for patients with asthma.1-5 As we proposed in our paper (

), only the design of large studies specifically addressing these issues in target and adequate control populations and a comprehensive molecular analysis ofCFTR will answer the question on the role of this gene in chronic pancreatic disease.

References

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