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Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers
Author(s) -
Cohn Jonathan A.,
Neoptolemos John P.,
Feng Jig,
Yan Jin,
Jiang Zefei,
Greenhalf William,
McFaul Christopher,
Mountford Roger,
Sommer Steve S.
Publication year - 2005
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20232
Subject(s) - allele , cystic fibrosis , genotype , cystic fibrosis transmembrane conductance regulator , pancreatitis , biology , trypsinogen , hereditary pancreatitis , allele frequency , mutation , medicine , gastroenterology , genetics , gene , biochemistry , trypsin , enzyme
Cystic fibrosis (CF) is a recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. The risk of idiopathic chronic pancreatitis (ICP) is increased in individuals who have CFTR genotypes containing a CF‐causing mutation plus a second pathogenic allele. It is unknown whether the risk of ICP is increased in CF carriers who have one CF‐causing mutation plus one normal allele. In this study, 52 sporadic cases of ICP were ascertained through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen mutations were excluded. DNA was comprehensively tested for CFTR mutations using a robotically enhanced, multiplexed, and highly redundant form of single‐strand conformation polymorphism (SSCP) analysis followed by DNA sequencing. Fifteen subjects had a total of 18 pathogenic CFTR alleles. Eight subjects had common CF‐causing mutations. This group included seven CF carriers in whom the second CFTR allele was normal (4.3 times the expected frequency, P=0.0002). Three subjects had compound heterozygotes genotypes containing two pathogenic alleles (31 times the expected frequency, P<0.0001). A variant allele of uncertain significance (p.R75Q) was detected in eight of the 52 ICP subjects and at a similar frequency (13/96) in random donors. ICP differs from other established CFTR‐related conditions in that ICP risk is increased in CF carriers who have one documented normal CFTR allele. Having two CFTR mutations imparts a higher relative risk, while having only one mutation imparts a higher attributable risk. Hum Mutat 26(4), 303–307, 2005. © 2005 Wiley‐Liss, Inc.