ABCMdb

PMID: 15181620

Maisonneuve P, Campbell P 3rd, Durie P, Lowenfels AB
Pancreatitis in hispanic patients with cystic fibrosis carrying the R334W mutation.
Clin Gastroenterol Hepatol. 2004 Jun;2(6):504-9., [PubMed]

Sentences

No. Mutations Sentence Comment

26 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ile148Thr ABCC7 p.Gly85Glu ABCC7 p.Arg560Thr Of Ͼ1000 identified mutations in the CFTR gene, only 25 proven disease-causing mutant alleles (⌬F508, G551D, G542X, R553X, W1282X, R347P, NI303K, R560T, ⌬I507, 1717-1GϾA, A455E, 3120ϩ1GϾA, 621ϩ1GϾT, R117H, 711ϩ1GϾT, R1162X, 3849ϩ10kbCϾT, 2789ϩ5GϾT, R334W, G85E, 1078delT, 1898ϩ1GϾT, 2184delA, 3659delC, and I148T) are recommended by the American College of Medical Genetics for routine diagnostic and carrier testing.16 Most of these are routinely recorded in the CFF registry, but rarer mutations can be recorded if identified by more comprehensive testing. Login to comment 28 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg560Thr Patients were classified according to their genotype: those carrying 2 severe mutations (⌬F508, ⌬I507, G542X, G551D, N1303K, R553X, R560T, R1162X, W1282X, 621ϩ1GϾT, 711ϩ1GϾT, 1717-1GϾA, 2184delA, and 3659delC), which generally are associated with pancreas insufficiency (PI); and those carrying at least 1 mild mutation (3849ϩ10kbCϾT, R117H, 2789ϩ5GϾA, R347P, R334W, and A455E), which are generally associated with PS. Login to comment 29 ABCC7 p.Gly85Glu The remaining patients were grouped as "genotype incompletely determined" if they carried either mutations for which pancreas function is not well determined (G85E, 1898ϩ1GϾA, and 1078delT) or other or unrecognized mutations.17 Data regarding pancreatitis and genotype were extracted directly from the CFF registry database and collected by using the standard CF registry questionnaire.18 We performed a nested case-control study. Login to comment 42 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly85Glu The greatest frequency of pancreatitis was reported in patients carrying at least 1 R334W mutation (19.0%), followed by patients with a 2789ϩ5GϾA mutation (14.9%), R117H mutation (11.7%), R347P mutation (11.6%), 3849ϩ10kbCϾT mutation (9.0%), A455E mutation (8.3%), or G85E mutation (8.0%; Table 1). Login to comment 44 ABCC7 p.Arg334Trp After adjustment for age at last visit, age at diagnosis of CF, year of diagnosis of CF, and sex, patients with an R334W mutation had a 25.8-fold (95% confidence interval [CI], 13.2-50.5) greater risk for reporting at least 1 episode of acute pancreatitis than patients with PI and 43.6-fold (95% CI, 15.3-124) greater risk for reporting multiple attacks of pancreatitis. Login to comment 46 ABCC7 p.Arg334Trp Eleven of 39 women (28%) with an R334W mutation reported pancreatitis against only 4 of 40 male patients (10%; P ϭ 0.048). Login to comment 47 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly85Glu This sex difference was unique for R334W and was not apparent for patients with other pancreatitis-related genotypes (R347P, R117H, G85E, 2789ϩ5GϾA, or 3849ϩ10kbCϾT) or for patients with pancreatitis in the PI group. Login to comment 48 ABCC7 p.Arg334Trp Thirty-eight of 79 patients (48%) carrying an R334W mutation were Hispanic, a much greater proportion than in the global CF population (5.6%; P Ͻ 0.001). Login to comment 50 ABCC7 p.Arg334Trp Thirty-four percent of Hispanic patients with CF from Puerto Rico carry the R334W mutation, the second most common mutation after ⌬F508. Login to comment 52 ABCC7 p.Arg334Trp Eight of 15 patients with pancreatitis carrying an R334W mutation were Hispanics. Login to comment 54 ABCC7 p.Arg334Trp When we restricted the cohort to patients with CF born after 1988, a period for which information on pancreatitis was recorded prospectively, 5 of 29 children (17.2%) Ͻ12 years carrying an R334W mutation developed pancreatitis. Login to comment 56 ABCC7 p.Arg117His Four of 54 patients (7.4%) with an R117H mutation and 2 of the remaining patients with PS (1.7%) developed pancreatitis. Login to comment 59 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Other mutants, such as R117H, R334W, and R347P, which are correctly processed and retain some residual apical chloride channel function, are associated with a milder form of the disease.20,21 However, the vast majority of CF centers in Europe and the United States do not formally assess pancreatic function at diagnosis, and many assume that a patient with a diagnosis of CF has PI and requires enzyme supplements. Login to comment 61 ABCC7 p.Arg334Trp However, we were able to identify a rare CFTR mutation (R334W) associated with a particularly high risk for developing pancreatitis that was not reported to date. Login to comment 62 ABCC7 p.Arg334Trp In a Spanish report of the genotype-phenotype relationship in patients carrying an R334W mutation, 67% of the 12 patients have PS.22 In our study, no patient carrying this Table 1. Login to comment 64 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro of patients Patients with pancreatitis At least 1 attack of pancreatitis Ն2 attacks of pancreatitis All genotyped patients with CF 17,871 364 (2.0) - - Pancreas insufficienta 12,997 114 (0.9) 1.0 (reference) 1.0 (reference) Pancreas sufficientb 868 103 (11.9) 9.3 (6.7-12.8) 14.8 (8.2-26.8) 3849ϩ10kbCϾT/anyc 256 23 (9.0) 5.3 (3.1-9.0) 7.1 (2.8-18.3) R117H/anyc 249 29 (11.7) 8.9 (5.5-14.5) 14.1 (6.1-32.7) 2789ϩ5GϾA/anyc 134 20 (14.9) 13.2 (7.3-23.8) 10.4 (3.1-35.5) R347P/anyc 95 11 (11.6) 11.1 (5.3-23.1) 26.6 (9.1-77.4) R334W/anyc,d 79 15 (19.0) 25.8 (13.2-50.5) 43.6 (15.3-124) A455E/anyc 60 5 (8.3) 3.4 (2.6-4.4) 18.3 (5.0-67.9) Genotype incompletely determinede 4006 147 (3.7) 3.4 (2.6-4.4) 6.3 (3.8-10.5) NOTE. Values expressed as number (percent) or odds ratio (95% confidence interval). Login to comment 67 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg560Thr aPatients with pancreas insufficiency (PI) carrying 2 PI mutations (⌬F508, ⌬I507, G542X, G551D, N1303K, R553X, R560T, R1162X, W1282X, 621ϩ1GϾT, 711ϩ1GϾT, 1717-1GϾA, 2184delA, 3659delC). Login to comment 68 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro bPatients with pancreas sufficiency (PS) carrying at least 1 PS mutation (3849ϩ10kbCϾT, R117H, 2789ϩ5GϾA, R347P, R334W, A455E). Login to comment 70 ABCC7 p.Arg334Trp dFive patients were homozygous for the R334W mutation; 2 patients (40%) reported pancreatitis. Login to comment 71 ABCC7 p.Gly85Glu ePatients with either genotype for which pancreas function is not well determined (G85E, 1898ϩ1GϾA, 1078delT) or with other or unrecognized mutations. Login to comment 73 ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Genotype Distribution of Patients With CF in Puerto Rico and Other States According to Ethnicity Genotypea Hispanics Non-Hispanics Puerto Rico United States United States ⌬F508/any 25 (66) 796 (83) 15,561 (92) R334W/any 13 (34) 25 (3) 41 (0.2) ⌬I507/any 4 (11) 78 (8) 436 (3) G542X/any 2 (5) 88 (9) 754 (4) R553X/any 1 (3) 15 (2) 324 (2) N1303K/any 1 (3) 28 (3) 424 (3) 621ϩ1GϾT/any 1 (3) 9 (1) 314 (2) Not identified/any 18 (47) 269 (28) 3137 (19) NOTE. Values expressed as number (percent). Login to comment 76 ABCC7 p.Arg334Trp Overall, the R334W mutation is a rare mutation and has been identified in only 79 of the genotyped patients with CF (0.44%) in this cohort, but was identified in 34% of Hispanic patients with CF living in Puerto Rico. Login to comment 79 ABCC7 p.Arg334Trp The R334W mutation originally was found in 2 Spanish patients with CF, but its frequency is relatively modest in most parts of Spain (1.6%) or neighboring countries (2.6%, south of France).23,24 The greatest rates have been reported in Andalucia (5%),25 the Canary Islands (4.3%), and Crete (11.5%),23 but they are still much lower than that we reported in Puerto Rico. Login to comment 81 ABCC7 p.Arg334Trp Puerto Rico itself was discovered by Columbus in 1493 and remained Spanish until it was ceded to the United States in 1898 after the Spanish- American War. Therefore, it is likely that the R334W mutation was brought to Puerto Rico by a Spaniard many generations ago to allow sufficient time for this mutant gene to achieve a prevalence rate of 34% in the current Puerto Rican CF population. Login to comment 82 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp The R334W mutation also has been found in 3.9% of patients with CF in Uruguay, another country with massive historical immigration from Spain.26 Several study groups have identified an excess of the R117H and other mild CFTR mutations in patients with idiopathic pancreatitis, but failed to identify patients with the R334W mutation. Login to comment 84 ABCC7 p.Arg334Trp Because the R334W mutation is associated strongly with a specific ethnic group and there is no obvious Table 3. Login to comment 85 ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Gly85Glu ABCC7 p.Gly85Glu Characteristics of 15 Patients With CF Carrying an R334W Mutation Who Developed Pancreatitis Genotype Sex Race Ethnicity Age at CF (yr) CF diagnosis Age (yr)a R334W/⌬F508 Female White Non-Hispanic 4 Respiratory symptoms 38 R334W/⌬F508 Male White Non-Hispanic 23 Respiratory symptoms, nasal polyps 51 R334W/⌬F508 Female White Non-Hispanic 7 Respiratory symptoms 28 R334W/⌬F508 Female White Non-Hispanic 16 Electrolyte imbalance, respiratory symptoms 34 R334W/⌬F508 Male White Hispanic 13 Respiratory symptoms, electrolyte imbalance, failure to thrive Dead 18 R334W/⌬I507 Female White Hispanic 29 Respiratory symptoms, steatorrhea 31 R334W/G542X Female White Hispanic 7 Respiratory symptoms 10 R334W/R553X Female White Hispanic 10 Respiratory symptoms 21 R334W/G85E Female White Hispanic 0 Respiratory symptoms 8 R334W/G85E Female White Hispanic 4 Failure to thrive 10 R334W/R334W Male White Hispanic 4 Meconium ileus 10 R334W/R334W Female White Hispanic 0 Respiratory symptoms 41 R334W/? Login to comment 86 ABCC7 p.Arg334Trp Male White Non-Hispanic 0 Respiratory symptoms, failure to thrive, family history 16 R334W/? Login to comment 87 ABCC7 p.Arg334Trp Female Black Non-Hispanic 0 Failure to thrive 6 R334W/? Login to comment 93 ABCC7 p.Arg334Trp reason to explain why this particular "mild" missense mutation carries an increased risk for this complication, there also is a possibility of an association between R334W and another non-CFTR "gene modifier," which itself increases the risk for pancreatitis. Login to comment 103 ABCC7 p.Arg334Trp There are no current data to determine whether asymptomatic carriers of the R334W mutation are at greater risk for developing pancreatitis or whether this mutation is frequent in Hispanic patients with idiopathic pancreatitis, especially those living in or originating from Puerto Rico. Login to comment 105 ABCC7 p.Arg334Trp Another alternative would be to obtain information on the history of pancreatitis in families in which 1 child has been identified with the R334W mutation. Login to comment 106 ABCC7 p.Arg334Trp These studies of patients heterozygous for CF with a single R334W mutant allele might help explain the pathogenesis of idiopathic pancreatitis. Login to comment