Carboxyl-ester lipase is a digestive pancreatic enzyme encoded by the highly polymorphic CEL gene1. Mutations in CEL cause maturity-onset diabetes of the young (MODY) with pancreatic exocrine dysfunction2. Here we identified a hybrid allele (CEL-HYB), originating from a crossover between CEL and its neighboring pseudogene CELP. In a discovery cohort of familial chronic pancreatitis cases, the carrier frequency of CEL-HYB was 14.1% (10/71) compared with 1.0% (5/478) in controls (odds ratio [OR] = 15.5, 95% confidence interval [CI] = 5.1-46.9, P = 1.3 × 10−6). Three replication studies in non-alcoholic chronic pancreatitis cohorts identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2, 95% CI = 3.2-8.5, P = 1.2 × 10−11; formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models revealed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. The hybrid variant of CEL is the first chronic pancreatitis gene identified outside the protease/antiprotease system of pancreatic acinar cells.
Background & Aims-Acute pancreatitis is characterized by an activation cascade of digestive enzymes in the pancreas. The first of these, trypsinogen, can be converted to active trypsin by the peptidase cathepsin B (CTSB). We investigated whether cathepsin L (CTSL), the second most abundant lysosomal cysteine proteinase, can also process trypsinogen to active trypsin and has a role in pancreatitis.
Using surface-enhanced laser desorption ionization mass spectrometry (SELDI/TOF-MS) and ProteinChip technology, coupled with a pattern-matching algorithm and serum samples, we screened for protein patterns to differentiate gastric cancer patients from noncancer patients. A classifier ensemble, consisting of 50 decision trees, correctly classified all gastric cancers and all controls of a training set (100% sensitivity and 100% specificity). Eight of 9 stage I gastric cancers (88.9% sensitivity for stage I) were correctly classified. In addition, 28 sera from gastric cancer patients taken in different hospitals were correctly classified (100% sensitivity). Furthermore, all 11 control sera obtained from patients without gastric cancer (100% specificity) were classified correctly and 29 of 30 healthy blood-donors were classified as noncancerous. ProteinChip technology in conjunction with bioinformatics allows the highly sensitive and specific recognition of gastric cancer patients.
To the Editor: I have several concerns about the metaanalysis by Dr Gould and colleagues 1 about positron emission tomography (PET) imaging for diagnosis of pulmonary nodules. First, the prevalence of malignancy in the articles that they included was extremely high (55%-100%; mean, 72%), suggesting that the types of lesions that have been evaluated thus far with PET imaging are those with a very high likelihood of malignancy. The accuracy of PET imaging may be far lower in a population in whom the risk of malignancy is lower. The sensitivity might be lower because of a milder spectrum of disease in patients with a lower risk of malignancy, and the specificity might be lower because of more overlapping PET findings in small lesions of varying etiologies. 2 Thus, the results of their review are only applicable to a population of patients with a very high prevalence of cancer. Until additional studies provide evidence that PET imaging is accurate in a population with a low prevalence of cancer, it is premature to suggest application of PET imaging in this group, as the authors have done.Second, Gould et al did not sufficiently address the issue of heterogeneity of the different studies in their meta-analysis. The data appear fairly consistent with respect to sensitivity but appear extremely variable with respect to specificity, and it is not appropriate to average the specificity estimates when the results are so inconsistent. While I believe that specificity is less important if patients would otherwise proceed to surgery in the absence of PET imaging, if PET imaging were applied to a low-risk population as the authors suggest, the false-positive rate would become quite important.Finally, the authors apply receiver operating characteristic (ROC) curve methods to the data, but it does not appear that the different accuracy reported by the different studies has much to do with threshold differences. Was there truly a significant correlation between the sensitivity and the false-positive rate? I would guess that sorting the studies in Figure 1 by sensitivity would not show an inverse relationship between sensitivity and specificity but rather would confirm that there is simply a lot of heterogeneity with respect to specificity. ROC curve methodology is complex and difficult to understand, and I think it is best used to compare the results of more than 1 test. In this case, the ROC curve does not provide accurate information for the clinician who would like to know what performance they can hope to obtain from this test. It seems clear that the sensitivity of PET imaging (in a high-risk population) is high but that the specificity is more difficult to estimate.
ObjectiveAlcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.Design1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.ResultsWe replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.ConclusionAn inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
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