Showing papers by "Emmanuelle Masson published in 2015"

A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis

Abstract: Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 × 10(-6) by two-tailed Fisher's exact test). In three replication studies of nonalcoholic chronic pancreatitis, we 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 showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.

Polymorphisms at PRSS1–PRSS2 and CLDN2–MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study

Abstract: Objective Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1 – PRSS2 ( rs10273639 ; near the gene encoding cationic trypsinogen) and CLDN2 – MORC4 loci ( rs7057398 in RIPPLY1 and rs12688220 in MORC4 ). We aimed to refine these findings in a large European cohort. Design We studied 3062 patients with alcohol-related CP (ACP) or NACP and 5107 controls. Also, 1559 German patients with alcohol-associated cirrhosis or alcohol dependence were included for comparison. We performed several meta-analyses to examine genotype–phenotype relationships. Results Association with ACP was found for rs10273639 (OR, 0.63; 95% CI 0.55 to 0.72). ACP was also associated with variants rs7057398 and rs12688220 in men (OR, 2.26; 95% CI 1.94 to 2.63 and OR, 2.66; 95% CI 2.21 to 3.21, respectively) and in women (OR, 1.57; 95% CI 1.14 to 2.18 and OR 1.71; 95% CI 1.41 to 2.07, respectively). Similar results were obtained when German patients with ACP were compared with those with alcohol-associated cirrhosis or alcohol dependence. In the overall population of patients with NACP, association with rs10273639 was absent (OR, 0.93; 95% CI 0.79 to 1.01), whereas rs7057398 of the X chromosomal single nucleotide polymorphisms was associated with NACP in women only (OR, 1.32; 95% CI 1.15 to 1.51). Conclusions The single-nucleotide polymorphisms rs10273639 at the PRSS1–PRSS2 locus and rs7057398 and rs12688220 at the CLDN2 – MORC4 locus are associated with CP and strongly associate with ACP, but only rs7057398 with NACP in female patients.

Identification of a functional PRSS1 promoter variant in linkage disequilibrium with the chronic pancreatitis-protecting rs10273639

Abstract: We read with interest the paper by Derikx et al 1 replicating the association of the minor T allele of single nucleotide polymorphism rs10273639C/T, which is located 408 bp upstream of the translation initiation codon of the cationic trypsinogen ( PRSS1 ) gene, with a protective effect against chronic pancreatitis.2 However, whether rs10273639 is the causal variant or not remains unknown. Resolving this issue is of intrinsic biological interest, and it may also have diagnostic and therapeutic value. During resequencing of the promoter region of PRSS1 in 287 French Caucasian individuals (see online supplementary material), we found that rs4726576C/A, which is located 204 bp upstream of the translation initiation codon of PRSS1 (figure 1A), is in perfect linkage disequilibrium (LD) with rs10273639C/T (figure 2A). To identify which polymorphism is of potential biological relevance, we performed a two-step luciferase promoter reporter assay (see online supplementary material). First, we sought to establish whether the proximal promoter of PRSS1 is sufficient to drive specific gene expression. We thus constructed two luciferase reporter plasmids in the context of the two major alleles, one encompassing the two polymorphic sites …

Genetic and Electrophysiological Characteristics of Recurrent Acute Pancreatitis

Abstract: Objectives:The aim was to present the workup of patients with acute recurrent pancreatitis (ARP) for genetic analysis and electrophysiological testing.Methods:Patients with ARP with unknown etiology were referred for genetic testing and evaluation of cystic fibrosis transmembrane conductor r

Overrepresentation of Rare CASR Coding Variants in a Sample of Young French Patients With Idiopathic Chronic Pancreatitis.

Abstract: octreotide LAR (n = 1). Both supportive treatments and surveillancewere performed, also on patients who achieved remission. Progression-free survival (PFS) in LMs was calculated from the diagnosis of LMs (the time of presentation) to the last radiological evaluation of liver according to Response Evaluation Criteria in Solid Tumors criteria. Overall survival (OS) duration was calculated from the date of diagnosis of LMs to last follow-up or tumor-specific death. The relapse timewas computed from the date of complete tumor remission to that of recurrence. The imaging reports were all assessed by double-blinded reviewers. The clinical characteristics of baseline patients are listed in Table 1. Three cases (14.3%) showed discordance in grading between the primary and LM: from G1 in primary to G2 in LM. The positive rate of somatostatin receptor 2A for primary NF-PNETs was 80.0% (28/35). For survival, the median follow-up interval was 31.5 months (mean, 52.4 ± 50.9 months). The 1-, 2-, and 5-year OS were 94%, 76%, and 32%, respectively. The median survival for all patients was 57.8 months after diagnosis of LM (95% CI, 25.9–83.7). Univariate analysis showed that WHO classification (P = 0.022), synchronous metastases (P = 0.019), and Ki-67 index (P = 0.035) were significantly more likely to predict a worse prognosis. Among 22 NF-PNETs that obtained complete tumor remission, 21 (95.5%) showed tumor relapse. The mean relapse time was 46.6 ± 51.6 months (95% CI, 23.1–70.1; median, 23.6 months). We found regional lymph node metastases (P = 0.035), WHO classification (P = 0.047), and primary Ki-67 index (P=0.027)were significantly associatedwith relapse-free survival after complete remission. With regard to NF-PNETs with LM, the mean PFS in LMwas 6.1 ± 3.5 months (95% CI, 4.9–7.3; median, 5.6 months), liver-directed strategies for LM could significantly prolong PFS in LM compared with systemic therapies (P = 0.003, median PFS in LM, 6.6 vs 2.5 months; hazard ratio,0.33; 95% CI, 0.15–0.72). Moreover, patients who received liver-directed strategies for LM had a trend toward prolonged

Report of 2 CTRC Intronic Mutations Associated With Acute or Chronic Pancreatitis and Delineation of Their Pathogenic Molecular Mechanisms.

Abstract: than 50 years (median, 7 cm; range, 1–20 cm; P = 0.005). Although the median tumor size in men was significantly smaller than that in women aged younger than 50 years (P = 0.002), no significant difference was found in the tumor size of women aged 50 years and older and that of men (P = 0.955). In some cases, reduction in the tumor sizewas noted during follow-up.Nakahara et al reported that the size of SPNs in 18-year-old women gradually decreased from 4.5 to 1.5 cm without medication for a period of 10 years. Suzuki et al reported that the size of an SPN found in a 13-yearold boy decreased within 6 years from 5.1 cm to nonmeasurable without medication; however, SPN was diagnosed only on the basis of imaging studies such as computed tomography, not pathological examination. Yoon et al reported that in a case of SPN with multiple liver metastasis found in a 14-year-old boy during the follow-up period of 13 years, the primary tumor size decreased from 11 to 3 cm and the metastatic tumor (maximum size, 6.0 cm) completely disappeared without medication. Whether female hormones influenced tumor shrinkage in these 3 aforementioned cases is unknown because the studies do not mention the serum levels of estrogen or progesterone. With regard to difference in tumor size between men and women, Takahashi et al reported that SPNs in men are smaller than those in women. In contrast, Tien et al reported no significant difference in the tumor size between men and women. According to our comparison, the tumor size of SPNs in women aged 50 years and older, presumed to be postmenopausal women, was significantly smaller than that in women aged younger than 50 years, presumed as premenopausal women. In addition, the tumor size in men was significantly smaller than that in all women, but no significant difference was observed between men and women aged 50 years and older. These results indicate that female hormones such as estrogen and progesterone may influence the proliferation of SPNs and that the tumor size may be reduced as a result of decreased secretion of estrogen and progesterone after menopause. In conclusion, we compared the tumor size of SPNs among premenopausal women as well as postmenopausal women and men by using published literature. The tumor size in postmenopausal women was significantly smaller than that in premenopausal women; however, no significant difference was observed when compared with that in men. Our results suggest that female hormones influence the growth of SPNs. In addition, antifemale hormone agents may be

Sitagliptin-Associated Pancreatitis: A Report of 4 Cases

Abstract: Objective: Sitagliptin is a new oral glucose-loweri ng medication that acts via the incretin hormone system. The most common side-effects are headache and pharyngitis. Acute pancreatitis are rarely described in literature.