No Association Between CEL-HYB Hybrid Allele and Chronic Pancreatitis in Asian Populations.
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ABSTRACT:
SUBMITTER: Zou WB
PROVIDER: S-EPMC5380763 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:CEL-HYB is a hybrid allele that arose from a crossover between the 3' end of the Carboxyl ester lipase (CEL) gene and the nearby CEL pseudogene (CELP) and was recently identified as a risk factor for chronic pancreatitis. Since chronic pancreatitis is a risk factor for the development of pancreatic cancer, we compared the prevalence of the CEL-HYB allele in patients with pancreatic ductal adenocarcinoma to spousal controls and disease controls. The CEL-HYB allele was detected using Sanger and next generation sequencing. There was no significant difference in the prevalence of the CEL-HYB allele between cases with pancreatic ductal adenocarcinoma compared to controls; 2.6% (22/850) vs. 1.8% (18/976) (p=0.35). CEL-HYB carriers were not more likely to report a history of pancreatitis. Patients with pancreatic cancer are not more likely than controls to be carriers of the CEL-HYB allele.
| S-EPMC5584208 | biostudies-literature
Project description: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.
| S-EPMC5321495 | biostudies-literature
Project description:The aims of this study were to summarize results on the association of HLA-DRB1 with rheumatoid arthritis (RA) in Asians and to determine if the shared epitope (SE) hypothesis could explain the meta-analysis results. Among the papers published between January 1987 and July 2006 on RA susceptibility in Asian-Mongoloid populations (Korean, Japanese, Chinese, and Thai), 12 were selected for the metaanalysis. Mongoloid-Asian patients with RA had significantly higher frequencies of HLA-DRB1*0101, *0401, *0410, and *1001 than controls (OR 1.5-2.1, p<0.05 for association). When analyses were restricted to more ethnically homogeneous populations, HLA-DRB1*0405 showed a significant susceptibility to RA in Koreans (OR 5.65, 95% CI 4.32-7.39), whereas the HLA-DRB1*0301, *0403, *0406, *0701, *1301, and *1405 alleles showed protective association with RA (OR 0.32-0.70, p<0.05 for association). In conclusion, it was found that HLA-DRB1 *0101, *0401, *0405, *0410, and *1001 are susceptible, while HLA-DRB1* 0301, *0403, *0406, *0701, *1301, and *1405 are protective in Asian-Mongoloids. All the RA-associated alleles except DRB1*0301 could be explained by the structural model supporting the SE hypothesis that RA susceptibility is determined by the combination of amino acid residues at HLA-DR beta71 and beta74, not by beta71 alone.
| S-EPMC2694263 | biostudies-literature
Project description:Genetic variants contribute to the risk of chronic pancreatitis (CP) in adults and children. The risk variant CEL-HYB1, a recombinant hybrid allele of CEL and its neighboring pseudogene (CELP), encodes a pathogenic variant of the pancreatic digestive enzyme carboxyl ester lipase (CEL). We previously identified combinations of two non-synonymous SNPs, c.1463T>C (p. Ile488Thr) and c.1643C>T (p. Thr548Ile), in the break point region of CEL-HYB1. Herein, we tested whether these missense variants alter CP risk and their impact on functional properties of the CEL-HYB1 protein. Examination of CEL-HYB1 haplotypes in European patients and controls revealed that the combinationThr488-Ile548 was present only in cases (p???.001). The lipase activity of purified recombinant CEL-HYB1 variants showed normal or near normal activity. CEL-HYB variants expressed in HEK293T cells all had decreased secretion compared with CEL, formed intracellular protein aggregates, and triggered endoplasmic reticulum stress. Thus, we propose that the presence of missense variants in CEL-HYB increases the pathogenicity of CEL-HYB1 through misfolding and gain-of-function proteotoxicity. Interestingly, Thr488-Ile548 and Thr488-Thr548 were equally pathogenic in the functional assays even though only the Thr488-Ile548 haplotype was significantly enriched in cases. The explanation for the mismatch between genetic and functional data requires further investigation.
| S-EPMC7663422 | biostudies-literature
Project description:Patients with chronic pancreatitis (CP) frequently have genetic risk factors for disease. Many of the identified genes have been connected to trypsinogen activation or trypsin inactivation. The description of CP in patients with mutations in the variable number of tandem repeat (VNTR) domain of carboxyl ester lipase (CEL) presents an opportunity to study the pathogenesis of CP independently of trypsin pathways. We tested the hypothesis that a deletion and frameshift mutation (C563fsX673) in the CEL VNTR causes CP through proteotoxic gain-of-function activation of maladaptive cell signaling pathways including cell death pathways. HEK293 or AR42J cells were transfected with constructs expressing CEL with 14 repeats in the VNTR (CEL14R) or C563fsX673 CEL (CEL maturity onset diabetes of youth with a deletion mutation in the VNTR (MODY)). In both cell types, CEL MODY formed intracellular aggregates. Secretion of CEL MODY was decreased compared with that of CEL14R. Expression of CEL MODY increased endoplasmic reticulum stress, activated the unfolded protein response, and caused cell death by apoptosis. Our results demonstrate that disorders of protein homeostasis can lead to CP and suggest that novel therapies to decrease the intracellular accumulation of misfolded protein may be successful in some patients with CP.
| S-EPMC5087739 | biostudies-literature
Project description:PurposeChronic pancreatitis (CP) can cause fat or bile acid malabsorption due to exocrine insufficiency. Fat or bile acid malabsorption has been reported to increase the risk of urolithiasis through increased intestinal oxalate absorption. However, no studies have reported an association between CP and urolithiasis.MethodsWe identified 15,848 patients (age: ≥20 years) diagnosed as having CP between 2000 and 2010 from the National Health Insurance Research Database as the study cohort. Beneficiaries without a history of CP were randomly selected and propensity-matched with the study cohort in a 1:4 ratio according to age; sex; comorbidities of hyperlipidemia, diabetes, obesity, hypertension, chronic obstructive pulmonary disease, alcohol-related illness, stroke, and coronary artery disease; and the index date. The prevalence of inflammatory bowel disease (0.44%), hyperparathyroidism (0.10%), or end stage renal disease (1.55%) in CP patients was low, but these comorbidities were also considered in the analysis. All patients were followed until the end of 2011 or withdrawal from the National Health Insurance program to determine the incidence of urolithiasis.ResultsThe cumulative incidence of urolithiasis was higher in the CP cohort than that in the non-CP cohort (log-rank test, P < 0.001) with a 1.89-fold risk of urolithiasis (95% confidence interval [CI] = 1.74-2.06). The prevalence of CP was higher in men (81.9%) and in patients younger than 49 years (63.5%; mean age: 48.5 ± 15.3 years). CP was associated with the development of urolithiasis in each age group (≤49 years: aHR = 2.00, 95% CI = 1.81-2.22; 50-64 years: aHR = 1.71, 95% CI = 1.40-2.09; ≥65 years: aHR = 1.54, 95% CI = 1.20-1.98) and each sex (women: aHR = 2.10, 95% CI = 1.67-2.66; men; aHR = 1.86, 95% CI = 1.70-2.04). Among the patients without comorbidities, the rate of urolithiasis increased from 2.93/1,000 person-years in non-CP patients to 8.28/1,000 person-years in CP patients. Among the patients with comorbidities, the rate of urolithiasis increased from 6.12/1,000 person-years in non-CP patients to 10.9/1,000 person-years in CP patients. The contribution of CP to the relative risk of urolithiasis was greater in patients without comorbidities (without comorbidities: aHR = 2.81, 95% CI = 2.30-3.44) than in those with comorbidities (aHR = 1.76, 95% CI = 1.61-1.94).ConclusionCP is associated with urolithiasis in this population-based cohort study. The contribution of CP to the relative risk of urolithiasis was even greater in patients with a lower risk of urolithiasis, such as those without other comorbidities. Our findings warrant a survey and education on urolithiasis for patients with CP.
| S-EPMC5844542 | biostudies-literature
Project description: Not available
| S-EPMC9256855 | biostudies-literature
Project description:AimsTo investigate the potential association between type 2 diabetes (T2D) and hepatocellular carcinoma (HCC) in East Asian populations using Mendelian randomization (MR) analyses.MethodsBidirectional Mendelian randomization (MR) studies were conducted using summary statistics from genome-wide association studies (GWAS) related to T2D and HCC. The potential effects of confounders such as chronic hepatitis B, chronic hepatitis C, body mass index, and alcohol intake frequency were corrected using a multivariate MR study. Various MR methods, including the inverse variance weighted (IVW) approach, were used to estimate the associations between T2D and HCC. Sensitivity analysis and assessment of heterogeneity were performed to ensure the robustness of the results.ResultsIn the forward MR study, the IVW approach of MR analysis suggested an inverse association between T2D and HCC, with a risk odds ratio of 0.8628 (95% confidence interval [CI], 0.7888-0.9438). Furthermore, even after adjusting for BMI, chronic hepatitis B, and alcohol intake frequency, this study still supports the inverse association between T2D and HCC. Additional MR methods provided further support for this relationship. Sensitivity analysis and assessment of heterogeneity confirmed the robustness of the results. The reverse MR analysis did not show a clear impact of genetic liability to HCC on reduced risk of T2D(OR=0.9788; 95% CI, 0.9061-1.0574).ConclusionThis study provides evidence of an inverse association between T2D and HCC in East Asian populations using MR analysis. Further studies are warranted to validate these findings.
| S-EPMC10791969 | biostudies-literature
Project description:PurposeTo evaluate the relationships between chronic kidney disease (CKD) with retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness profiles of eyes in Asian and White populations.DesignCross-sectional analysis.ParticipantsA total of 5066 Asian participants (1367 Malays, 1772 Indians, and 1927 Chinese) from the Singapore Epidemiology of Eye Diseases Study (SEED) were included, consisting of 9594 eyes for peripapillary RNFL analysis and 8661 eyes for GCIPL analysis. Additionally, 45 064 White participants (87 649 eyes) from the United Kingdom Biobank (UKBB) were included for both macular RNFL analysis and GCIPL analysis.MethodsNonglaucoma participants aged ≥ 40 years with complete data for estimated glomerular filtration rate (eGFR) were included from both SEED and UKBB. In SEED, peripapillary RNFL and GCIPL thickness were measured by Cirrus HD-OCT 4000. In UKBB, macular RNFL and GCIPL were measured by Topcon 3D-OCT 1000 Mark II. Chronic kidney disease was defined as eGFR < 60 ml/min/1.73 m2 in both data sets. To evaluate the associations between kidney function status with RNFL and GCIPL thickness profiles, multivariable linear regression with generalized estimating equation models were performed in SEED and UKBB data sets separately.Main outcome measuresAverage peripapillary and macular RNFL thickness and macular GCIPL thickness.ResultsIn SEED, after adjusting for age, gender, ethnicity, systolic blood pressure, antihypertensive medication, diabetes, hyperlipidemia, body mass index, smoking status, and intraocular pressure, presence of CKD (β = -1.31; 95% confidence interval [CI], -2.37 to -0.26; P = 0.015) and reduced eGFR (per 10 ml/min/1.73 m2; β = -0.32; 95% CI, -0.50 to -0.13; P = 0.001) were associated with thinner average peripapillary RNFL. Presence of CKD (β = -1.63; 95% CI, -2.42 to -0.84) and reduced eGFR (per 10 ml/min/1.73 m2; β = -0.30; 95% CI, -0.44 to -0.16) were consistently associated with thinner GCIPL in SEED (all P < 0.001). In UKBB, after adjusting for the above-mentioned covariates (except ethnicity), reduced eGFR (per 10 ml/min/1.73 m2; β = -0.06; 95% CI, -0.10 to -0.01; P = 0.008) was associated with thinner macular RNFL and CKD (β = -0.62; 95% CI, -1.16 to -0.08; P = 0.024) was associated with thinner average GCIPL.ConclusionWe consistently observed associations between CKD and thinning of RNFL and GCIPL across Asian and White populations' eyes. These findings further suggest that compromised kidney function is associated with RNFL and GCIPL thinning.Financial disclosuresThe author(s) have no proprietary or commercial interest in any materials discussed in this article.
| S-EPMC10587624 | biostudies-literature
Project description:Endoscopic ultrasound (EUS) is widely recognized for its non-invasiveness and for its usefulness in chronic pancreatitis (CP) diagnosis, including early CP. Although it is desirable to obtain a definitive diagnosis of CP by tissue sampling with EUS-guided fine needle aspiration, histopathological changes in CP are heterogeneous in terms of the extent and the distribution of lesions. Therefore, histopathological diagnosis of appropriate tissue sampling by EUS-fine needle aspiration is expected to be difficult. Furthermore, it is virtually impossible to match EUS images with pathological sections, making direct contrast between EUS findings and pathology difficult. This narrative review presents a discussion of the diagnosis of CP/early CP by EUS, particularly assessing the association between ultrasound and pathological findings. Recently, the histological corroboration and correlation of EUS findings related to CP have been clarified by surgical specimens, including those obtained from animal studies. Furthermore, remarkable advances have occurred in the objective and quantitative diagnosis of pancreatic fibrosis by EUS-elastography. Future technological advances in EUS are expected to improve the accuracy of diagnosis of pancreatic fibrosis at earlier stages.
| S-EPMC9478231 | biostudies-literature