Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitis
Abstract The CEL-HYB1 hybrid allele of the carboxyl ester lipase (CEL) gene and its pseudogene (CELP) has been associated with chronic pancreatitis (CP). Recent work indicated that amino acid positions 488 and 548 in CEL-HYB1 determined pathogenicity. Haplotype Thr488-Ile548 was associated with CP w...
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Nature Portfolio
2024-12-01
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| Online Access: | https://doi.org/10.1038/s41598-024-82077-4 |
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| author | Gergő Berke Máté Sándor Xunjun K. Xiao Mark E. Lowe Maren Ewers Bálint Erőss Emmanuelle Masson Balázs Csaba Németh Áron Vincze László Czakó Agnieszka Magdalena Rygiel Jonas Rosendahl Jian-Min Chen Heiko Witt Péter Hegyi Miklós Sahin-Tóth Eszter Hegyi |
| author_facet | Gergő Berke Máté Sándor Xunjun K. Xiao Mark E. Lowe Maren Ewers Bálint Erőss Emmanuelle Masson Balázs Csaba Németh Áron Vincze László Czakó Agnieszka Magdalena Rygiel Jonas Rosendahl Jian-Min Chen Heiko Witt Péter Hegyi Miklós Sahin-Tóth Eszter Hegyi |
| author_sort | Gergő Berke |
| collection | DOAJ |
| description | Abstract The CEL-HYB1 hybrid allele of the carboxyl ester lipase (CEL) gene and its pseudogene (CELP) has been associated with chronic pancreatitis (CP). Recent work indicated that amino acid positions 488 and 548 in CEL-HYB1 determined pathogenicity. Haplotype Thr488-Ile548 was associated with CP while haplotypes Thr488-Thr548 and Ile488-Thr548 were benign. However, functional analysis revealed that Thr488 is the primary determinant of CEL-HYB1 misfolding and associated endoplasmic reticulum (ER) stress. To address this contradiction, we analyzed a cohort from Hungary and found significantly increased CEL-HYB1 carrier frequency in CP cases (9/319, 2.8%) versus controls (5/618, 0.8%), yielding an odds ratio of 3.6 (95% confidence interval 1.2–10.7, P = 0.024). All CEL-HYB1 positive carriers from Hungary had the Thr488-Thr548 haplotype. We analyzed the haplotype distribution of reported CEL-HYB1 carriers from three European cohorts and found that 14/29 CP cases from Germany and 2/6 CP cases from Poland carried the Thr488-Ile548 haplotype, which was absent in CEL-HYB1 positive controls from Germany (n = 13) and Poland (n = 8). All patients (n = 17) and controls (n = 9) from France carrying CEL-HYB1 contained the Thr488-Thr548 haplotype. Functional studies using transfected cells indicated that both CEL-HYB1 haplotypes induced significant ER stress and the Thr488-Ile548 haplotype had a stronger effect. We conclude that the Thr488-Thr548 haplotype of CEL-HYB1 is widespread in Europe and increases CP risk by almost fourfold. In contrast, the Thr488-Ile548 haplotype is regionally restricted, but confers markedly stronger CP risk. |
| format | Article |
| id | doaj-art-4939d8c0c883479b9a2572b713b88d7c |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-4939d8c0c883479b9a2572b713b88d7c2024-12-29T12:19:02ZengNature PortfolioScientific Reports2045-23222024-12-011411710.1038/s41598-024-82077-4Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitisGergő Berke0Máté Sándor1Xunjun K. Xiao2Mark E. Lowe3Maren Ewers4Bálint Erőss5Emmanuelle Masson6Balázs Csaba Németh7Áron Vincze8László Czakó9Agnieszka Magdalena Rygiel10Jonas Rosendahl11Jian-Min Chen12Heiko Witt13Péter Hegyi14Miklós Sahin-Tóth15Eszter Hegyi16Institute for Translational Medicine, Medical School, University of PécsDepartment of Surgery, University of California Los AngelesDepartment of Pediatrics, Washington University School of MedicineDepartment of Pediatrics, Washington University School of MedicinePediatric Nutritional Medicine & Else Kröner-Fresenius-Centre (EKFZ) for Nutritional Medicine, Technical University Munich (TUM)Institute for Translational Medicine, Medical School, University of PécsUMR 1078, Univ Brest, GGBHungarian Centre of Excellence for Molecular Medicine, Translational Pancreatology Research Group, University of SzegedDivision of Gastroenterology, First Department of Medicine, Medical School, University of PécsDepartment of Medicine, Albert Szent-Györgyi Medical School, University of SzegedDepartment of Medical Genetics, Institute of Mother and ChildDepartment of Internal Medicine I, Martin-Luther-University Halle-WittenbergUMR 1078, Univ Brest, GGBPediatric Nutritional Medicine & Else Kröner-Fresenius-Centre (EKFZ) for Nutritional Medicine, Technical University Munich (TUM)Institute for Translational Medicine, Medical School, University of PécsDepartment of Surgery, University of California Los AngelesInstitute for Translational Medicine, Medical School, University of PécsAbstract The CEL-HYB1 hybrid allele of the carboxyl ester lipase (CEL) gene and its pseudogene (CELP) has been associated with chronic pancreatitis (CP). Recent work indicated that amino acid positions 488 and 548 in CEL-HYB1 determined pathogenicity. Haplotype Thr488-Ile548 was associated with CP while haplotypes Thr488-Thr548 and Ile488-Thr548 were benign. However, functional analysis revealed that Thr488 is the primary determinant of CEL-HYB1 misfolding and associated endoplasmic reticulum (ER) stress. To address this contradiction, we analyzed a cohort from Hungary and found significantly increased CEL-HYB1 carrier frequency in CP cases (9/319, 2.8%) versus controls (5/618, 0.8%), yielding an odds ratio of 3.6 (95% confidence interval 1.2–10.7, P = 0.024). All CEL-HYB1 positive carriers from Hungary had the Thr488-Thr548 haplotype. We analyzed the haplotype distribution of reported CEL-HYB1 carriers from three European cohorts and found that 14/29 CP cases from Germany and 2/6 CP cases from Poland carried the Thr488-Ile548 haplotype, which was absent in CEL-HYB1 positive controls from Germany (n = 13) and Poland (n = 8). All patients (n = 17) and controls (n = 9) from France carrying CEL-HYB1 contained the Thr488-Thr548 haplotype. Functional studies using transfected cells indicated that both CEL-HYB1 haplotypes induced significant ER stress and the Thr488-Ile548 haplotype had a stronger effect. We conclude that the Thr488-Thr548 haplotype of CEL-HYB1 is widespread in Europe and increases CP risk by almost fourfold. In contrast, the Thr488-Ile548 haplotype is regionally restricted, but confers markedly stronger CP risk.https://doi.org/10.1038/s41598-024-82077-4PancreatitisGenetic association studyLipaseMisfoldingEndoplasmic reticulum stress |
| spellingShingle | Gergő Berke Máté Sándor Xunjun K. Xiao Mark E. Lowe Maren Ewers Bálint Erőss Emmanuelle Masson Balázs Csaba Németh Áron Vincze László Czakó Agnieszka Magdalena Rygiel Jonas Rosendahl Jian-Min Chen Heiko Witt Péter Hegyi Miklós Sahin-Tóth Eszter Hegyi Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitis Scientific Reports Pancreatitis Genetic association study Lipase Misfolding Endoplasmic reticulum stress |
| title | Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitis |
| title_full | Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitis |
| title_fullStr | Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitis |
| title_full_unstemmed | Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitis |
| title_short | Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitis |
| title_sort | carboxyl ester lipase hybrid 1 cel hyb1 haplotypes confer varying risk for chronic pancreatitis |
| topic | Pancreatitis Genetic association study Lipase Misfolding Endoplasmic reticulum stress |
| url | https://doi.org/10.1038/s41598-024-82077-4 |
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