A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10−17, OR = 1.36, 95% CI = 1.31–1.40) and identified colocalization (PP = 0.87) with aberrant exon 5–7 CTRB2 splicing in pancreatic tissues (pGTEx = 1.40 × 10−69, βGTEx = 1.99; pLTG = 1.02 × 10−30, βLTG = 1.99). Imputation of a 584 bp structural variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (p = 2.83 × 10−16, OR = 1.36, 95% CI = 1.31–1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsinogen B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). We propose that intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein leads to ER stress and pancreatic inflammation, which may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | American Journal of Human Genetics |
| Vol/bind | 108 |
| Udgave nummer | 10 |
| Sider (fra-til) | 1852-1865 |
| Antal sider | 14 |
| ISSN | 0002-9297 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
We thank Dominic Esposito at the Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, and his team for cloning full-length and truncated CTRB2 expression clones. We thank Sara Olson, now retired but formerly at the Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center in New York, NY, USA, for her collaboration and support in providing tissue samples for the LTG eQTL dataset. We thank Kevin Brown, Laboratory of Translational Genomics, DCEG, NCI, NIH for careful reading of the manuscript and helpful suggestions. We also thank Kari Rabe and Jennifer Brooks for coordinating Mayo Clinic patient biospecimen and data contributions to this study. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD, USA. This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. Additional funding information is listed in the supplemental information. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The authors declare no competing interests.
Funding Information:
We thank Dominic Esposito at the Protein Expression Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, and his team for cloning full-length and truncated CTRB2 expression clones. We thank Sara Olson, now retired but formerly at the Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center in New York, NY, USA, for her collaboration and support in providing tissue samples for the LTG eQTL dataset. We thank Kevin Brown, Laboratory of Translational Genomics, DCEG, NCI, NIH for careful reading of the manuscript and helpful suggestions. We also thank Kari Rabe and Jennifer Brooks for coordinating Mayo Clinic patient biospecimen and data contributions to this study. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD, USA. This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics , National Cancer Institute , National Institutes of Health . Additional funding information is listed in the supplemental information . The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.
Publisher Copyright:
© 2021
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546220/pdf/main.pdf
Forlagets udgivne version
ID: 286488294