Carrier frequencies of antithrombin, protein C, and protein S deficiency variants estimated using a public database and expression experiments
Abstract Background Genetic deficiencies of antithrombin (AT), protein C (PC), and protein S (PS) are risk factors for venous thromboembolism. In the general population, the prevalence of heterozygous deficiency of AT, PC, and PS are reported as approximately 0.02%‐0.2%, 0.2%‐0.4%, and 0.03%‐0.5%, r...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Research and Practice in Thrombosis and Haemostasis |
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| Online Access: | https://doi.org/10.1002/rth2.12456 |
| _version_ | 1797721594971291648 |
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| author | Keiko Maruyama Koichi Kokame |
| author_facet | Keiko Maruyama Koichi Kokame |
| author_sort | Keiko Maruyama |
| collection | DOAJ |
| description | Abstract Background Genetic deficiencies of antithrombin (AT), protein C (PC), and protein S (PS) are risk factors for venous thromboembolism. In the general population, the prevalence of heterozygous deficiency of AT, PC, and PS are reported as approximately 0.02%‐0.2%, 0.2%‐0.4%, and 0.03%‐0.5%, respectively. The Exome Aggregation Consortium (ExAC) provides a public database containing reference data for over 60 000 exomes. Objective This study aimed to determine the frequency of AT, PC, and PS deficiencies using the ExAC database and transient expression experiments. Methods In total, 133, 157, and 221 variants of SERPIN1 (encoding AT), PROC (PC), and PROS1 (PS), respectively, were registered as missense and putative loss‐of‐function variants in the ExAC database. Variants with relatively high allele frequencies were selected and randomly sampled. Recombinant proteins were expressed in human embryo kidney 293 cells and their secretion and anticoagulant activities examined. Results and Conclusion We assessed 9 AT, 4 PC, and 14 PS variants with relatively high allele frequencies and randomly sampled 12 AT, 15 PC, and 19 PS missense variants. All 21 AT variants showed normal or mildly reduced secretion, and 6 showed reduced total activity (specific activity × antigen level). Of the 19 PC variants, 11 showed impaired total activity. All 33 PS variants showed normal or mildly reduced secretion, and 4 showed reduced total activity. Based on allele frequencies in the ExAC database, we calculated the frequencies of AT, PC, and PS genetic deficiency as 0.36%, 0.63%, and 0.39%, respectively. |
| first_indexed | 2024-03-12T09:35:24Z |
| format | Article |
| id | doaj.art-b38ca8706cd24696b0010041a309a46b |
| institution | Directory Open Access Journal |
| issn | 2475-0379 |
| language | English |
| last_indexed | 2024-03-12T09:35:24Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Research and Practice in Thrombosis and Haemostasis |
| spelling | doaj.art-b38ca8706cd24696b0010041a309a46b2023-09-02T13:42:59ZengElsevierResearch and Practice in Thrombosis and Haemostasis2475-03792021-01-015117918610.1002/rth2.12456Carrier frequencies of antithrombin, protein C, and protein S deficiency variants estimated using a public database and expression experimentsKeiko Maruyama0Koichi Kokame1Department of Molecular Pathogenesis National Cerebral and Cardiovascular Center Suita JapanDepartment of Molecular Pathogenesis National Cerebral and Cardiovascular Center Suita JapanAbstract Background Genetic deficiencies of antithrombin (AT), protein C (PC), and protein S (PS) are risk factors for venous thromboembolism. In the general population, the prevalence of heterozygous deficiency of AT, PC, and PS are reported as approximately 0.02%‐0.2%, 0.2%‐0.4%, and 0.03%‐0.5%, respectively. The Exome Aggregation Consortium (ExAC) provides a public database containing reference data for over 60 000 exomes. Objective This study aimed to determine the frequency of AT, PC, and PS deficiencies using the ExAC database and transient expression experiments. Methods In total, 133, 157, and 221 variants of SERPIN1 (encoding AT), PROC (PC), and PROS1 (PS), respectively, were registered as missense and putative loss‐of‐function variants in the ExAC database. Variants with relatively high allele frequencies were selected and randomly sampled. Recombinant proteins were expressed in human embryo kidney 293 cells and their secretion and anticoagulant activities examined. Results and Conclusion We assessed 9 AT, 4 PC, and 14 PS variants with relatively high allele frequencies and randomly sampled 12 AT, 15 PC, and 19 PS missense variants. All 21 AT variants showed normal or mildly reduced secretion, and 6 showed reduced total activity (specific activity × antigen level). Of the 19 PC variants, 11 showed impaired total activity. All 33 PS variants showed normal or mildly reduced secretion, and 4 showed reduced total activity. Based on allele frequencies in the ExAC database, we calculated the frequencies of AT, PC, and PS genetic deficiency as 0.36%, 0.63%, and 0.39%, respectively.https://doi.org/10.1002/rth2.12456antithrombingenetic deficiencyprotein Cprotein Svenous thromboembolism |
| spellingShingle | Keiko Maruyama Koichi Kokame Carrier frequencies of antithrombin, protein C, and protein S deficiency variants estimated using a public database and expression experiments Research and Practice in Thrombosis and Haemostasis antithrombin genetic deficiency protein C protein S venous thromboembolism |
| title | Carrier frequencies of antithrombin, protein C, and protein S deficiency variants estimated using a public database and expression experiments |
| title_full | Carrier frequencies of antithrombin, protein C, and protein S deficiency variants estimated using a public database and expression experiments |
| title_fullStr | Carrier frequencies of antithrombin, protein C, and protein S deficiency variants estimated using a public database and expression experiments |
| title_full_unstemmed | Carrier frequencies of antithrombin, protein C, and protein S deficiency variants estimated using a public database and expression experiments |
| title_short | Carrier frequencies of antithrombin, protein C, and protein S deficiency variants estimated using a public database and expression experiments |
| title_sort | carrier frequencies of antithrombin protein c and protein s deficiency variants estimated using a public database and expression experiments |
| topic | antithrombin genetic deficiency protein C protein S venous thromboembolism |
| url | https://doi.org/10.1002/rth2.12456 |
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