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Carrier frequencies of antithrombin, protein C, and protein S deficiency variants estimated using a public database
Keiko Maruyama1, Koichi Kokame1
1Department of Molecular Pathogenesis National Cerebral and Cardiovascular Center Suita Japan.
Insights
Genetic deficiencies in antithrombin (AT), protein C (PC), and protein S (PS) increase venous thromboembolism risk. This study found AT, PC, and PS genetic deficiency frequencies of 0.36%, 0.63%, and 0.39% using the ExAC database.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Genetic deficiencies of antithrombin (AT), protein C (PC), and protein S (PS) are established risk factors for venous thromboembolism (VTE).
- Previous estimates for heterozygous deficiencies in the general population range from 0.02% to 0.5%.
- The Exome Aggregation Consortium (ExAC) database offers extensive genetic variation data.
Purpose of the Study:
- To determine the prevalence of AT, PC, and PS deficiencies.
- To utilize the ExAC database for variant frequency analysis.
- To validate findings through transient expression experiments.
Main Methods:
- Analysis of 133, 157, and 221 variants in SERPIN1 (AT), PROC (PC), and PROS1 (PS) from the ExAC database.
- Selection and random sampling of variants with high allele frequencies.
- Expression of recombinant proteins in HEK293 cells to assess secretion and anticoagulant activity.
Main Results:
- Assessed 9 AT, 4 PC, and 14 PS variants for high allele frequency, and randomly sampled additional missense variants.
- Found 6 of 21 AT variants had reduced total activity; 11 of 19 PC variants showed impaired total activity; 4 of 33 PS variants had reduced total activity.
- Calculated AT, PC, and PS genetic deficiency frequencies as 0.36%, 0.63%, and 0.39%, respectively, based on ExAC allele frequencies.
Conclusions:
- The study provides updated prevalence estimates for AT, PC, and PS genetic deficiencies.
- Findings suggest a higher frequency of these deficiencies than previously reported in some populations.
- The ExAC database is a valuable resource for assessing the population frequency of genetic thrombophilia risk factors.
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.
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