Abstract Number: PB2194
Meeting: ISTH 2020 Congress
Background: Genetic deficiencies of antithrombin (AT), protein C (PC), and protein S (PS) are risk factors for venous thromboembolism. The prevalences of heterozygous AT, PC, and PS deficiencies are reported to be approximately 0.02-0.2%, 0.2-0.4%, and 0.03-0.5%, respectively. The Exome Aggregation Consortium (ExAC) browser provides a public database displaying reference data information from over 60,000 exomes.
Aims: The present study is aimed to estimate the frequencies of congenital AT, PC, and PS deficiencies in the worldwide population, in combination with the ExAC database and transient expression experiments.
Methods: In the ExAC database, 133, 157, and 221 variants of SERPINC1 (encoding AT), PROC (PC), and PROS1(PS), respectively, were registered as missense and putative loss-of-function variants. We first selected 9 SERPINC1, 4 PROC, and 14 PROS1 variants with relatively high allele frequencies (≥0.1% and ≥2 counts in all regions or in each region). In addition, we randomly selected 12 of 122 SERPINC1, 15 of 146 PROC, and 19 of 192 PROS1 missense variants. In total, 73 variant and wild-type (WT) recombinant proteins were transiently expressed in HEK293 cells. Their expression levels were assessed by ELISA and the anticoagulant activities were measured by chromogenic and clot-based assays.
Results: All the 21 SERPINC1 variants showed normal or mildly reduced secretion in the culture media, and 9 of them showed reduced activity. Among the 19 PROC variants, 7 and 8 showed impaired secretion and reduced activity, respectively. All the 33 PROS1 variants showed normal or mildly reduced secretion, and 8 of them showed reduced activity. In reference to their allele frequencies in the database, we estimated the frequencies of congenital AT, PC and PS deficiencies are 0.33%, 0.51%, and 0.44%, respectively.
Conclusions: The present study demonstrated that the frequencies of congenital AT, PC and PS deficiencies may be comparable with each other ranging from approximately 0.3-0.5% worldwide.
To cite this abstract in AMA style:Maruyama K, Kokame K. Carrier Frequencies of Antithrombin-, Protein C-, or Protein S-deficient Variants Estimated Using a Public Database and Expression Experiments [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/carrier-frequencies-of-antithrombin-protein-c-or-protein-s-deficient-variants-estimated-using-a-public-database-and-expression-experiments/. Accessed January 21, 2022.
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