You are here
Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.
Thursday,2024-07-11 11:57 America/Los_Angeles — ecterry
| Title | Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels. |
| Publication Type | Journal Article |
| Year of Publication | 2023 |
| Authors | Ji, Y, Temprano-Sagrera, G, Holle, LA, Bebo, A, Brody, JA, Le, N-Q, Kangro, K, Brown, MR, Martinez-Perez, A, Sitlani, CM, Suchon, P, Kleber, ME, Emmert, DB, Ozel, ABilge, Dobson, D'VA, Tang, W, Llobet, D, Tracy, RP, Deleuze, J-F, Delgado, GE, Gögele, M, Wiggins, KL, Souto, JCarlos, Pankow, JS, Taylor, KD, Trégouët, D-A, Moissl, AP, Fuchsberger, C, Rosendaal, FR, Morrison, AC, Soria, JManuel, Cushman, M, Morange, P-E, März, W, Hicks, AA, Desch, KC, Johnson, AD, de Vries, PS, Wolberg, AS, Smith, NL, Sabater-Lleal, M |
| Corporate/Institutional Authors | CHARGE Consortium Hemostasis Working Group, INVENT Consortium |
| Journal | Arterioscler Thromb Vasc Biol |
| Volume | 43 |
| Issue | 7 |
| Pagination | e254-e269 |
| Date Published | 2023 Jul |
| ISSN | 1524-4636 |
| Keywords | Anticoagulants, Antithrombin III, Antithrombins, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Protein C, Protein S, Transcriptome |
| Abstract | <p><b>BACKGROUND: </b>Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total.</p><p><b>METHODS: </b>Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes.</p><p><b>RESULTS: </b>Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (, , and ) and 1 with PS levels (-). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (), 1 with PC (), and 1 with PS (). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of , , and genes in antithrombin regulation.</p><p><b>CONCLUSIONS: </b>The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.</p> |
| DOI | 10.1161/ATVBAHA.122.318213 |
| Alternate Journal | Arterioscler Thromb Vasc Biol |
| PubMed ID | 37128921 |
| PubMed Central ID | PMC10330350 |
| Grant List | R01 HL139553 / HL / NHLBI NIH HHS / United States R01 HL059367 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States R01 HL126974 / HL / NHLBI NIH HHS / United States R01 HL141291 / HL / NHLBI NIH HHS / United States R01 HL141399 / HL / NHLBI NIH HHS / United States R01 HL134894 / HL / NHLBI NIH HHS / United States |
ePub date:
23/07