Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels
Authors: Ji Yuekai , Temprano-Sagrera Gerard , Holle Lori A. , Bebo Allison , Brody Jennifer A. , Le Ngoc-Quynh , Kangro Kadri , Brown Michael R. , Martinez-Perez Angel , Sitlani Colleen M. , Suchon Pierre , Kleber Marcus E. , Emmert David B. , Bilge Ozel Ayse , Dobson Dre’Von A. , Tang Weihong , Llobet Dolors , Tracy Russell P. , Deleuze Jean-François , Delgado Graciela E. , Gögele Martin , Wiggins Kerri L. , Souto Juan Carlos , Pankow James S. , Taylor Kent D. , Trégouët David-Alexandre , Moissl Angela P. , Fuchsberger Christian , Rosendaal Frits R. , Morrison Alanna C. , Soria Jose Manuel , Cushman Mary , Morange Pierre-Emmanuel , März Winfried , Hicks Andrew A. , Desch Karl C. , Johnson Andrew D. , de Vries Paul S. ,   CHARGE Consortium Hemostasis Working Group, INVENT Consortium, Wolberg Alisa S. , Smith Nicholas L. , Sabater-Lleal Maria 
Published: April 2023

Background:

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.

Methods:

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.

Results:

Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (
GCKR
,
BAZ1B
, and
HP-TXNL4B
) and 1 with PS levels (
ORM1
-
ORM2
). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (
FCGRT
), 1 with PC (
GOLM2
), and 1 with PS (
MYL7
). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of
GCKR
,
SNX17
, and
HP
genes in antithrombin regulation.

Conclusions:

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.