Genetic variants in ADAMTS13 as well as smoking are major determinants of plasma ADAMTS13 levels

Qianyi Ma; Paula M. Jacobi; Brian T. Emmer; Colin A. Kretz; Ayse Bilge Ozel; Beth McGee; Chava Kimchi-Sarfaty; David Ginsburg; Jun Z. Li; Karl C. Desch

Blood Advances (Jun 2017)

Genetic variants in ADAMTS13 as well as smoking are major determinants of plasma ADAMTS13 levels

Qianyi Ma,
Paula M. Jacobi,
Brian T. Emmer,
Colin A. Kretz,
Ayse Bilge Ozel,
Beth McGee,
Chava Kimchi-Sarfaty,
David Ginsburg,
Jun Z. Li,
Karl C. Desch

Affiliations

Qianyi Ma: Department of Human Genetics, University of Michigan, Ann Arbor, MI;
Paula M. Jacobi: Department of Pediatrics and Communicable Disease, University of Michigan, Ann Arbor, MI;
Brian T. Emmer: Department of Internal Medicine, University of Michigan, Ann Arbor, MI;
Colin A. Kretz: Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI;
Ayse Bilge Ozel: Department of Human Genetics, University of Michigan, Ann Arbor, MI;
Beth McGee: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI;
Chava Kimchi-Sarfaty: Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
David Ginsburg: Department of Human Genetics, University of Michigan, Ann Arbor, MI;; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI;
Jun Z. Li: Department of Human Genetics, University of Michigan, Ann Arbor, MI;; Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada
Karl C. Desch: Department of Pediatrics and Communicable Disease, University of Michigan, Ann Arbor, MI;; Karl C. Desch, Department of Pediatrics and Communicable Diseases, University of Michigan, 8-621 C&W Mott Hospital, SPC 4254, 1540 Hospital Dr, Ann Arbor, MI 48109;

Journal volume & issue: Vol. 1, no. 15
pp. 1037 – 1046

Abstract

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Abstract: The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) in circulating blood, limiting the size of VWF multimers and regulating VWF activity. Abnormal regulation of VWF contributes to bleeding and to thrombotic disorders. ADAMTS13 levels in plasma are highly variable among healthy individuals, although the heritability and the genetic determinants of this variation are unclear. We performed genome-wide association studies of plasma ADAMTS13 concentrations in 3244 individuals from 2 independent cohorts of healthy individuals. The heritability of ADAMTS13 levels was between 59.1% (all individuals) and 83.5% (siblings only), whereas tobacco smoking was associated with a decrease in plasma ADAMTS13 levels. Meta-analysis identified common variants near the ADAMTS13 locus on chromosome 9q34.2 that were significantly associated with ADAMTS13 levels and collectively explained 20.0% of the variance. The top single nucleotide polymorphism (SNP), rs28673647, resides in an intron of ADAMTS13 (β, 6.7%; P = 1.3E-52). Conditional analysis revealed 3 additional independent signals represented by rs3739893 (β, −22.3%; P = 1.2E-30) and rs3124762 (β, 3.5%; P = 8.9E-9) close to ADAMTS13 and rs4075970 (β, 2.4%; P = 6.8E-9) on 21q22.3. Linkage analysis also identified the region around ADAMTS13 (9q34.2) as the top signal (LOD 3.5), consistent with our SNP association analyses. Two nonsynonymous ADAMTS13 variants in the top 2 independent linkage disequilibrium blocks (Q448E and A732V) were identified and characterized in vitro. This study uncovered specific common genetic polymorphisms that are key genetic determinants of the variation in plasma ADAMTS13 levels in healthy individuals.

Published in Blood Advances

ISSN: 2473-9529 (Print); 2473-9537 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine
Website: https://ashpublications.org/bloodadvances

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