TY - JOUR
T1 - Variants in chondroitin sulfate metabolism genes in thrombotic storm
AU - Nuytemans, Karen
AU - Ortel, Thomas L.
AU - Gomez, Lissette
AU - Hofmann, Natalia
AU - Alves, Natalie
AU - Dueker, Nicole
AU - Beecham, Ashley
AU - Whitehead, Patrice
AU - Hahn Estabrooks, Susan
AU - Kitchens, Craig S.
AU - Erkan, Doruk
AU - Brandão, Leonardo R.
AU - James, Andra H.
AU - Kulkarni, Roshni
AU - Manco-Johnson, Marilyn J.
AU - Pericak-Vance, Margaret A.
AU - Vance, Jeffery M.
N1 - Funding Information:
This work was supported by a gift from the John P. Hussman Foundation . We thank Sharon Hall and Keith Klemp in the Duke Hemostasis and Thrombosis Center Core Laboratory for performing the antiphospholipid antibody testing. All reagents for antiphospholipid antibody testing were kindly provided by Stago (Gennevilliers, France). We thank the Center for Genome Technology at the John P. Hussman Institute for Human Genomics for performing the exome sequencing and the exome chip genotyping. We would also like to extend our thanks to all patients and their families supporting this study, as well as collaborators and their clinical teams contributing to this study (University of Florida, Gainesville, The Hospital for Special Surgery at the Weill Cornell Medicine in NY, the Hospital for Sick Children in Toronto, Canada, Duke University Medical Center in Durham, NC, Michigan State University in East Landing, MI and the University of Miami, Miami, FL). This paper is dedicated to the memory of JJ Vance ( www.jjvance.org ).
Publisher Copyright:
© 2017 The Authors
PY - 2018/1
Y1 - 2018/1
N2 - Introduction Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders. Material and methods We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (< 5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality. Results We observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden). Conclusions As CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors.
AB - Introduction Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders. Material and methods We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (< 5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality. Results We observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden). Conclusions As CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors.
KW - Chondroitin sulfates
KW - Glycocalyx
KW - Thrombosis
KW - Whole exome sequencing
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U2 - 10.1016/j.thromres.2017.11.016
DO - 10.1016/j.thromres.2017.11.016
M3 - Article
C2 - 29178990
AN - SCOPUS:85034816438
VL - 161
SP - 43
EP - 51
JO - Thrombosis Research
JF - Thrombosis Research
SN - 0049-3848
ER -