Variants in chondroitin sulfate metabolism genes in thrombotic storm

Karen Nuytemans, Thomas L. Ortel, Lissette Gomez, Natalia Hofmann, Natalie Alves, Nicole Dueker, Ashley Beecham, Patrice Whitehead, Susan Hahn Estabrooks, Craig S. Kitchens, Doruk Erkan, Leonardo R. Brandão, Andra H. James, Roshni Kulkarni, Marilyn J. Manco-Johnson, Margaret A Pericak-Vance, Jeffery M Vance

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)43-51
Number of pages9
JournalThrombosis Research
Volume161
DOIs
StatePublished - Jan 1 2018

Fingerprint

Chondroitin Sulfates
Genes
Genome
Exome
Phenotype
Glycocalyx
Heparitin Sulfate
Blood Coagulation
Causality
Young Adult
Thrombosis
Endothelial Cells
Proteins

Keywords

  • Chondroitin sulfates
  • Glycocalyx
  • Thrombosis
  • Whole exome sequencing

ASJC Scopus subject areas

  • Hematology

Cite this

Variants in chondroitin sulfate metabolism genes in thrombotic storm. / Nuytemans, Karen; Ortel, Thomas L.; Gomez, Lissette; Hofmann, Natalia; Alves, Natalie; Dueker, Nicole; Beecham, Ashley; Whitehead, Patrice; Hahn Estabrooks, Susan; Kitchens, Craig S.; Erkan, Doruk; Brandão, Leonardo R.; James, Andra H.; Kulkarni, Roshni; Manco-Johnson, Marilyn J.; Pericak-Vance, Margaret A; Vance, Jeffery M.

In: Thrombosis Research, Vol. 161, 01.01.2018, p. 43-51.

Research output: Contribution to journalArticle

Nuytemans, K, Ortel, TL, Gomez, L, Hofmann, N, Alves, N, Dueker, N, Beecham, A, Whitehead, P, Hahn Estabrooks, S, Kitchens, CS, Erkan, D, Brandão, LR, James, AH, Kulkarni, R, Manco-Johnson, MJ, Pericak-Vance, MA & Vance, JM 2018, 'Variants in chondroitin sulfate metabolism genes in thrombotic storm', Thrombosis Research, vol. 161, pp. 43-51. https://doi.org/10.1016/j.thromres.2017.11.016
Nuytemans, Karen ; Ortel, Thomas L. ; Gomez, Lissette ; Hofmann, Natalia ; Alves, Natalie ; Dueker, Nicole ; Beecham, Ashley ; Whitehead, Patrice ; Hahn Estabrooks, Susan ; Kitchens, Craig S. ; Erkan, Doruk ; Brandão, Leonardo R. ; James, Andra H. ; Kulkarni, Roshni ; Manco-Johnson, Marilyn J. ; Pericak-Vance, Margaret A ; Vance, Jeffery M. / Variants in chondroitin sulfate metabolism genes in thrombotic storm. In: Thrombosis Research. 2018 ; Vol. 161. pp. 43-51.
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abstract = "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.",
keywords = "Chondroitin sulfates, Glycocalyx, Thrombosis, Whole exome sequencing",
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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

PY - 2018/1/1

Y1 - 2018/1/1

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.

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