Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis.

<h4>Background</h4>We previously described the association between rare ADAMTS13 single nucleotide variants (SNVs) and deep vein thrombosis (DVT). Moreover, DVT patients with at least one rare ADAMTS13 SNV had a lower ADAMTS13 activity than non-carriers.<h4>Aims</h4>To confir...

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Autores principales:	Maria Teresa Pagliari, Andrea Cairo, Marco Boscarino, Ilaria Mancini, Emanuela Pappalardo, Paolo Bucciarelli, Ida Martinelli, Frits R Rosendaal, Flora Peyvandi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a85d2ac68da24df7898413d3fb12c77e
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spelling	oai:doaj.org-article:a85d2ac68da24df7898413d3fb12c77e2021-12-02T20:16:49ZRole of ADAMTS13, VWF and F8 genes in deep vein thrombosis.1932-620310.1371/journal.pone.0258675https://doaj.org/article/a85d2ac68da24df7898413d3fb12c77e2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0258675https://doaj.org/toc/1932-6203<h4>Background</h4>We previously described the association between rare ADAMTS13 single nucleotide variants (SNVs) and deep vein thrombosis (DVT). Moreover, DVT patients with at least one rare ADAMTS13 SNV had a lower ADAMTS13 activity than non-carriers.<h4>Aims</h4>To confirm ADAMTS13 variants association with DVT and reduced plasma ADAMTS13 activity levels in a larger population. To investigate the role of VWF and F8 variants.<h4>Methods</h4>ADAMTS13, VWF and F8 were sequenced using next-generation sequencing in 594 Italian DVT patients and 571 controls. Genetic association testing was performed using logistic regression and gene-based tests. The association between rare ADAMTS13 variants and the respective plasmatic activity, available for 365 cases and 292 controls, was determined using linear regression. All analyses were age-, sex- adjusted.<h4>Results</h4>We identified 48 low-frequency/common and 272 rare variants. Nine low-frequency/common variants had a P<0.05, but a false discovery rate between 0.06 and 0.24. Of them, 7 were found in ADAMTS13 (rs28641026, rs28503257, rs685523, rs3124768, rs3118667, rs739469, rs3124767; all protective) and 2 in VWF (rs1800382 [risk], rs7962217 [protective]). Rare ADAMTS13 variants were significantly associated with DVT using the burden, variable threshold (VT) and UNIQ (P<0.05), but not with C-ALPHA, SKAT and SKAT-O tests. Rare VWF and F8 variants were not associated with DVT. Carriers of rare ADAMTS13 variants had lower ADAMTS13 activity than non-carriers (ß -6.2, 95%CI -11,-1.5). This association was stronger for DVT patients than controls (ß -7.5, 95%CI -13.5,-1.5 vs. ß -2.9, 95%CI -10.4,4.5).<h4>Conclusions</h4>ADAMTS13 and VWF low-frequency/common variants mainly showed a protective effect, although their association with DVT was not confirmed. DVT patients carrying a rare ADAMTS13 variants had slightly reduced ADAMTS13 activity levels, but a higher DVT risk. Rare VWF and FVIII variants were not associated with DVT suggesting that other mechanisms are responsible for the high VWF and FVIII levels measured in DVT patients.Maria Teresa PagliariAndrea CairoMarco BoscarinoIlaria ManciniEmanuela PappalardoPaolo BucciarelliIda MartinelliFrits R RosendaalFlora PeyvandiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10, p e0258675 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maria Teresa Pagliari Andrea Cairo Marco Boscarino Ilaria Mancini Emanuela Pappalardo Paolo Bucciarelli Ida Martinelli Frits R Rosendaal Flora Peyvandi Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis.
description	<h4>Background</h4>We previously described the association between rare ADAMTS13 single nucleotide variants (SNVs) and deep vein thrombosis (DVT). Moreover, DVT patients with at least one rare ADAMTS13 SNV had a lower ADAMTS13 activity than non-carriers.<h4>Aims</h4>To confirm ADAMTS13 variants association with DVT and reduced plasma ADAMTS13 activity levels in a larger population. To investigate the role of VWF and F8 variants.<h4>Methods</h4>ADAMTS13, VWF and F8 were sequenced using next-generation sequencing in 594 Italian DVT patients and 571 controls. Genetic association testing was performed using logistic regression and gene-based tests. The association between rare ADAMTS13 variants and the respective plasmatic activity, available for 365 cases and 292 controls, was determined using linear regression. All analyses were age-, sex- adjusted.<h4>Results</h4>We identified 48 low-frequency/common and 272 rare variants. Nine low-frequency/common variants had a P<0.05, but a false discovery rate between 0.06 and 0.24. Of them, 7 were found in ADAMTS13 (rs28641026, rs28503257, rs685523, rs3124768, rs3118667, rs739469, rs3124767; all protective) and 2 in VWF (rs1800382 [risk], rs7962217 [protective]). Rare ADAMTS13 variants were significantly associated with DVT using the burden, variable threshold (VT) and UNIQ (P<0.05), but not with C-ALPHA, SKAT and SKAT-O tests. Rare VWF and F8 variants were not associated with DVT. Carriers of rare ADAMTS13 variants had lower ADAMTS13 activity than non-carriers (ß -6.2, 95%CI -11,-1.5). This association was stronger for DVT patients than controls (ß -7.5, 95%CI -13.5,-1.5 vs. ß -2.9, 95%CI -10.4,4.5).<h4>Conclusions</h4>ADAMTS13 and VWF low-frequency/common variants mainly showed a protective effect, although their association with DVT was not confirmed. DVT patients carrying a rare ADAMTS13 variants had slightly reduced ADAMTS13 activity levels, but a higher DVT risk. Rare VWF and FVIII variants were not associated with DVT suggesting that other mechanisms are responsible for the high VWF and FVIII levels measured in DVT patients.
format	article
author	Maria Teresa Pagliari Andrea Cairo Marco Boscarino Ilaria Mancini Emanuela Pappalardo Paolo Bucciarelli Ida Martinelli Frits R Rosendaal Flora Peyvandi
author_facet	Maria Teresa Pagliari Andrea Cairo Marco Boscarino Ilaria Mancini Emanuela Pappalardo Paolo Bucciarelli Ida Martinelli Frits R Rosendaal Flora Peyvandi
author_sort	Maria Teresa Pagliari
title	Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis.
title_short	Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis.
title_full	Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis.
title_fullStr	Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis.
title_full_unstemmed	Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis.
title_sort	role of adamts13, vwf and f8 genes in deep vein thrombosis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/a85d2ac68da24df7898413d3fb12c77e
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Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis.

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