Background: Cerebral vein thrombosis (CVT) is a rare, life-threatening disease affecting one adult per 100,000 per year. Genetic risk factors are deficiencies of the natural anticoagulant proteins antithrombin, protein C, protein S or single nucleotide polymorphisms such as factor V Leiden and prothrombin 20210A. In 20% of patients, the cause of CVT remains unknown. Aim: To identify novel genetic risk factors for CVT using targeted next-generation DNA sequencing (NGS). Methods: We investigated 171 CVT patients and 298 healthy controls. Patients were selected using the following criteria: objective diagnosis of CVT, no active cancer. We performed targeted NGS analysis of the protein-coding regions of 734 candidate genes related to hemostasis and inflammation, 150 ancestry informative markers and 28 thrombosis-associated variants. Results: We identified 3723 common and low frequency variants with minor allele frequency (MAF) >1% in 590 genes. Single variant association testing using logistic regression analysis identified rs8176719 insertion/deletion (indel) variant in the ABO gene associated with CVT (age and sex adjusted OR 2.03; 95% CI 1.52–2.73; P = 2.07 × 10−6; Bonferroni P = 0.008). In addition, we identified 8839 rare variants (MAF ≤ 1%) in 723 genes. Gene-based association analysis of these rare variants using a burden test revealed only a tentative association of non-coding variants located in the F8 locus with CVT. Conclusion: Targeted NGS identified a common indel variant rs8176719 in the ABO gene. Gene-based tests of association failed to reveal genomic loci with a cumulative burden of rare variants associated with CVT.

Next-generation DNA sequencing to identify novel genetic risk factors for cerebral vein thrombosis / M.M. Gorski, H.G. de Haan, I. Mancini, L.A. Lotta, P. Bucciarelli, S.M. Passamonti, A. Cairo, E. Pappalardo, A. van Hylckama Vlieg, I. Martinelli, F.R. Rosendaal, F. Peyvandi. - In: THROMBOSIS RESEARCH. - ISSN 0049-3848. - 169(2018 Sep), pp. 76-81.

Next-generation DNA sequencing to identify novel genetic risk factors for cerebral vein thrombosis

M.M. Gorski
Primo
;
I. Mancini;L.A. Lotta;P. Bucciarelli;S.M. Passamonti;E. Pappalardo;F. Peyvandi
Ultimo
2018-09

Abstract

Background: Cerebral vein thrombosis (CVT) is a rare, life-threatening disease affecting one adult per 100,000 per year. Genetic risk factors are deficiencies of the natural anticoagulant proteins antithrombin, protein C, protein S or single nucleotide polymorphisms such as factor V Leiden and prothrombin 20210A. In 20% of patients, the cause of CVT remains unknown. Aim: To identify novel genetic risk factors for CVT using targeted next-generation DNA sequencing (NGS). Methods: We investigated 171 CVT patients and 298 healthy controls. Patients were selected using the following criteria: objective diagnosis of CVT, no active cancer. We performed targeted NGS analysis of the protein-coding regions of 734 candidate genes related to hemostasis and inflammation, 150 ancestry informative markers and 28 thrombosis-associated variants. Results: We identified 3723 common and low frequency variants with minor allele frequency (MAF) >1% in 590 genes. Single variant association testing using logistic regression analysis identified rs8176719 insertion/deletion (indel) variant in the ABO gene associated with CVT (age and sex adjusted OR 2.03; 95% CI 1.52–2.73; P = 2.07 × 10−6; Bonferroni P = 0.008). In addition, we identified 8839 rare variants (MAF ≤ 1%) in 723 genes. Gene-based association analysis of these rare variants using a burden test revealed only a tentative association of non-coding variants located in the F8 locus with CVT. Conclusion: Targeted NGS identified a common indel variant rs8176719 in the ABO gene. Gene-based tests of association failed to reveal genomic loci with a cumulative burden of rare variants associated with CVT.
ABO blood group; Cerebral vein thrombosis; Next-generation DNA sequencing; rs8176719; ABO Blood-Group System; Adult; Case-Control Studies; Cerebral Veins; Female; Gene Frequency; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; INDEL Mutation; Intracranial Thrombosis; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Hematology
Settore MED/09 - Medicina Interna
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/622105
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