title: Association of Polymorphisms in Coagulation Factor Genes and Enzymes of Homocysteine Metabolism With Arterial Ischemic Stroke in Children.
abstract: Despite the identification of a wide range of inherited and acquired risk factors for arterial ischemic stroke (AIS) in children, genetic risk factors are incompletely characterized and may vary among different populations. We investigated the role of individual and combined inherited prothrombotic and intermediate-risk factors in 73 children with perinatal (n = 35) and childhood AIS (n = 38) and 100 age- and sex-matched controls. Ten polymorphisms in 8 candidate genes encoding coagulation and fibrinolytic proteins (factor V [FV] Leiden, FV HR2, factor II [FII] G20210A, β-fibrinogen [β-FBG]-455G>A, factor XIII [FXIII]-A p.Val34Leu, plasminogen activator inhibitor 1 4G/5G), homocysteine metabolism (methylenetetrahydrofolate reductase [MTHFR] C677T, MTHFR A1298C), and intermediate-risk factors (angiotensin-converting enzyme I/D, apoE ∊2-4) were detected using a multilocus genotyping assay. Allele-specific polymerase chain reaction was used for the determination of human platelet alloantigens (HPA-1, HPA-2, HPA-3, and HPA-5). Factor V Leiden was associated with an increased risk of AIS (odds ratio [OR]: 4.72, 95% confidence interval [CI]: 1.22-18.27) and perinatal AIS (OR: 8.29, 95% CI: 1.95-35.24). Human platelet antigen-3b allele carriers had a 2-fold lower risk of AIS (OR: 0.51, 95% CI: 0.26-0.98) and perinatal AIS (OR: 0.40, 95% CI: 0.18-0.92). A 2.21-fold increased risk of childhood AIS (95% CI: 1.03-4.73) was identified in FXIII-A Leu34 allele carriers. Combined FV Leiden/FV HR2, FV Leiden/MTHFR A1298C, FV Leiden/MTHFR C677T/MTHFR A1298C, and FV Leiden/FV HR2/MTHFR A1298C heterozygosity was identified in children with AIS but not in controls, which revealed a statistically significant difference. This case-control study shows that besides already documented association between FV Leiden and AIS, other previously unreported polymorphisms (FXIII-A p.Val34Leu, HPA-3) and several genotype combinations that always include heterozygous FV Leiden can be related to AIS in Croatian population.
authors.affiliation: 1 Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: Désirée
authors.initials: D
authors.lastname: Coen Herak
authors.affiliation: 2 Department of Laboratory Diagnostics, Children's Hospital Zagreb, Zagreb, Croatia.
authors.forename: Jasna
authors.initials: J
authors.lastname: Lenicek Krleza
authors.affiliation: 1 Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: Margareta
authors.initials: M
authors.lastname: Radic Antolic
authors.affiliation: 1 Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Horvat
authors.affiliation: 3 Department of Neuropediatrics, Children's Hospital Zagreb, Zagreb, Croatia.
authors.forename: Vlasta
authors.initials: V
authors.lastname: Djuranovic
authors.affiliation: 4 Department of Clinical Laboratory Diagnostics, Children's Hospital Srebrnjak, Zagreb, Croatia.
authors.forename: Renata
authors.initials: R
authors.lastname: Zrinski Topic
authors.affiliation: 1 Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia.|5 University of Zagreb, Faculty of Pharmacy and Biochemistry, Zagreb, Croatia.
authors.forename: Renata
authors.initials: R
authors.lastname: Zadro
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D001779:Blood Coagulation Factors / Q000235:genetics*; D002545:Brain Ischemia / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006710:Homocysteine / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D020521:Stroke / Q000235:genetics*
chemical_list: D001779:Blood Coagulation Factors; D006710:Homocysteine; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: arterial ischemic stroke; children; coagulation factors; genetic polymorphisms; homocysteine metabolism