Polymorphisms in coagulation factor genes and enzymes of homocysteine metabolism in children stroke

Moždani udar (MU) u djece heterogeni je poremećaj s višestrukom etiologijom, koja je još uvijek nepoznata u približno 30% slučajeva. Genetički čimbenici nisu do kraja karakterizirani, a raspodjela gena kandidata za nastanak MU različita je u pojedinim populacijama. U istraživanje je bilo uključeno 100 djece starosne dobi do 18 godina s potvrđenim MU i 100 zdrave djece podudarne po dobi i spolu djeci s MU. Napravljena je genotipizacija 14 polimorfizama u 12 gena kandidata koji kodiraju proteine uključene u sustav zgrušavanja i fibrinolize (FV Leiden, FV HR2, FII G20210A, beta-fibrinogen -455G>A, FXIII-A Val34Leu, PAI-1 4G/5G), ljudskih trombocitnih antigena (HPA-1, -2, -3 i -5), metabolizma homocisteina (MTHFR C677T, MTHFR A1298C) i intermedijernih rizicnih cimbenika (ACE I/D i ApoE 2-4). Utvrđena je cešća pojavnost MU u dječaka, koja je uočena i u svim ispitivanim podskupinama. Najveći rizik za nastanak MU zabilježen je u prvoj godini života, kao i 2,7 puta veći broj arterijskih ishemijskih MU (AIMU) u odnosu na hemoragijski MU (HMU). Rezultati genotipizacije potvrdili su prije opisanu povezanost FV Leiden s nastankom (pojavom) MU. Dokazana je i povezanost 4 polimorfizma (FV Leiden, FXIII-A Val34Leu, HPA-3 i apoE _2-4) s AIMU i to različitih polimorfizama u pojedinim podskupinama prema spolu i dobi pojave AIMU, kao i povezanost kombinacija genotipova polimorfizama MTHFR C677T i MTHFR A1298 (CC/AC) i dvostrukog heterozigotnog oblika (GA/AG) polimorfizama FV Leiden i FV HR2 s AIMU, te kombinacije genotipova GA/AA s perinatalnim AIMU. Utvrđen je i umjereno povećan rizik za pojavu HMU u nosioca haplotipa HA2 (HPA- 1a2a3a-ACED). Ovo istraživanje ukazalo je na povezanost pojedinih dosad nedovoljno istraženih polimorfizama kao i kombinacija polimorfizama s etiologijom MU u djece u Hrvatskoj, što upotpunjuje i proširuje dosadašnje spoznaje o etiološkim rizičnim čimbenicima.Although stroke in children is a relatively rare and heterogeneous disorder with a wide range of identified risk factors, the etiology of stroke is still undetermined in up to 30% of children. Taking into consideration that genetic risk factors are incompletely characterized at present and the frequency of genetic factors may vary among different populations, a genotype analysis was perforrmed of 14 polymorphisms in 12 candidate genes encoding proteins of the coagulation and fibrinolysis systems (FV Leiden, FV HR2, FII G20210A, beta-fibrinogen - 455G>A, FXIII-A Val34Leu, PAI-1 4G/5G), human platelet alloantigens (HPA-1, -2, -3 and -5), homocysteine metabolism (MTHFR C677T, MTHFR A1298C) and intermediate risk factors (ACE I/D and apoE 2-4) was performed. The subject group comprised 100 children with a confirmed diagnosis of stroke aged £18 years and 100 age- and sex-matched control subjects. Obtained results were also analyzed in gender-specific stroke group and subgroups according to the type of stroke: arterial ischemic (AIS) and hemorrhagic stroke (HS), and according to the time of stroke onset (perinatal and childhood AIS). The predominance of boys was found among (in) children with stroke and in all tested subgroups. The greatest risk for stroke was identified in the first year of life, and AIS was found 2.7 times more frequently than HS. This case-control study has confirmed the association between FV Leiden and stroke that was also observed in numerous studies so far, but it has also shown that other previously not reported polymorhisms (FXIII-A Val34Leu, HPA-3 and the combination of FV Leiden and FV HR2 polymorphisms) can be related to AIS in Croatian population. Analysis performed in gender-specific stroke subgroups revealed the association of different polymorphisms in boys (FXII-A Val34Leu, HPA-3 and combination of MTHFR polymorphisms) and girls (apoE 4 allele). The strongest association (with OR>10.0) was found between FV Leiden and perinatal AIS for both genders whereas the lowest risk for perinatal AIS was observed in girls who were carriers of at least one HPA-3b allele. Obtained results have at least partially elucidated the role (impact) of new evaluated polymorphisms in the etiology of stroke in children and their impact according to gender, type of stroke and time of stroke onset