Polimorfizmi u genima za koagulacijske čimbenike i enzime metabolizma homocisteina u djece s moždanim udarom

doctoral thesis

• Title (english): Polymorphisms in coagulation factor genes and enzymes of homocysteine metabolism in children stroke
• Author: Desiree Coen Herak
• Mentor: Renata Zadro (mentor)
• Committee member: Tihana Žanić Grubišić (predsjednik povjerenstva)
• Committee member: Vida Demarin (član povjerenstva); MBZ: 39356
• Committee member: Karmela Barišić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; Zagreb
• Defense date and country: 2016, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Medical Biochemistry
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

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.

Abstract (english)

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.

• Keywords: moždani udar; djeca; genski polimorfizmi; koagulacijski čimbenici; metabolizam homocisteina
• Keywords (english): pediatric stroke; children; genetic polymorphisms; coagulation factors; homocystein metabolism
• Language: croatian
• URN:NBN: urn:nbn:hr:163:402167
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2016-11-25 11:34:56