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.

Is the 1298A>C polymorphism in the MTHFR gene a risk factor for arterial ischaemic stroke in children? The results of meta-analysis

“…Unfortunately, none of the studies included to the present meta-analysis show full data of genotype distribution; thus, we were not able to analyse sex subgroups to observe whether a similar relationship concerns the 1298A>C polymorphism. The study by Herak et al [14] showed no relationship between the MTHFR 1298A>C polymorphism and AIS when considered alone. However, some specific combinations of MTHFR 1298 genotypes with the Factor V Leiden, MTHFR 677C>T polymorphism and FV HR2 polymorphism were observed.…”

“…1. Finally, eight case-control studies were included in the meta-analysis with a total number of 426 paediatric patients with AIS and 778 control subjects [12][13][14][20][21][22][23][24].…”

“…Caucasians were the most common race. In order to genotype the MTHFR 1298A>C polymorphism, PCR-RFLP analysis was used in four of the studies [12,13,20,21], CVD StripAssays in two studies [14,22] and Taqman PCR in one study [23]. The genotyping method was not specified in one of the studies [24].…”

“…The genotyping method was not specified in one of the studies [24]. The largest groups of AIS patients were recruited by Balcerzyk et al [12], Herak et al [14] and Komitopoulou et al [22], whereas the fewest patients were recruited by Gelfand et al [23] and Morita et al [24]. The largest group of control subjects was analysed in the study by Sirachainan et al [21] and the lowest one in the study by Biswas et al [13].…”

“…However, the role of another common MTHFR polymorphism, 1298A>C in paediatric stroke, is still uncertain. Conflicting results of the studies on the relationship between the 1298A>C polymorphism and AIS, both in children and adults, can be found [12][13][14][15][16][17]. Previously, it was observed that the MTHFR 1298A>C polymorphism in combined analysis with the 677C>T polymorphism increased homocysteine levels as well as lowered plasma folate levels [18].…”