Plasma glutathione peroxidase in pediatric stroke families

Promoter polymorphisms in the plasma glutathione peroxidase gene (GPX3), which encodes a major antioxidant enzyme implicated in post-translational modification of fibrinogen, have been implicated as risk factors for arterial ischemic stroke (AIS) and cerebral sinovenous thrombosis (CSVT) in young adults. However, the contribution of these polymorphisms could not be confirmed by other studies.

The aim of the present study was to investigate the association of three haplotype-tagging single-nucleotide polymorphisms (htSNPs) in GPX3 in a large family-based study sample comprising 268 nuclear families with different pediatric AIS subtypes, i.e. arteriopathy stroke (AS) and thromboembolic stroke (TS). In addition, an independent study sample comprising 154 nuclear families of pediatric CSVT was investigated. Single-point and haplotype association was assessed with the transmission disequilibrium test implemented in haploview.

Single-point analysis revealed that the G allele of htSNP rs8177412 was significantly overtransmitted to affected AS children (T/U = 25 : 11, χ(2) = 5.54, P = 0.019), but not to affected TS children (T/U = 49 : 40, χ(2) = 0.91, P = 0.34). The corresponding GG haplotype (H2: frequency 0.18) was also significantly overtransmitted to AS children (T/U = 23 : 11, χ(2) = 4.28, P= 0.03), but not to TS children or in children with CSVT. These results remained significant following 10,000 bootstrap permutations. Our findings indicate that genetic variants of GPX3 are risk factors for AS, but not for thromboembolic AIS or CSVT, in children.

Our results further highlight the need to analyze the contribution of genetic variants to pediatric AS, TS or CSVT separately, as these subcategories probably result from different combinations of risk-conferring and protective genetic variations.