Submitted October 6, 2008
Accepted November 25, 2008
Association of the protein Z ATG haplotype with symptomatic non-vascular stroke or thromboembolism in white children - a family-based cohort study
Ulrike Nowak-Gottl*, Birgit Frohlich, Sabine Thedieck, Andreas Huge, and Monika Stoll
Pediatric Hematology/Oncology, University Clinics Muenster, Muenster, Germany
Leibniz-Institute for Arteriosclerosis Research, University of Muenster, Genetic Epidemiology of Vascular Disorders, Muenster, Germany
* Corresponding author; email: leagottl{at}uni-muenster.de.
To clarify the role of protein Z (PZ) in children with stroke/thromboembolism (TE) the present haplotype (HT)-based family study was performed. We genotyped 365 pediatric stroke/TE families (stroke n=216; TE n=149) for four single nucleotide polymorphisms (SNPs: rs3024718, rs3024731, rs3024772 and rs3024778) to assess the association between genetic variation within a conserved block of linkage disequilibrium harboring the PZ gene and pediatric TE. Association was assessed using the Transmission Disequilibrium Test (TDT), corrected for multiple testing (permutation testing: HAPLOVIEW). In addition, PZ antigen was determined and correlated with carriership of PZ haplotypes and the FV G1691A mutation. Rs3024718, rs3024731, rs3024772 are in tight linkage disequilibrium (LD) and define four haplotypes, capturing 97% of the genetic variation for this LD block. HT1 (ATG) was significantly over-transmitted from parents to affected offspring (HT frequency 73.5%, T:U 122:80, 
2=8.791, p=0.003). The ATG risk haplotype was significantly correlated with higher PZ antigen levels. Multivariate analysis adjusted for age, sex, established thrombophilias, smoking, fibrinogen and PZ levels revealed a significant association of the ATG haplotype and TE in children (OR/95%CI: 1.4/1.08-1.93). Our results suggest that the ATG haplotype of the PZ gene is a genetic marker for symptomatic TE in white German children.
