Association of the protein Z ATG haplotype with symptomatic nonvascular stroke or thromboembolism in white children: a family-based cohort study.
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 4 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 with use of 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, and rs3024772 are in tight linkage disequilibrium (LD) and define 4 haplotypes, capturing 97% of the genetic variation for this LD block. HT1 (ATG) was significantly overtransmitted from parents to affected offspring (HT frequency 73.5%, T:U 122:80, chi(2) = 8.791, P = .003). The ATG risk haplotype was significantly correlated with greater 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 (odds ratio [OR] 1.4; 95% confidence interval [95% CI] 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.
Nowak-Göttl
Ulrike
U
Pediatric Hematology/Oncology, University Clinics Münster, Münster, Germany. leagottl@unimuenster.de
Fröhlich
Birgit
B
Thedieck
Sabine
S
Huge
Andreas
A
Stoll
Monika
M
D000293:Adolescent; D001798:Blood Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005190:Family; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015810:Linkage Disequilibrium; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D020521:Stroke / Q000235:genetics*; D013923:Thromboembolism / Q000235:genetics*; D044465:White People / Q000235:genetics
D001798:Blood Proteins; D005819:Genetic Markers; C026080:plasma protein Z