Abstract
We recently reported a family-based genome wide association study (GWAS) for pediatric stroke pointing our attention to two significantly associated genes of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family ADAMTS2 (rs469568, p = 8x10-6) and ADAMTS12 (rs1364044, p = 2.9x10-6). To further investigate these candidate genes, we applied a targeted resequencing approach on 48 discordant sib-pairs for pediatric stroke followed by genotyping of the detected non-synonymous variants in the full cohort of 270 offspring trios and subsequent fine mapping analysis. We identified eight non-synonymous SNPs in ADAMTS2 and six in ADAMTS12 potentially influencing the respective protein function. These variants were genotyped within a cohort of 270 affected offspring trios, association analysis revealed the ADAMTS12 variant rs77581578 to be significantly under-transmitted (p = 6.26x10-3) to pediatric stroke patients. The finding was validated in a pediatric venous thromboembolism (VTE) cohort of 189 affected trios. Subsequent haplotype analysis of ADAMTS12 detected a significantly associated haplotype comprising the originally identified GWAS variant. Several ADAMTS genes such as ADAMTS13 are involved in thromboembolic disease process. Here, we provide further evidence for ADAMTS12 to likely play a role in pediatric stroke. Further functional studies are warranted to assess the functional role of ADAMTS12 in the pathogenesis of stroke.
Highlights
Pediatric stroke happens with an incidence of 2.6–6.4 per 100 000 children per year and is still one of the top 10 causes of death in children [1, 2]
Based on our association findings in the previous GWA study [1] for ADAMTS2 and ADAMTS12 we selected two candidate regions for subsequent next generation sequencing (NGS) based on linkage disequilibrium (LD) information using the postgwas package [19]
Our study confirms the role of ADAMTS12 as a promising candidate gene for pediatric stroke
Summary
Pediatric stroke happens with an incidence of 2.6–6.4 per 100 000 children per year and is still one of the top 10 causes of death in children [1, 2]. Extracellular matrix components like members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family, primarily ADAMTS13, in combination with misbalanced coagulation signals appear to play an important role in pediatric stroke etiology after postnatal vascular injuries [3, 4]. We have reported results of a family-based genome wide association study (GWAS) for pediatric stroke pointing our attention to ADAMTS2 and ADAMTS12 [1]. ADAMTS2 (rs469568, p = 8x10-6) and ADAMTS12 (rs1364044, p = 2.9x10-6) were both highly associated with pediatric stroke. ADAMTS12, is classified as proteinase of the cartilage oligomeric matrix protein (COMP), it is inducing neutrophil apoptosis in mice, and silenced ADAMTS12 genes were found in human tumor cells. As ADAMTS2, the protein is showing antiangiogenic characteristics [7]
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