title: Novel loci involved in platelet function and platelet count identified by a genome-wide study performed in children.
abstract: BACKGROUND
  Genome-wide association studies are currently identifying new loci with potential roles in thrombosis and hemostasis: these loci include novel polymorphisms associated with platelet function traits and count. However, no genome-wide study performed on children has been reported to date, in spite of the potential that these subjects have in genetic studies, when compared to adults, given the minimal degree of confounders, i.e., acquired and environmental factors, such as smoking, physical activity, diet, and drug or hormone intake, which are particularly important in platelet function.
  
  
  METHODS
  To identify new genetic variants involved in platelet reactivity and count, we performed a genome-wide association study on 75 children (8.5±1.8 years) using the Illumina Sentrix Human CNV370-Quad BeadChip containing 320,610 single nucleotide polymorphisms. Functional analyses included assessment of platelet aggregation and granule secretion triggered by different agonists (arachidonic acid, collagen, epinephrine, ADP), as well as platelet count. Associations were selected based on statistical significance and physiological relevance for a subsequent replication study in a similar sample of 286 children.
  
  
  RESULTS
  We confirmed previously established associations with plasma levels of factors XII, VII and VIII as well as associations with platelet responses to ADP. Additionally, we identified 82 associations with platelet reactivity and count with a P value less than 10(-5). From the associations selected for further replication, we validated two single nucleotide polymorphisms with mildly increased platelet reactivity (rs4366150 and rs1787566) on the LPAR1 and MYO5B genes, encoding lisophosphatidic acid receptor-1 and myosin VB, respectively; and rs1937970, located on the NRG3 gene coding neuroregulin-3, associated with platelet count.
  
  
  CONCLUSIONS
  Our genome-wide association study performed in children, followed by a validation analysis, led us to the identification of new genes potentially relevant in platelet function and biogenesis.
authors.affiliation: University of Murcia, Centro Regional de Hemodonación, Murcia, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Guerrero
authors.forename: José
authors.initials: J
authors.lastname: Rivera
authors.forename: Teresa
authors.initials: T
authors.lastname: Quiroga
authors.forename: Angel
authors.initials: A
authors.lastname: Martinez-Perez
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Antón
authors.forename: Constantino
authors.initials: C
authors.lastname: Martínez
authors.forename: Olga
authors.initials: O
authors.lastname: Panes
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.forename: Diego
authors.initials: D
authors.lastname: Mezzano
authors.forename: José-Manuel
authors.initials: JM
authors.lastname: Soria
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
mesh_terms: D000483:Alleles; D001792:Blood Platelets / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D010976:Platelet Count; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results