Thrombotic antiphospholipid syndrome shows strong haplotypic association with SH2B3-ATXN2 locus

PLoS One. 2013 Jul 3;8(7):e67897. doi: 10.1371/journal.pone.0067897. Print 2013.


Background: Thrombotic antiphospholipid syndrome is defined as a complex form of thrombophilia that is developed by a fraction of antiphospholipid antibody (aPLA) carriers. Little is known about the genetic risk factors involved in thrombosis development among aPLA carriers.

Methods: To identify new loci conferring susceptibility to thrombotic antiphospholipid syndrome, a two-stage genotyping strategy was performed. In stage one, 19,000 CNV loci were genotyped in 14 thrombotic aPLA+ patients and 14 healthy controls by array-CGH. In stage two, significant CNV loci were fine-mapped in a larger cohort (85 thrombotic aPLA+, 100 non-thrombotic aPLA+ and 569 healthy controls).

Results: Array-CGH and fine-mapping analysis led to the identification of 12q24.12 locus as a new susceptibility locus for thrombotic APS. Within this region, a TAC risk haplotype comprising one SNP in SH2B3 gene (rs3184504) and two SNPs in ATXN2 gene (rs10774625 and rs653178) exhibited the strongest association with thrombotic antiphospholipid syndrome (p-value = 5,9 × 10(-4) OR 95% CI 1.84 (1.32-2.55)).

Conclusion: The presence of a TAC risk haplotype in ATXN2-SH2B3 locus may contribute to increased thrombotic risk in aPLA carriers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Antiphospholipid Syndrome / genetics
  • Ataxins
  • Chromosome Mapping
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • Female
  • Gene Order
  • Genetic Association Studies
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Haplotypes*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Proteins / genetics*


  • Ataxins
  • Intracellular Signaling Peptides and Proteins
  • LNK protein, human
  • Nerve Tissue Proteins
  • Proteins

Grant support

This work was supported by the Basque Government (Etortek IE09-256, Saiotek S-PE10UN82 and Plan +Euskadi 09UE09+/57 to AMZ and Saiotek- PE08UN73 and Saiotek- PE09UN64 to AE) and by the UPV/EHU (UFI 11/20 to AMZ). Dr. Ruiz-Irastorza is supported by the Department of Education, Universities and Research of the Basque Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.