Thrombotic Antiphospholipid Syndrome Shows Strong Haplotypic Association with <i>SH2B3-ATXN2</i> Locus

<div><p>Background</p><p>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.</p><p>Methods</p><p>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).</p><p>Results</p><p>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 <i>TAC</i> risk haplotype comprising one SNP in <i>SH2B3</i> gene (rs3184504) and two SNPs in <i>ATXN2</i> 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)).</p><p>Conclusion</p><p>The presence of a <i>TAC</i> risk haplotype in <i>ATXN2-SH2B3</i> locus may contribute to increased thrombotic risk in aPLA carriers.</p>