title: LDLR and PCSK9 Are Associated with the Presence of Antiphospholipid Antibodies and the Development of Thrombosis in aPLA Carriers.
abstract: BACKGROUND
  The identification of the genetic risk factors that could discriminate non- thrombotic from thrombotic antiphospholipid antibodies (aPLA) carriers will improve prognosis of these patients. Several human studies have shown the presence of aPLAs associated with atherosclerotic plaque, which is a known risk factor for thrombosis. Hence, in order to determine the implication of atherosclerosis in the risk of developing thrombosis in aPLA positive patients, we performed a genetic association study with 3 candidate genes, APOH, LDLR and PCSK9.
  
  
  METHODS
  For genetic association study we analyzed 190 aPLA carriers -100 with non-thrombotic events and 90 with thrombotic events- and 557 healthy controls. Analyses were performed by χ2 test and were corrected by false discovery rate. To evaluate the functional implication of the newly established susceptibility loci, we performed expression analyses in 86 aPLA carrier individuals (43 with thrombotic manifestations and 43 without it) and in 45 healthy controls.
  
  
  RESULTS
  Our results revealed significant associations after correction in SNPs located in LDLR gene with aPLA carriers and thrombotic aPLA carriers, when compared with healthy controls. The most significant association in LDLR gene was found between SNP rs129083082 and aPLA carriers in recessive model (adjusted P-value = 2.55 x 10-3; OR = 2.18; 95%CI = 1.49-3.21). Furthermore, our work detected significant allelic association after correction between thrombotic aPLA carriers and healthy controls in SNP rs562556 located in PCSK9 gene (adjusted P-value = 1.03 x 10-2; OR = 1.60; 95%CI = 1.24-2.06). Expression level study showed significantly decreased expression level of LDLR gene in aPLA carriers (P-value <0.0001; 95%CI 0.16-2.10; SE 0.38-1.27) in comparison to the control group.
  
  
  CONCLUSIONS
  Our work has identified LDLR gene as a new susceptibility gene associated with the development of thrombosis in aPLA carriers, describing for the first time the deregulation of LDLR expression in individuals with aPLAs. Besides, thrombotic aPLA carriers also showed significant association with PCSK9 gene, a regulator of LDLR plasma levels. These results highlight the importance of atherosclerotic processes in the development of thrombosis in patients with aPLA.
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, School of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Eguzkine
authors.initials: E
authors.lastname: Ochoa
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, School of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Mikel
authors.initials: M
authors.lastname: Iriondo
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, School of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Manzano
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, School of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Asier
authors.initials: A
authors.lastname: Fullaondo
authors.affiliation: Autoimmune Disease Research Unit, Service of Internal Medicine, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain.
authors.forename: Irama
authors.initials: I
authors.lastname: Villar
authors.affiliation: Autoimmune Disease Research Unit, Service of Internal Medicine, BioCruces Health Research Institute, Hospital Universitario Cruces, Barakaldo, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ruiz-Irastorza
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, School of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Zubiaga
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, School of Science and Technology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Andone
authors.initials: A
authors.lastname: Estonba
mesh_terms: D000328:Adult; D000368:Aged; D017152:Antibodies, Antiphospholipid / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics*; D040641:Quantitative Trait Loci; D011973:Receptors, LDL / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics*; D013927:Thrombosis / Q000097:blood / Q000235:genetics* / Q000276:immunology; D053482:beta 2-Glycoprotein I / Q000235:genetics
chemical_list: D017152:Antibodies, Antiphospholipid; D011973:Receptors, LDL; D053482:beta 2-Glycoprotein I; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
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