title: Pro-inflammatory genotype as a risk factor for aPL-associated thrombosis: Report of a family with multiple anti-phospholipid positive members.
abstract: OBJECTIVE
  Inflammation might represent a second hit for anti-phospholipid antibody (aPL)-mediated thrombosis. Inflammatory responses have been linked to gene polymorphisms of several cytokines and Toll Like Receptors (TLRs). We examined IL1 beta, TNFalpha, TGFbeta, IL6, IFN gamma, IL10, tlr4 gene polymorphisms in a family with several members positive for IgG anti-beta2 glycoprotein I (beta 2GPI) antibodies but with recurrent thrombosis in one member only.
  
  
  METHODS
  Lupus anticoagulant, anti-cardiolipin, anti-beta 2GPI IgG/IgM antibodies, IL1beta, TNFalpha, TGF beta1, IL6, IL10, IFN gamma, tlr4 gene polymorphisms (by allele-specific polymerase chain reaction) in addition to standard thrombophilic risk factors and cytokine serum levels (IL-1 beta, TNFalpha, IL-10) were evaluated.
  
  
  RESULTS
  Recurrent thrombotic events was reported only in the proband, but not in three healthy siblings persistently positive for IgG anti-beta2GPI antibodies, respectively. The wild type tlr4 gene and cytokine polymorphisms associated with a high pro-inflammatory response (IL-1 beta promoter-511C/T; TNFalpha G/A; TGFbeta+10T/C, +25C/G; IL-6 -174C/G) were found only in the proband. Serum cytokine levels were normal.
  
  
  CONCLUSIONS
  This case report confirms that protective tlr4 gene polymorphisms are more frequent in asymptomatic aPL carriers. In line with the role of inflammatory mediators as second hits for aPL-associated thrombosis, the polymorphisms of cytokines linked to higher inflammatory response were found in the proband only.
authors.affiliation: Department of Internal Medicine, Clinical Immunology & Rheumatology Unit, University of Milan, Italy; IRCCS Istituto Auxologico Italiano, Italy.
authors.forename: V
authors.initials: V
authors.lastname: De Angelis
authors.forename: S
authors.initials: S
authors.lastname: Scurati
authors.forename: E
authors.initials: E
authors.lastname: Raschi
authors.forename: A
authors.initials: A
authors.lastname: Liutkus
authors.forename: A
authors.initials: A
authors.lastname: Belot
authors.forename: M O
authors.initials: MO
authors.lastname: Borghi
authors.forename: P L
authors.initials: PL
authors.lastname: Meroni
authors.forename: R
authors.initials: R
authors.lastname: Cimaz
mesh_terms: D017152:Antibodies, Antiphospholipid / Q000097:blood / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000150:complications*; D002648:Child; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007378:Interleukins / Q000097:blood / Q000235:genetics; D010290:Parents; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D035781:Siblings; D013927:Thrombosis / Q000209:etiology* / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D053482:beta 2-Glycoprotein I / Q000276:immunology
chemical_list: D017152:Antibodies, Antiphospholipid; D016207:Cytokines; D007378:Interleukins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D053482:beta 2-Glycoprotein I; D007371:Interferon-gamma