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Antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial and venous thrombosis. The classical autoimmune markers of APS are antiphospholipid antibodies (aPL). Recently, the CD40 ligand (CD40L) has been shown to be associated with aPL. The role of CD40L polymorphisms in the pathogenesis of APS and thrombosis is not fully understood. We assessed the association between CD40L polymorphisms and late-onset APS, defined as patients >50 years of age, and thrombotic complications. Forty-eight patients with APS and 49 control subjects (35 with SLE and 14 with systemic sclerosis) from both Greece and Australia were studied. CD40L polymorphisms were determined using polymerase chain reaction and sequence-specific oligonucleotide probe methods. In the APS group, the frequency of the mutant allele was 0.65 in the APS group compared with 0.21 in the control group (P = 0.0001). The frequency of the mutant allele was significantly higher among patients in the late-onset group compared with the early-onset APS group (P = 0.03). The PTPN22 C1858T polymorphism was not associated with APS or thrombotic complications. This study suggests an association between the CD40L polymorphism and late-onset APS in patients from Australia and Greece, supporting a role for CD40L in late-onset APS