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||A case-control study reveals immunoregulatory gene haplotypes that influence inhibitor risk in severe haemophilia A.
||Lozier JN, Rosenberg PS, Goedert JJ, Menashe I
||Several genes that modify risk of factor VIII (FVIII) inhibitors in haemophilia A patients have been identified. Aside from the underlying mutations that cause haemophilia A, inhibitor risk appears to be modified by polymorphisms in various cytokines and immunomodulators including IL10, TNFÎ± and CTLA4. HLA haplotypes have not been strong determinants of inhibitor risk. We sought to confirm previous observations on FVIII inhibitor risk-modifying genes and to test new candidate genes encoding various otherTH1/TH2 cytokines. We also sought to determine whether normal FVIII gene polymorphisms affect inhibitor risk in caucasians. We studied 915 caucasian, severe haemophilia A patients (282 inhibitor cases and 633 non-inhibitor controls). Genes were analysed using 368 tagging single nucleotide polymorphisms starting 20 kb 5' and ending 10 kb 3' of each gene's coding sequence; four other polymorphisms (factor V Leiden & prothrombin 20210 polymorphisms and two in HFE) were also evaluated. Haplotypes that increased inhibitor risk were found in IL10 (OR = 1.33, P = 0.04), IL12 (OR = 1.31, P = 0.04) and IL1Î± (OR = 2.16, P = 0.034). Protective haplotypes were seen in IL2 (OR =â .69, P = 0.008) and IL1Î² (OR = 0.75, P = 0.02). One rare haplotype in the FVIII gene increased the risk of inhibitor development by nearly fourfold (OR = 3.8, P = 0.004). We replicate previous findings for IL10; identify new associations with IL1, IL2 and IL12; and identify a rare FVIII haplotype in caucasians that is associated with increased inhibitor risk.