RESUMO
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, TNFα 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 IL1α (OR = 2.16, P = 0.034). Protective haplotypes were seen in IL2 (OR = .69, P = 0.008) and IL1ß (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.
Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/genética , Haplótipos/genética , Hemofilia A/genética , Hemofilia A/imunologia , Interleucinas/genética , Adolescente , Adulto , Estudos de Casos e Controles , Genótipo , Humanos , Polimorfismo Genético/genética , Adulto JovemRESUMO
Of all five senses, olfaction is the most complex molecular mechanism, as it comprises hundreds of receptor proteins enabling it to detect and discriminate thousands of odorants. Until lately, the understanding of this highly sophisticated sensory neuronal pathway has been rather sketchy. The sequencing of the human genome and the consequent advent of new genomic tools have opened new opportunities to better understand this multifaceted biological system. Here, we present the relevant progresses made in the last decade and highlight the possible genetic mechanisms of human olfactory variability.
