title: Polymorphisms in genes involved in autoimmune disease and the risk of FVIII inhibitor development in Italian patients with haemophilia A.
abstract: One of the most severe and important complication in the treatment of patients with haemophilia A is the formation of neutralizing antibodies (FVIII inhibitors) that inhibit the clotting activity of substituted FVIII. Both genetic and environmental factors influence the susceptibility of patients to develop inhibitors. The objective of this study was to evaluate whether polymorphisms in different genes involved in the regulation of the immune system may confer susceptibility to inhibitor development in patients with HA. We analysed the distribution of polymorphisms in the CTLA4, PTPN22, IL10, TNFalpha, FOXP3 and IRF5 genes that have been reported to be associated with a number of autoimmune disease. In addition, we evaluated the distribution of IL10 haplotypes in haemophilic patients and healthy controls to assess whether specific polymorphisms in IL10 gene were associated to the risk of inhibitor development. We focused on a cohort of Italian unrelated haemophilic patients with and without a history of inhibitors. Genotyping was carried out with standard methods including RFLP, real time PCR and direct DNA sequencing. Our data show that, considering single nucleotide variations, genotype frequencies in patients with inhibitors were not significantly different from those observed in patients without inhibitors, suggesting a lack of association between these polymorphisms and the development of inhibitors. Moreover, no relationship was found between specific combinations of IL10 alleles and the antibody production. Previous contradictory association studies may depend on the different genetic background of the population examined. Further studies may contribute to a clearer understanding of this process.
authors.affiliation: Genetica Medica, Dipartimento di Scienze Biomediche, Università degli Studi di Foggia, Foggia, Italy. valeria.b@libero.it
authors.forename: V
authors.initials: V
authors.lastname: Bafunno
authors.forename: R
authors.initials: R
authors.lastname: Santacroce
authors.forename: M
authors.initials: M
authors.lastname: Chetta
authors.forename: G
authors.initials: G
authors.lastname: D'Andrea
authors.forename: D
authors.initials: D
authors.lastname: Pisanelli
authors.forename: F
authors.initials: F
authors.lastname: Sessa
authors.forename: T
authors.initials: T
authors.lastname: Trotta
authors.forename: G
authors.initials: G
authors.lastname: Tagariello
authors.forename: F
authors.initials: F
authors.lastname: Peyvandi
authors.forename: M
authors.initials: M
authors.lastname: Margaglione
mesh_terms: D015703:Antigens, CD / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics*; D019774:Blood Coagulation Factor Inhibitors / Q000235:genetics*; D060908:CTLA-4 Antigen; D005091:Exons / Q000235:genetics; D005169:Factor VIII / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics; D005787:Gene Frequency; D006467:Hemophilia A / Q000150:complications / Q000235:genetics* / Q000276:immunology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D007558:Italy; D011110:Polymorphism, Genetic; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D015703:Antigens, CD; D019774:Blood Coagulation Factor Inhibitors; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005169:Factor VIII; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22