title: Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A.
abstract: The HLA class I/II alleles and the tumor necrosis factor alpha (TNFA) locus are closely linked in the MHC complex. We have characterized the causative factor VIII mutation, HLA alleles as well as 4 polymorphisms (-827C>T, -308G>A, -238A>G, and 670A>G) in the TNFA gene in 164 patients (124 severe, 26 moderate, and 14 mild) in 78 families with hemophilia A enrolled in the Malmö International Brother Study (MIBS). Inhibitors were identified in 77.8% of patients with a single haplotype (Hap 2) and 72.7% of the patients with the TNFA -308 A/A genotype within this haplotype compared with 39.7% for TNFA -308 G/G patients and 46.9% for TNFA -308 G/A heterozygotes (OR 4.0; 95% CI, 1.4-11.5; P = .008). The association between the -308 A/A genotype and inhibitors was enhanced in subgroups of patients with severe hemophilia (OR 19.2; 95% CI 2.4-156.5; P < .001) and with inversions (n = 75; OR, 11.8; 95% CI, 1.3-105.1; P = .013). Associations were found for the HLA A26 and B44 alleles, but these were not consistent in the subgroup analysis. Our data imply that the TNFA -308G>A polymorphism within Hap 2 is a useful marker and potential modulator of the immune response to replacement therapy in patients with hemophilia.
authors.affiliation: Department for Coagulation Disorders, Malmö University Hospital, SE-205 02 Malmö, Sweden. jan.astermark@med.lu.se
authors.forename: Jan
authors.initials: J
authors.lastname: Astermark
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Joyce
authors.initials: J
authors.lastname: Carlson
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlova
authors.forename: Kaan
authors.initials: K
authors.lastname: Kavakli
authors.forename: Erik
authors.initials: E
authors.lastname: Berntorp
authors.forename: Ann-Kari
authors.initials: AK
authors.lastname: Lefvert
mesh_terms: D019774:Blood Coagulation Factor Inhibitors / Q000235:genetics / Q000276:immunology*; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006467:Hemophilia A / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics / Q000276:immunology; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D005819:Genetic Markers; D006680:HLA Antigens; D014409:Tumor Necrosis Factor-alpha