title: The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients.
abstract: The issue of factors predisposing for inhibitor development in haemophilia patients is still largely unresolved. In an attempt to address this problem, we initiated a registry in 1996 of siblings with haemophilia and with or without a history of inhibitors. Four hundred and sixty families have accrued, of whom 388 suffer from haemophilia A and 72 haemophilia B. Twenty-five of the brother pairs are twins. The inhibitor incidence in all families with severe haemophilia A was 31.7%. The corresponding figure in the caucasian patients was 27.4%, whereas a higher incidence of inhibitors was reported in the black subjects (55.6%). Twins were reported in six of the 100 inhibitor families, for whom monozygocity was confirmed in three cases. In 32 families (32%), at least two brothers had a history of inhibitors. In 22 (69%) of these families, the inhibitor was also of the same type, i.e. either high- or low-responding. The overall concordance within the severe haemophilia A families was found to be 78.3% (195/249) compared to an expected figure of 68.0% and 58.0% using an inhibitor incidence of 20 and 30%, respectively (P < 0.0001). The corresponding figure for the twins was 88.2% (15/17). Moreover, the risk for inhibitor development in families with a previous inhibitor history was found to be 48% (95% confidence interval [CI] 35-62%), whereas the risk in families with no previous known inhibitor was only 15% (95% CI 11-21%) corresponding to a relative risk of 3.2 (95% CI 2.1-4.9). Immune-tolerance induction was reported in 24 families, of whom 13 siblings were successfully treated. Our data clearly support the concept that a genetic predisposition for inhibitor development exists. However, the markers of this predisposition remain to be elucidated and we believe that the MIBS registry will be useful for this purpose.
authors.affiliation: Department for Coagulation Disorders, University of Lund, Malmö, Sweden. jan.astermark@medforsk.mas.lu.se
authors.forename: J
authors.initials: J
authors.lastname: Astermark
authors.forename: E
authors.initials: E
authors.lastname: Berntorp
authors.forename: G C
authors.initials: GC
authors.lastname: White
authors.forename: B L
authors.initials: BL
authors.lastname: Kroner
mesh_terms: D016009:Chi-Square Distribution; D005169:Factor VIII / Q000276:immunology*; D005192:Family Health; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D006467:Hemophilia A / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D002836:Hemophilia B / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D006801:Humans; D007518:Isoantibodies / Q000097:blood / Q000235:genetics*; D008297:Male; D009679:Nuclear Family; D044469:Racial Groups; D012042:Registries
chemical_list: D007518:Isoantibodies; D005169:Factor VIII