The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development

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 accru ed, 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 wi th severe haemophilia A was 31.7%. The corresponding figure in the caucasia n 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 inhib itor families, for whom monozygocity was confirmed in three cases. In 32 fa milies (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 h igh- or low-responding. The overall concordance within the severe haemophil ia A families was found to be 78.3% (195/249) compared to an expected figur e of 68.0% and 58.0% using an inhibitor incidence of 20 and 30%, respective ly (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 in hibitor 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). I mmune-tolerance induction was reported in 24 families, of whom 13 siblings were successfully treated. Our data clearly support the concept that a gene tic predisposition for inhibitor development exists. However, the markers o f this predisposition remain to be elucidated and we believe that the MIBS registry will be useful for this purpose.