ORIGINAL ARTICLE Genetic factors influencing inhibitor development in a cohort of South African haemophilia A patients A. LOCHAN,* S. MACAULAY,* W. C. CHEN,* J. N. MAHLANGU † and A. KRAUSE* *Division of Human Genetics, National Health Laboratory Service (NHLS) and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand; and †Molecular Medicine and Haematology, NHLS and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa Summary. A critical complication of factor VIII (FVIII) replacement therapy in Haemophilia A (HA) treatment is inhibitor development. Known genetic factors predisposing to inhibitor development include FVIII (F8) gene mutations, ethnicity, a family history of inhibitors and FVIII haplotype mismatch. The aim of this study was to characterize and correlate these genetic factors in a cohort of South African HA patients. This was a retrospective study that included 229 patients and involved the analysis of patient files, HA molecular and clinical databases and molecular analysis of the F8 gene haplotype. Of the 229 patients, 51% were of black ethnicity, 49% were white, 5% had mild HA, 4% were moderate and 91% were severe, 36% were int22 positive and 13% were inhibitor positive. Of the inhibitor positive patients, 72% were black patients. Inhibitors were reported in 27% of black int22 positive patients, 13% of black int22 negative patients, 9% of white int22 positive patients and 7% of white int22 negative. The H1 haplotype was more common in whites (75%) and H2 was more common in blacks (74%). H3 and H5 were only found in black patients and had a higher frequency of inhibitor development than H1 and H2. In this small HA cohort, black patients had a significantly higher frequency of inhibitor development and the results were indicative of an association between inhibitor development, ethnicity and haplotype. Keywords: F8 gene haplotype, factor VIII, factor VIII inhibitors, genetic factors, haemophilia A, South Africa Introduction Haemophilia A (HA) is a bleeding disorder caused by mutations in the factor VIII (F8) gene encoding the coagulation factor VIII (FVIII) protein [1]. F8 gene mutations demonstrate high mutational heterogeneity with gross rearrangements, such as the common intron 22 inversion (int22) mutation accounting for approxi- mately 20% of all HA cases [2]. The int22 mutation has been identified as the causative mutation in 45% to 55% of patients with severe HA in large cohort studies [3–5]. Two main types of the int22 mutation have been identified, namely, type 1 (proximal inver- sion) and type 2 (distal inversion) [6]; accounting for approximately 83% and 16% of cases respectively [7]. Although FVIII concentrate replacement therapy in HA has proven to be effective in preventing or reduc- ing secondary complications such as pain, chronic joint disease and disability, a critical and challenging complication of treatment is inhibitor development to the FVIII protein [8]. Inhibitor formation has been recognized in 15–20% of all HA patients [8] with approximately 20–30% of severe HA patients having inhibitor development [9]. As FVIII replacement therapy is the standard of care in HA treatment, the development of inhibitors to FVIII has a substantial impact as FVIII bypassing therapeutic agents, surgical procedures, increased hospitalizations and rehabilita- tion may be required, all of which increase the cost and affordability of haemophilia care [10]. Inhibitor development is associated with predispos- ing genetic and environmental factors [11]. The genetic risk factors include F8 gene mutation type, ethnic origin (F8 gene haplotype), a positive family history of inhibitor development and polymorphisms of immune response genes [12]. Four single nucleotide Correspondence: Anneline Lochan, Division of Human Genetics, National Health Laboratory Service (NHLS) and School of Pathology, Faculty of Health Sciences, University of the Witwa- tersrand, Johannesburg, Gauteng, South Africa. Tel.: +27 11 489 9223; fax: +27 11 489 9226; e-mail: anneline.lochan@gmail.com Accepted after revision 9 March 2014 © 2014 John Wiley & Sons Ltd 1 Haemophilia (2014), 1–6 DOI: 10.1111/hae.12436