Relationship Between Factor VIII Mutation and Inhibitor Development in Previously Treated Patients with Hemophilia a in Korea

We reported the results of genetic analysis (factor VIII gene, interleukin-10, TNF-alpha) in 54 previously treated patients (PTPs, at least 100 exposure days or 1 year) including 18 with inhibitor history with severe hemophilia A in Korea. We confirmed 20 novel mutations among 35 different factor VIII mutations (intron 22 inversion, missense, deletion, nonsense and splicing), not reported by HAMSTeRS. As our patients were small group, it was not verified that relationship between factor VIII mutation and inhibitor incidence was statistically significant. 9 PTPs with inhibitor history had intron 22 inversion, 7 had missense, 3 had substitution, 1 had nonsense, 1 had small deletion and 1 had splicing. We did not find large deletion. 40 (74.1%) of 54 PTPs were found to have interleukin-10 (IL10) 134 bp microsatellite. IL10 134 bp microsatellite negative group showed statistically higher incidence of inhibitors (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.12 – 14.35; P=0.047). No association was found between inhibitor formation and TNF-alpha gene. Inhibitors were identified in 88.9% of the patients with the TNF-alpha -308 G/G genotype, compared with 11.1% for the TNF-alpha -308 G/A genotype and 0% for the TNF-alpha -308 A/A genotype. Based on this report, prospective study with large sample size may lead to the development of preventive measures to minimize inhibitor formation.