Risk factors associated with inhibitor development in Chinese patients with haemophilia B

Inhibitor development is a severe complication of factor IX substitution treatment for haemophilia B (HB). Current research examined the association between inhibitor development and F9 genotypes and polymorphisms in immune response genes in Chinese HB patients.

11 inhibitor-positive HB patients and 41 inhibitor-negative HB patients were enrolled. Direct sequencing, copy number variation (CNV) detection and fragment length analysis were applied to identify F9 genotypes and 15 polymorphisms in immune response genes.

7 patients developed high titer inhibitors, with 5 of them having histories of consecutive exposure to FIX products on demand for at least 5 days. Allergic reactions/anaphylaxis to prothrombin complex concentrates (PCC) occurred in 3 patients before inhibitors were detected. Five nonsense mutations (E54X, R75X, Q185X, R298X and R379X), two large deletions (E1~6del and E1~8del) and one missense mutation (S411G) were identified in patients with inhibitors. Missense mutations had a low odds ratio for FIX inhibitors development (IOR) of 0.078 (P = 0.02), while nonsense mutation presented a high IOR of 8.500 (P = 0.0044). The frequency of allele T in CD44(95102) (A/T) was significantly higher in inhibitor-negative patients, with OR of 0.324 (P = 0.04).

Nonsense mutations conferred a higher risk for while allele T in CD44(95102) (A/T) might play a protective role against inhibitor development in Chinese HB patients.