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


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J
J
Zhou
Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Q
Q
Ding
Hematology-Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Z
Z
Chen
Department of Hemotology, Xiangya Hospital, Central South University, Changsha, China.
H
H
Yang
Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
L
L
Lin
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
H
H
Wang
Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
X
X
Wang
Hematology-Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China.
R
R
Wu
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000906:Antibodies / Q000276:immunology; D044466:Asian People / Q000235:genetics*; D019774:Blood Coagulation Factor Inhibitors / Q000097:blood*; D001779:Blood Coagulation Factors / Q000276:immunology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002681:China; D018389:Codon, Nonsense; D056915:DNA Copy Number Variations; D005164:Factor IX / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D002836:Hemophilia B / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D007223:Infant; D016753:Interleukin-10 / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D012307:Risk Factors; D017384:Sequence Deletion; D055815:Young Adult
D000906:Antibodies; D019774:Blood Coagulation Factor Inhibitors; D001779:Blood Coagulation Factors; D018389:Codon, Nonsense; D018960:Hyaluronan Receptors; D016753:Interleukin-10; C025667:prothrombin complex concentrates; D005164:Factor IX
F9 gene mutation; anaphylaxis; haemophilia B; immune response genes; inhibitor development