Descriptively Probabilistic Relationship Between Mutated Primary Structure of coagulation factor IX and clinical Sever- ity of hemophilia B

Hemophilia B is a recessive bleeding disorder resulting from mutations in the coagulation factor IX gene. As this disease is characterized by clinical and molecular heterogeneity, the building of relationship between its genotype and phenotype would be great helpful for better diagnosis, prognosis and treatment. We use a descriptively probabilistic method, cross-impact analysis, to couple the changed primary structure of mutant human coagulation factor IX with the severity of hemophilia B with the help of the amino-acid distribution probability as a quantitative measure for mutation. Then we use the Bayesian equation to calculate the probability that the severity of hemophilia can be defined under a mutation. A patient has larger than 0.5 chance of being defined as severity of hemophilia B when a new mutation is found in coagulation factor IX. In this way, we take the first step towards further modeling of genotype-phenotype relationship in human coagulation factor IX. INTRODUCTION The coagulation factor IX precursor contains coagulation factor IXa light chain and heavy chain. After activation of coagulation factor IX to factor IXa, this enzyme interacts with the active cofactor form of factor VIII, to form a complex on membrane surfaces. This complex converts factor X to factor Xa [1]. Thus, the coagulation factor IX is one of critical components of the blood coagulation pathways, and its deficiency causes hemophilia B [2]. Hemophilia B is a recessive bleeding disorder that results from mutations in the coagulation factor IX gene on the X chromosome [3-5]. It occurs in one of 30 000 live male births in all populations [6, 7]. Major acute and chronic complications are often secondary to recurrent bleeding [8]. The unpredictable, recurrent, spontaneous bleedings mainly appear in soft tissues and/ or major joints. Recurrent bleeding in large joints usually leads to crippling arthropathies in a majority of severely affected patients. The clinical severity of hemophilia B corresponds to the level of circulating coagulation factor IX. Severe hemophilia occurs in less than 1% of coagulation factor IX activity. With moderate hemophilia, 1 – Descriptively Probabilistic Relationship Between Mutated Primary Structure of coagulation factor IX and clinical Severity of hemophilia B Shaomin Yan1 Guang Wu2 1Guangxi Academy of Sciences, 98 Daling Road, Nanning, Guangxi, CN-530007, China, 2Computational Mutation Project, DreamSciTech Consulting, Shenzhen, Guangdong Province CN-518054, China