Variations in Certain Immune Genes May Help Predict Risk for Developing FVIII Inhibitors in Hemophilia A

Genetic variations in certain immune-related genes, namely the HLA and IL-10 genes, are linked with an increased risk for developing inhibitors against factor VIII replacement therapies in patients with severe hemophilia A.

The study that determined that finding, “Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A,” was published in the journal PLOS One.

Factor VIII replacement therapy is a standard treatment for hemophilia patients. Factor VIII is a coagulation factor that helps prevent spontaneous bleeds, and reduces the need for blood infusions to treat uncontrolled bleeding. However, 30% of patients develop an immune response against factor VIII therapy in the first 20 days of treatment, which halts the treatment’s effectiveness. These patients ultimately become resistant to the treatment.

Researchers estimated that factors related to the patient and product could explain why some patients develop antibodies against factor VIII. Mutations in the factor VIII gene, family history, ethnicity, and treatment intensity have been pointed to as potential risk factors.

This team of researchers sought to identify genetic markers that could help predict which patients were prone to develop an immune response against external factor VIII.

They analyzed data from patients with severe hemophilia A from two German centers in Bonn and Frankfurt, who were recruited for the European ABIRISK tranSMART database. They investigated clinical and genetic components behind factor VIII inhibitors’ development, looking specifically to immune-related genes.

The genetic sequence of several immune-related genes — HLA, IL-10, CTLA4, CD32, MAPK9, and CD86 — was analyzed. Specifically, researchers analyzed HLA haplotypes (a set of DNA variations that tend to be inherited together), and the content of the other genes for single nucleotide polymorphism (SNP), which is a difference in a single nucleotide, the building blocks of DNA.

In total, 586 patients from Bonn were analyzed, of which 113 (19%) developed inhibitors, and 79 from Frankfurt, of which 32 patients (41%) developed inhibitors.

The analysis revealed that patients from Bonn with a familial history of inhibitor development had 5.94 times higher risk of developing inhibitors, compared to patients without a family history of an immune response against factor VIII. Familial history was not available for the Frankfurt patients.

Although not significant in the two centers’ data, the team observed that patients with a blood type other than O were 1.46 more likely to develop inhibitors.

Next, the team established a statistical model to understand how different genetic and clinical parameters could explain the development of inhibitors in some patients. They did this analysis in 142 patients from the Bonn database.

Results showed that patients with a specific HLA haplotype (called HLA-DRB1*15), and with a particular SNP in the IL-10 gene, had higher risk for developing inhibitors. Of 30 patients in this group, 23 developed an immune response against factor VIII.

Patients negative for the haplotypes HLA-DRB1*15 and HLA-DQB1*02, and for certain SNPs in the gene, had the lowest risk, with only four of 36 patients within this subgroup developing inhibitors.

Overall, the results “show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients,” the team concluded.