Genetic Factors Associated with Inhibitor Development in Hemophilia A: Initial Results From the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.

Both genetic and environmental factors have been implicated as potential risk factors for the development of inhibitory factor VIII (FVIII) antibodies. Previous studies suggest that genetic factors are of major importance. The causative FVIII mutation likely sets the stage for inhibitor risk, with other genetic markers important in determining the final outcome. Data suggest that the process of inhibitor development is complex, involving a variety of immune regulatory genes, several of which have the potential to modify risk. Through a collaboration among three multi-center studies: the Hemophilia Inhibitor Genetics Study (HIGS), the Malmö International Brother Study (MIBS), and the Hemophilia Growth and Development Study (HGDS), a combined cohort was formed to conduct an association study to test the hypothesis that antibody development to FVIII is mediated by immune response genes.

The study includes clinical and laboratory data for 680 people with hemophilia A. Participants from Europe and North America account for 43% and 57% of the population, respectively. Eighty-five percent have severe (<0.01 IU/mL), 10% moderate (0.01 – 0.05% IU/mL), and 4.4% mild (>0.05 – 0.4 IU/mL) hemophilia. The cohort is predominately Caucasian, 81.0%, with 6.2% of African heritage, 8.8% Hispanic, and the remaining 4% of other races and ethnicities. Forty-nine percent have a current, or history of, an inhibitor ≥1 BU. Using the Illumina iSelect platform, 14,626 single nucleotide polymorphisms (SNPs) from 1,081 candidate genes were genotyped. These included immune response and immune modifier genes: cytokines and their receptors, chemokines and their receptors, and pathway genes involved in inflammatory and immune responses. Analyses were completed among the total group and the subgroup with severe hemophilia to identify SNPs associated with inhibitor status. The models were adjusted for population admixture, severity of hemophilia, type of mutation (high vs. low risk), year of birth, and geographic region. Meta analyses were used to obtain single odds ratios (OR) and p-values for the three cohorts.

13,952 of the 14,626 (95.4%) SNPs were successfully genotyped. One hundred fourteen were associated with inhibitor status at the p<0.01 level. Strong SNP associations for the total group were observed in the DOCK2 (OR 0.28, p= 0.00004, and OR 3.9, p=0.0002), MAPK9 (OR 2.0, p=0.0003), F13A1 (OR 0.32, p=0.00007), CD36 (OR 0.56, p=0.0002), and PTPRR (OR 0.51, p=0.0003) genes. For four markers located within the MAPK9, DOCK2, and CD36 genes, the associations were similar, or stronger, for the subgroup with severe hemophilia. Analysis of polymorphisms in the FVIII gene, completion of HLA Class II typing, and haplotype analysis are underway.

Our findings suggest that functional pathways involved in a variety of cellular processes will be important in inhibitor development, but these results warrant further study and replication in similarly powered case-control or cohort studies.

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