The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

Abstract

Studies of determinants of development of inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort was formed to extend our understanding of the genetic background of risk. The study group contains 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13 331 single-nucleotide polymorphisms from 1081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status using the criteria of odds ratios in the same direction in all cohorts or allowing for a 20% interval around an odds ratio = 1 in 1 of the 3 and significant in at least 2. Of the 53 markers, 13 had meta P < .001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response and encourage further research with the goal of understanding the pathways involved.

Trial registration: ClinicalTrials.gov NCT00166387 NCT00231751.

Figures

Figure 1

SNPs having a meta P < .001, having odds in the same direction in all 3 cohorts, or allowing for a 20% interval around an OR = 1 in 1 of the 3 and 2 cohorts having significance at α = 0.05. Data are presented for the total cohort and for the severe and inversion mutation subsets. The left column lists the gene, the rs number of the SNP, and lines for results for the total cohort (N = 833), the subset with severe hemophilia (n = 733), and the subset with a F8 inversion mutation (n = 402). The ORs and confidence intervals are plotted for each group. A vertical line drawn from the x-axis indicates an OR = 1. The right columns show the numeric values for the ORs, lower and upper confidence limits, and P values.

Figure 2

SNPs significant in discordant pairs (P < .05). Data are presented for the discordant pairs, the total Combined Cohort, and severe and inversion mutation subsets of the Combined Cohort. The left column lists the gene, the rs number of the SNP, and lines for results for the discordant pairs (n = 104), total cohort (N = 833), the subset with severe hemophilia (n = 733), and the subset with a F8 inversion mutation (n = 402). The ORs and confidence intervals are plotted for each group. A vertical line drawn from the x-axis indicates an OR = 1. The right columns show the numeric values for the ORs, lower and upper confidence limits, and P values.