Genetic variants at the chromosomal region 2q21.3 underlying inhibitor development in patients with severe haemophilia A

Abstract

Introduction: Inhibitor development affects about 30% of patients with severe haemophilia A (HA) and results from different environmental and genetic risk factors. Previously, we identified the missense variant rs3754689 in the LCT gene linked with this predisposition. Since rs3754689 variant is benign and is located in a conserved haplotype region, we hypothesized that the association signal captured by this variant is located in coinherited, neighbouring genes. Aim: To identify novel genetic risk factors associated with inhibitor development in coding regions of R3HDM1, UBXN4, CXCR4, MCM6, DARS and miR128-1 genes. Methods: Targeted sequencing was performed in 246 severe HA patients (72 with and 174 without inhibitor): 181 previously and 65 newly enrolled. Results: Forty-one common and 152 rare variants passed the quality control. Logistic regression analysis of common variants identified rs3754689 and four additional variants (.011 < P  < P