A genome-wide association study identifies SNPs and genes as risk factor (s) in symptomatic bleeding patients with FVII-deficiency

Introduction Congenital factor VII (FVII) deficiency is a rare bleeding disorder caused by mutations in F7 gene with autosomal recessive inheritance. Recent genome-wide association studies (GWAS) have confirmed risk mutations in FVII-deficient patients and identified novel susceptibility loci for cardiovascular disease (CVD) in adults. However, clinical heterogeneity with poor correlation with FVII:C levels has been described and predictive FVII threshold levels remain uncertain to effectively manage treatment and bleeding prophylaxis in affected patients. We recently reported known and novel mutations in the F7 gene in a large cohort of FVII-deficient women, including exons, exon/intron boundaries and the promoter region in up to 42% of cases and further common single nucleotide polymorphisms (SNPs) in 95% of subjects, detected by Sanger method & multiplex ligation-dependent probe amplification . Method Here we present a GWAS including 203 FVII-deficient patients (bleeders and asymptomatic subjects) and 901 healthy blood donors using Illumina Infinium HTS genotyping arrays to identify susceptibility factors contributing to bleeding in FVII-deficient patients. Logistic regression adjusted for age, sex, ABO blood group and FVIIc plasma levels was performed. In a second step, we compared asymptomatic subjects (referred for laboratory work up) with patients who presented with mild, moderate or severe bleeding episodes (classified with ISTH BAT score) within the FVII-deficiency group of patients. Results In the case control analysis, we found 375 significant SNPs associated with FVII-deficiency (p-value