Genetic determinants of normal variation in coagulation factor (F) IX levels: Genome-wide scan and examination of the FIX structural gene

Background: High-normal and elevated plasma FIX activity (FIX:C) levels are associated with increased risk for venous- and possibly arterial-thrombosis. Objective: Because the broad normal range for FIX:C involves a substantial unknown genetic component, we ought to identify quantitative- trait loci (QTLs) for this medically important hemostasis Methods: We performed a genome-wide screen and are sequencing-based variation scan of the known functional regions of every distinct FIX gene (F9) in the genetic analysis of idiopathic thrombophilia project (GAIT), a collection of 398 Spanish-Caucasians from 21 pedigrees. Results: We found no evidence for linkage (LOD scores <1.5) despite genotyping more than 540 uniformly-spaced microsatellites. We identified 27 candidate F9 polymorphisms, including three in cis-elements responsible for the increase in FIX:C that occurs with aging, but found no significant genotype-specific differences in mean FIX:C levels (P-values - 0.11) despite evaluating every polymorphism in GAIT by marginal multicovariate measured-genotype association analysis. Conclusions: The heritable component of interindividual FIX:C variability likely involves a collection of QTLs with modest effects that may reside in genes other than F9. Nevertheless, because the alleles of these 27 polymorphisms exhibited a low overall degree of linkage disequilibrium, we are currently defining their haplotypes to interrogate several highly-conserved non-exonic sequences and other F9 segments not examined here.