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

M. Khachidze, A. Buil, K. R. Viel, S. Porter, D. Warren, D. K. Machiah, J. M. Soria, J. C. Souto, A. Ameri, M. Lathrop, J. Blangero, J. Fontcuberta, S. T. Warren, L. Almasy, Tom E. Howard

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1537-1545
Number of pages9
JournalJournal of Thrombosis and Haemostasis
Issue number7
StatePublished - Jul 2006


  • Association
  • Linkage
  • Linkage disequilibrium
  • Quantitative-trait loci
  • Single-nucleotide polymorphism
  • Thrombosis

ASJC Scopus subject areas

  • Hematology


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