title: Genetic determinants of normal variation in coagulation factor (F) IX levels: genome-wide scan and examination of the FIX structural gene.
abstract: 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 sought to identify quantitative-trait loci (QTLs) for this medically important hemostasis trait.
  
  
  METHODS
  We performed a genome-wide screen and a resequencing-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 > or = 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.
authors.affiliation: Department of Pathology and Laboratory-Medicine, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA.
authors.forename: M
authors.initials: M
authors.lastname: Khachidze
authors.forename: A
authors.initials: A
authors.lastname: Buil
authors.forename: K R
authors.initials: KR
authors.lastname: Viel
authors.forename: S
authors.initials: S
authors.lastname: Porter
authors.forename: D
authors.initials: D
authors.lastname: Warren
authors.forename: D K
authors.initials: DK
authors.lastname: Machiah
authors.forename: J M
authors.initials: JM
authors.lastname: Soria
authors.forename: J C
authors.initials: JC
authors.lastname: Souto
authors.forename: A
authors.initials: A
authors.lastname: Ameri
authors.forename: M
authors.initials: M
authors.lastname: Lathrop
authors.forename: J
authors.initials: J
authors.lastname: Blangero
authors.forename: J
authors.initials: J
authors.lastname: Fontcuberta
authors.forename: S T
authors.initials: ST
authors.lastname: Warren
authors.forename: L
authors.initials: L
authors.lastname: Almasy
authors.forename: T E
authors.initials: TE
authors.lastname: Howard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005164:Factor IX / Q000032:analysis / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D019851:Thrombophilia / Q000235:genetics
chemical_list: D005164:Factor IX