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 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.
Khachidze
M
M
Department of Pathology and Laboratory-Medicine, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Buil
A
A
Viel
K R
KR
Porter
S
S
Warren
D
D
Machiah
D K
DK
Soria
J M
JM
Souto
J C
JC
Ameri
A
A
Lathrop
M
M
Blangero
J
J
Fontcuberta
J
J
Warren
S T
ST
Almasy
L
L
Howard
T E
TE
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
D005164:Factor IX