A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels.
Plasma factor VIII coagulant activity (FVIII:C) level is a highly heritable quantitative trait that is strongly correlated with thrombosis risk. Polymorphisms within only 1 gene, the ABO blood-group locus, have been unequivocally demonstrated to contribute to the broad population variability observed for this trait. Because less than 2.5% of the structural FVIII gene (F8) has been examined previously, we resequenced all known functional regions in 222 potentially distinct alleles from 137 unrelated nonhemophilic individuals representing 7 racial groups. Eighteen of the 47 variants identified, including 17 single-nucleotide polymorphisms (SNPs), were previously unknown. As the degree of linkage disequilibrium across F8 was weak overall, we used measured-genotype association analysis to evaluate the influence of each polymorphism on the FVIII:C levels in 398 subjects from 21 pedigrees known as the Genetic Analysis of Idiopathic Thrombophilia project (GAIT). Our results suggested that 92714C>G, a nonsynonymous SNP encoding the B-domain substitution D1241E, was significantly associated with FVIII:C level. After accounting for important covariates, including age and ABO genotype, the association persisted with each C-allele additively increasing the FVIII:C level by 14.3 IU dL(-1) (P = .016). Nevertheless, because the alleles of 56010G>A, a SNP within the 3' splice junction of intron 7, are strongly associated with 92714C>G in GAIT, additional studies are required to determine whether D1241E is itself a functional variant.
Viel
Kevin R
KR
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
Machiah
Deepa K
DK
Warren
Diane M
DM
Khachidze
Manana
M
Buil
Alfonso
A
Fernstrom
Karl
K
Souto
Juan C
JC
Peralta
Juan M
JM
Smith
Todd
T
Blangero
John
J
Porter
Sandra
S
Warren
Stephen T
ST
Fontcuberta
Jordi
J
Soria
Jose M
JM
Flanders
W Dana
WD
Almasy
Laura
L
Howard
Tom E
TE
D000017:ABO Blood-Group System / Q000097:blood / Q000235:genetics; D000483:Alleles; D019943:Amino Acid Substitution; D005169:Factor VIII / Q000032:analysis* / Q000235:genetics*; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011486:Protein C / Q000032:analysis / Q000235:genetics; D044469:Racial Groups; D019851:Thrombophilia / Q000097:blood / Q000235:genetics
D000017:ABO Blood-Group System; D011486:Protein C; D005169:Factor VIII