A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Viel KR,Machiah DK,Warren DM,Khachidze M,Buil A,Fernstrom K,Souto JC,Peralta JM,Smith T,Blangero J,Porter S,Warren ST,Fontcuberta J,Soria JM,Flanders WD,Almasy L,Howard TE

doi

10.1182/blood-2006-06-026104

subject

Has Abstract

pub_date

2007-05-01 00:00:00

pages

3713-24

issue

9

eissn

0006-4971

issn

1528-0020

pii

blood-2006-06-026104

journal_volume

109

pub_type

临床试验,杂志文章,多中心研究

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