A SEQUENCE VARIATION SCAN OF THE COAGULATION FACTOR ( F ) VIII STRUCTURAL GENE AND ASSOCIATIONS WITH PLASMA FVIII ACTIVITY ( FVIII : C ) LEVELS

Plasma FVIII:C level is a highly heritable quantitative-trait that is strongly correlated with thrombosis risk. Polymorphisms within only one 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 non-hemophilic individuals representing seven 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 C92714G, a nonsynonymous-SNP encoding the B-domain substitution D1241E, was significantly associated with FVIII:C. 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 (p = 0.016). Nevertheless, because the alleles of G56010A, a SNP within the 3’-splice-junction of intron-7, are strongly associated with C92714G in GAIT, additional studies are required to determine whether D1241E is itself a functional variant. For personal use only. by on January 30, 2008. www.bloodjournal.org From

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