TY - JOUR
T1 - Influence of single nucleotide polymorphisms in factor VIII and von Willebrand factor genes on plasma factor VIII activity
T2 - The ARIC Study
AU - Campos, Marco
AU - Buchanan, Ashley
AU - Yu, Fuli
AU - Barbalic, Maja
AU - Xiao, Yang
AU - Chambless, Lloyd E.
AU - Wu, Kenneth K.
AU - Folsom, Aaron R.
AU - Boerwinkle, Eric
AU - Dong, Jing Fei
PY - 2012/2/23
Y1 - 2012/2/23
N2 - Factor VIII (FVIII) functions as a cofactor for factor IXa in the contact coagulation pathway and circulates in a protective complex with von Willebrand factor (VWF). Plasma FVIII activity is strongly influenced by environmental and genetic factors through VWF-dependent and -independent mechanisms. Single nucleotide polymorphisms (SNPs) of the coding and promoter sequence in the FVIII gene have been extensively studied for effects on FVIII synthesis, secretion, and activity, but impacts of non- disease-causing intronic SNPs remain largely unknown. We analyzed FVIII SNPs and FVIII activity in 10 434 healthy Americans of European (EA) or African (AA) descent in theAtherosclerosis Risk inCommunities (ARIC) study. Among covariates, age, race, diabetes, and ABO contributed 2.2%, 3.5%, 4%, and 10.7% to FVIII intersubject variation, respectively. Four intronic FVIII SNPsassociated with FVIII activityand8 with FVIII-VWF ratio in a sex- and race-dependent manner. The FVIII haplotypes AT and GCTTTT also associated with FVIII activity. SevenVWFSNPs were associated with FVIII activity in EA subjects, but no FVIII SNPs were associated with VWF Ag. These data demonstrate that intronic SNPs could directly or indirectly influence intersubject variation of FVIII activity. Further investigation may reveal novel mechanisms of regulating FVIII expression and activity.
AB - Factor VIII (FVIII) functions as a cofactor for factor IXa in the contact coagulation pathway and circulates in a protective complex with von Willebrand factor (VWF). Plasma FVIII activity is strongly influenced by environmental and genetic factors through VWF-dependent and -independent mechanisms. Single nucleotide polymorphisms (SNPs) of the coding and promoter sequence in the FVIII gene have been extensively studied for effects on FVIII synthesis, secretion, and activity, but impacts of non- disease-causing intronic SNPs remain largely unknown. We analyzed FVIII SNPs and FVIII activity in 10 434 healthy Americans of European (EA) or African (AA) descent in theAtherosclerosis Risk inCommunities (ARIC) study. Among covariates, age, race, diabetes, and ABO contributed 2.2%, 3.5%, 4%, and 10.7% to FVIII intersubject variation, respectively. Four intronic FVIII SNPsassociated with FVIII activityand8 with FVIII-VWF ratio in a sex- and race-dependent manner. The FVIII haplotypes AT and GCTTTT also associated with FVIII activity. SevenVWFSNPs were associated with FVIII activity in EA subjects, but no FVIII SNPs were associated with VWF Ag. These data demonstrate that intronic SNPs could directly or indirectly influence intersubject variation of FVIII activity. Further investigation may reveal novel mechanisms of regulating FVIII expression and activity.
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U2 - 10.1182/blood-2011-10-383661
DO - 10.1182/blood-2011-10-383661
M3 - Article
C2 - 22219226
AN - SCOPUS:84857517603
SN - 0006-4971
VL - 119
SP - 1929
EP - 1934
JO - Blood
JF - Blood
IS - 8
ER -