Common genetic variation in five thrombosis genes and relations to plasma hemostatic protein level and cardiovascular disease risk.
OBJECTIVE
We undertook a linkage disequilibrium (LD)-based genetic approach to investigate the hypothesis that common sequence variants in 5 thrombosis genes influence plasma hemostatic protein levels or risk of cardiovascular disease (CVD).


RESULTS
In a reference panel, we characterized LD structure at the fibrinogen gene cluster (fibrinogen-beta[FGB], FGA, and FGG), factor VII (F7), and tissue plasminogen activator (PLAT) loci. Forty-one tag single nucleotide polymorphisms (SNPs) were genotyped in 1811 unrelated Framingham Heart Study participants. There were significant associations of 9 FGB SNPs with fibrinogen level (minimum P=0.002) and of 7 F7 SNPs and factor VII level (minimum P<0.0001). SNPs at the PLAT locus were not associated with PLAT level. In stepwise analysis, a single FGB variant explained 1% of the residual variance in fibrinogen level, and 2 F7 SNPs together explained 10% of the residual variance in factor VII level. Two PLAT haplotypes were associated with CVD (multivariable-adjusted global P=0.0004).


CONCLUSIONS
A comprehensive survey of common sequence variation demonstrates that cis-regulatory SNPs explain a modest proportion of the residual variance in circulating fibrinogen and factor VII level and PLAT haplotypes increase the risk of CVD. Additional studies are warranted to confirm the association of PLAT sequence variation and risk of CVD.
Kathiresan
Sekar
S
National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA 01702-5827, USA.
Yang
Qiong
Q
Larson
Martin G
MG
Camargo
Amy L
AL
Tofler
Geoffrey H
GH
Hirschhorn
Joel N
JN
Gabriel
Stacey B
SB
O'Donnell
Christopher J
CJ
D000368:Aged; D001483:Base Sequence; D001798:Blood Proteins / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000235:genetics*; D002874:Chromosome Mapping; D005167:Factor VII / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006490:Hemostatics / Q000097:blood*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D005810:Multigene Family; D010960:Plasminogen Activators / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013927:Thrombosis / Q000235:genetics*
D001798:Blood Proteins; D006490:Hemostatics; D005167:Factor VII; D005340:Fibrinogen; D010960:Plasminogen Activators