Comprehensive survey of common genetic variation at the plasminogen activator inhibitor-1 locus and relations to circulating plasminogen activator inhibitor-1 levels.
BACKGROUND
Using a linkage disequilibrium (LD)-based approach, we sought to comprehensively define common genetic variation at the plasminogen activator inhibitor-1 (PAI-1) locus and relate common single nucleotide polymorphisms (SNPs) and haplotypes to plasma PAI-1 levels.


RESULTS
In reference pedigrees, we defined LD structure across a 50-kb genomic segment spanning the PAI-1 locus via a dense SNP map (1 SNP every 2 kb). Eighteen sequence variants that capture underlying common genetic variation were genotyped in 1328 unrelated Framingham Heart Study participants who had plasma PAI-1 antigen levels measured. Regression analyses were used to examine associations of individual SNPs and of inferred haplotypes with multivariable-adjusted PAI-1 levels. Two genetic variants, SNP rs2227631 and the 4G/5G polymorphism, were strongly associated (P<0.0001) with PAI-1 levels. SNP rs2227631 is in tight LD (D'=0.97, r2=0.78) with the 4G/5G polymorphism, which makes it difficult to distinguish which of these 2 polymorphisms is responsible for the association with PAI-1 levels. In stepwise analysis considering all polymorphisms tested, 3 SNPs, rs2227631 (or the correlated 4G/5G polymorphism), rs6465787, and rs2227674, each explained 2.5%, 1%, and 1%, respectively, of the residual variance in multivariable-adjusted PAI-1 levels (stepwise P<0.0001, P=0.04, and P=0.03, respectively). A single common haplotype, at 50% frequency among Framingham Heart Study participants, was strongly associated with higher PAI-1 levels (haplotype-specific P=0.00001). The susceptibility haplotype harbors the minor alleles of SNP rs2227631 and the 4G/5G polymorphism.


CONCLUSIONS
Three sequence variants at the PAI-1 locus, in sum, explain approximately 5% of the residual variance in multivariable-adjusted PAI-1 levels. For quantitative cardiovascular traits such as circulating biomarkers, defining LD structure in a candidate gene followed by association analyses with both SNPs and haplotypes is an effective approach to localize common susceptibility alleles.
Kathiresan
Sekar
S
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA.
Gabriel
Stacey B
SB
Yang
Qiong
Q
Lochner
Amy L
AL
Larson
Martin G
MG
Levy
Daniel
D
Tofler
Geoffrey H
GH
Hirschhorn
Joel N
JN
O'Donnell
Christopher J
CJ
D000368:Aged; D001794:Blood Pressure; D015992:Body Mass Index; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D017395:Plasminogen Activator Inhibitor 1