Association analysis of the plasminogen activator inhibitor-1 4G/5G polymorphism in Hispanics and African Americans: the IRAS family study.
OBJECTIVE
Plasminogen activator inhibitor type-1 (PAI-1) plays a central role in fibrolysis and has recently been hypothesized to influence components of the insulin resistance syndrome. We consider whether the 4G/5G polymorphism influences components of insulin resistance and obesity solely through PAI-1 protein levels or also though a secondary pathway. In addition, we explore whether transforming growth factor (TGF-beta1), a key regulator of PAI-1 expression, modifies the influence of the PAI-1 4G/5G polymorphism on these traits.


RESULTS
The Insulin Resistance and Atherosclerosis (IRAS) Family Study genotyped 287 African American (18 pedigrees) and 811 Hispanic American (45 pedigrees) individuals for the 4G/5G PAI-1 and two TGF-beta1 polymorphisms (R25P, C-509T). Individuals were recruited from three clinical centers located in San Antonio (urban Hispanic), San Luis Valley (rural Hispanic) and Los Angeles (African American). The presence of the 4G PAI-1 allele was positively associated with PAI-1 protein level (combined sample p < 0.0001). Hispanic Americans average 65% higher PAI-1 protein levels than African Americans (p < 0.0001). Consistently across ethnic groups, increased PAI-1 protein levels were associated with increased insulin resistance and overall and central obesity (p value < 0.0001, combined sample). Adjusting for PAI-1 protein levels, there was evidence of an association of PAI-1 genotype (4G) with insulin sensitivity (p < 0.002) and subcutaneous fat (p < 0.01). These associations were not influenced by TGF-beta1 genotypes.


CONCLUSIONS
PAI-1 protein is a strong correlate of insulin resistance (IR) and obesity in Hispanics and African Americans. However, PAI-1 4G/5G polymorphism appears to influence insulin resistance and obesity beyond its direct influence on serum PAI-1 protein levels.
Bensen
Jeannette T
JT
Center for Human Genomics, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA. jbensen@med.unc.edu
Hsu
Fang-Chi
FC
Brown
W Mark
WM
Sutton
Beth S
BS
Norris
Jill M
JM
Tracy
Russell P
RP
Jenny
Nancy S
NS
Saad
Mohammed F
MF
Haffner
Steven
S
Bowden
Donald W
DW
Langefeld
Carl D
CD
D001741:Black or African American; D001823:Body Composition; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D005838:Genotype; D005951:Glucose Tolerance Test; D006630:Hispanic or Latino; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D009765:Obesity / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci / Q000235:genetics; D011863:Radioimmunoassay; D014057:Tomography, X-Ray Computed; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014481:United States
D017931:DNA Primers; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1