Plasminogen activator inhibitor type-1 (PAI-1) polymorphism 4G/5G is associated with prostate cancer among men with a positive family history.
BACKGROUND
Variation in the expression of plasminogen activator inhibitor type-1 (PAI-1) is associated with many human diseases, including several types of cancer. In particular, tumor cell overexpression of PAI-1 has been found to inhibit prostate cancer tumor growth, angiogenesis, and metastasis in mouse models. Normal host cell expression of PAI-1 is influenced by the 4G/5G insertion/deletion polymorphism in the promoter region of the PAI-1 gene. To evaluate the effect of PAI-1 expression on cancer development, we examined the association of the 4G/5G polymorphism in a sibling-based case-control study of prostate cancer.


METHODS
One thousand one hundred thirty seven subjects, 655 cases, and 482 sibling controls from 526 families, were recruited from the major medical institutions in the greater Cleveland, OH area and from the Henry Ford Health System, Detroit, MI. A Cox age-of-onset model with robust variance estimation was used to evaluate the association between the PAI-1 4G/5G polymorphism and prostate cancer.


RESULTS
No association was observed between the PAI-1 4G/5G polymorphism and prostate cancer in the entire sample. We did, however, identify a statistically significant association between the PAI-1 4G/5G polymorphism and prostate cancer in subjects with a family history of this disease (OR = 1.28, 95% CI 1.02-1.61, P-value = 0.036). The PAI-1 5G/5G genotype, associated with lower PAI-1 expression, appears to drive this result as it was associated with an increased risk of prostate cancer and an earlier mean age of onset compared to those with the 4G/4G genotype (OR = 1.83, 95% CI 1.12-2.99) while the 4G/5G genotype group did not show a significant difference in prostate cancer risk compared to the 4G/4G genotype group (OR = 0.98, 95% CI 0.75-1.28).


CONCLUSIONS
These observations suggest that the 4G/5G polymorphism in PAI-1 may explain some of the increased risk and earlier mean age of onset of prostate cancer due to a positive family history.
Jorgenson
Eric
E
Department of Epidemiology and Biostatistics, Center for Human Genetics, University of California, San Francisco, San Francisco, California 94143-0794, USA. Eric.Jorgenson@ucsf.edu
Deitcher
Steven R
SR
Cicek
Mine
M
Liu
Xin
X
Plummer
Sarah
S
Casey
Graham
G
Witte
John S
JS
D017668:Age of Onset; D005192:Family Health; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008824:Michigan / Q000453:epidemiology; D008875:Middle Aged; D009820:Ohio / Q000453:epidemiology; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics*; D011110:Polymorphism, Genetic; D011471:Prostatic Neoplasms / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D012307:Risk Factors; D035781:Siblings; D011795:Surveys and Questionnaires
D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human