PAI-1 Gene 4G/5G polymorphism and risk of type 2 diabetes in a population-based sample.
Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) increase risk for type 2 diabetes. The PAI-1 4G/5G polymorphism is a major genetic determinant of plasma PAI-1 levels, with 4G/4G homozygotes having elevated PAI-1 levels relative to 5G allele carriers. These observations suggest the hypothesis that the PAI-1 4G/5G polymorphism could be a genetic risk factor for diabetes. We tested this hypothesis among 2169 participants of the Framingham Offspring Study followed for seven examinations over 26 years for 216 cases of type 2 diabetes. PAI-1 4G/4G homozygotes (genotype frequency, 27.4%) were not at significantly (p > 0.05) increased risk of incident diabetes compared with 5G allele carriers and did not have elevated levels of diabetes-related quantitative traits including BMI, fasting plasma glucose, or fasting insulin. In proportional hazards regression models accounting for correlation among siblings, with the 5G/5G genotype as the referent, the hazard ratio for incident diabetes for 4G/5G carriers was 0.93 (95% confidence interval, 0.68 to 1.28) and for 4G/4G carriers was 1.20 (95% confidence interval, 0.83 to 1.92). Results were not altered by further adjustment for sex or levels of BMI, triglycerides, or PAI-1. We conclude that the PAI-1 4G/5G polymorphism is not an important genetic risk factor for type 2 diabetes in this community-based sample. Elevated PAI-1 levels may be associated with an increased risk for diabetes as a marker for underlying endothelial dysfunction rather than by a direct effect of genetically mediated elevated levels.
Meigs
James B
JB
General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. jmeigs@partners.org
Dupuis
Josée
J
Liu
Chunyu
C
O'Donnell
Christopher J
CJ
Fox
Caroline S
CS
Kathiresan
Sekar
S
Gabriel
Stacey B
SB
Larson
Martin G
MG
Yang
Qiong
Q
Herbert
Alan G
AG
Wilson
Peter W F
PW
Feng
Dali
D
Tofler
Geoffrey H
GH
Cupples
L Adrienne
LA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D012307:Risk Factors
D001786:Blood Glucose; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1