Abstract

BACKGROUND: Plasminogen activator inhibitor type-1 (PAI-1, aka SERPINE1) is a moderately heritable glycoprotein that regulates fibrin clot dissolution (fibrinolysis). OBJECTIVES: Test whether the heritabilities (h² ) of PAI-1 and other hemostatic factors are constant throughout their distribution or whether they are quantile-specific (i.e., a larger or smaller h² depending on whether their concentrations are high or low). METHODS: Quantile regression was applied to 5606 parent-offspring pairs and 5310 full siblings of the Framingham Heart Study. Quantile-specific heritability was estimated from the parent-offspring regression slope (β_PO , h²  = 2β_PO /(1+r_spouse )) and the full-sib regression slope (β_FS , h²  = {(1+8r_spouse β_FS )^0.5 -1}/(2r_spouse )). RESULTS: Heritability (h²  ± SE) increased significantly with increasing percentiles of the offspring's age- and sex-adjusted PAI-1 distribution when estimated from β_PO (p_{linear trend}  = 0.0001): 0.09 ± 0.02 at the 10th, 0.09 ± 0.02 at the 25th, 0.16 ± 0.02 at the 50th, 0.29 ± 0.04 at the 75th, and 0.26 ± 0.08 at the 90th percentile of the PAI-1 distribution, and when estimated from β_FS (p_{linear trend}  = 6.5x10^-7 ). There was no significant evidence for quantile-specific heritability for factor VII (p_{linear trend}  = 0.35), D-dimer (p_{linear trend}  = 0.08), tPA (p_{linear trend}  = 0.74), or von Willebrand factor (p_{linear trend}  = 0.79). CONCLUSION: Higher mean plasma PAI-1 antigen concentrations tend to accentuate genetic effects (quantile-dependent expressivity), which is consistent with the greater reported differences in PAI-1 concentrations between rs1799889 SERPINE1 (4G/5G) genotypes in patients with osteonecrosis, meningococcal sepsis, obesity, prior myocardial infarction, deep vein thrombosis, and polycystic ovarian syndrome than in healthy controls. It is also consistent with the greater increases in PAI-1 concentrations in 4G-allele carriers than 5G/5G homozygotes following fibrinolytic treatment, low-salt intake, and high saturated fat intake.