Segregation Analysis of Plasminogen Activator Inhibitor-1 and Fibrinogen Levels in the NHLBI Family Heart Study

From the Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill (J.S.P.); Division of Epidemiology, School of Public Health, University of Minnesota (A.R.F., T.A.S.), and Department of Laboratory Medicine and Pathology, University of Minnesota Medical School (J.E.), Minneapolis, Minn; Division of Biostatistics, Washington University School of Medicine, St Louis, Mo (M.A.P., D.C.R.); and Cardiovascular Genetics, University of Utah, Salt Lake City, Utah (R.R.W.).

Correspondence to Dr James S. Pankow, Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, NationsBank Plaza, Suite 306, 137 E Franklin St, Chapel Hill, NC 27514. E mail jim_pankow@unc.edu

Abstract—Elevated plasminogen activator inhibitor-1 (PAI-1) and fibrinogen concentrations are risk factors for coronary heart disease. We investigated environmental, familial, and genetic influences on PAI-1 antigen and fibrinogen concentrations in 2029 adults from 512 randomly ascertained families in 4 US communities. We used maximum-likelihood segregation analysis to fit several genetic and nongenetic modes of inheritance to the data to determine whether mendelian inheritance of a major gene could best explain the familial distributions of these 2 hemostatic factors. Age- and gender-adjusted familial correlations for PAI-1 antigen level averaged 0.16 in first-degree relatives (95% CI=0.11 to 0.21); the spouse correlation was positive but not statistically significant (r=0.10, 95% CI=-0.02 to 0.23). Complex segregation analysis indicated a major gene associated with higher PAI-1 concentrations in 65% of individuals from these families. Demographic, anthropometric, lifestyle, and metabolic characteristics together explained 37% to 47% of the variation in PAI-1 antigen levels, and the inferred major gene explained an additional 17% of the variance. Positive and statistically significant age- and gender-adjusted familial correlations in first-degree relatives indicated a possible heritable component influencing plasma fibrinogen concentration (r=0.17, 95% CI=0.13 to 0.22); however, segregation analysis did not provide statistical evidence of a major gene controlling fibrinogen level. These family data suggest that there are modest familial and genetic effects on the concentration of PAI-1.

Key Words: plasminogen activator inhibitor-1 • fibrinogen • heritability • segregation analysis

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