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We seek to detennine whether significant gene X smoking interaction effects exist on plasma triglyceride (TG) levels, HDL cholesterol (HDL-C) level, and median LDL particle diameter (LDL-MPD) in Mexican American families enrolled in the San Antonio Family Heart Study. The sample consisted of 1,392 individuals distributed in 42 extended pedigrees, ranging in age from 16 years to 92 years. Separate quantitative genetic analyses were carried out for TG and HDL-C level and LDL-MPD using a maximum-likelihood-based variance decomposition approach while simultaneously adjusting for age and sex. Initial heritability estimates demonstrated significant (p < 0.001) additive genetic contributions to all three traits (h2 range 0.50-0.54). To test for a gene X smoking interaction, we included in the model additional smoking-status-specific variance tenns and a genetic correlation tenn between smokers and nonsmokers. Comparisons of nested models revealed significant evidence (p < 0.0 I) for a gene X smoking interaction effect on TG level and LDL-MPD and possible evidence for an effect on HDL-C level. These results indicate that the gene or suite of genes regulating each of these phenotypes is likely the same in smokers and nonsmokers but that smoking may alter the expression of genes, particularly those influencing TG level and LDL-MPD.