Quantitative Genetic Analysis of Lipid Research Clinic Family Data

BACKGROUND:

Although coronary heart disease has long been known to aggregate in families, in 1986 little was known about the relative importance of genetic and environmental factors. This was partly due to the heterogeneous nature of the disease. Instead of analyzing complex endpoints, the tendency had been to focus on the individual risk factors or phenotypes. Plasma lipids and lipoproteins are heterogeneous risk factors that have been analyzed as subgroups from a genetic epidemiological perspective. Attention turned to the familial aggregation of risk factors, particularly the hyperlipidemias, hypertension, and diabetes.

In 1971, the National Heart and Lung Institute began a series of epidemiologic studies at several North American sites under the Lipid Research Clinics Program. The Family Study was designed to investigate the familial association of blood lipids, lipoproteins, and dyslipoproteinemias. This study complemented and did not duplicate ongoing analysis of Lipid Research Clinics data.

DESIGN NARRATIVE:

The study addressed seven phenotypes, all derived from fasting blood samples: total cholesterol, total triglyceride, LDL-cholesterol, HDL-cholesterol, VLDL-cholesterol, uric acid, and glucose levels. The data had already been collected at Lipid Research Clinics in Cincinnati, Iowa, Oklahoma, Minneapolis, and Stanford. Univariate and bivariate segregation analysis were conducted on the mode of inheritance of familial combined hyperlipidemia and familial primary hypoalphalipoproteinemia. Path analysis was used to resolve cultural and biological inheritance for each phenotype within each clinic and for resolution of population heterogeneity among the five Lipid Research Clinics. A general bivariate path model was used to analyze the associations among the various phenotypes. General models were used to analyze temporal trends in family resemblance for the seven phenotypes.