Human pedigree-based quantitative-trait-locus mapping: Localization of twogenes influencing HDL-cholesterol metabolism

Common disorders with genetic susceptibilities involve the action of multip le genes interacting with each other and with environmental factors, making it difficult to localize the specific genetic loci responsible. An importa nt route to the disentangling-of this complex inheritance is through the st udy of normal physiological variation in quantitative risk factors that may underlie liability to disease. We present an analysis of HDL-cholesterol ( HDL-C), which is inversely correlated with risk of heart disease. A variety of HDL subphenotypes were analyzed, including HDL particle-size classes an d the concentrations and:proportions of esterified and unesterified HDL-C. Results of a complete genomic screen in large, randomly ascertained pedigre es implicated two loci, one on chromosome 8 and the other on chromo-some 15 , that influence a component of HDL-C-namely, unesterified HDL2a-C. Multiva riate analyses of multiple HDL phenotypes and simultaneous multilocus analy sis of the quantitative-trait loci identified permit further characterizati on of the genetic effects on HDL-C. These analyses suggest that the action of the chromosome 8 locus is specific to unesterified cholesterol levels, w hereas the chromosome 15 locus appears to influence both HDL-C concentratio n and distribution of cholesterol among HDL particle sizes.