Identification of candidate genes regulating HDL cholesterol using a chromosomal region expression array.

To identify candidate genes encoding QTLs in baboons, we have developed a novel strategy that integrates comparative mapping, bioinformatics, and expression arrays. A genome-wide scan, performed previously on pedigreed baboons to localize QTLs for phenotypes that are known risk factors for atherosclerosis, revealed a QTL on chromosome 18q that influences high-density lipoprotein cholesterol (HDL-C) phenotypes. After ruling out the only two biologically relevant positional candidate genes in this chromosomal region, we combined information from baboon pedigrees and HDL-C phenotypes with a baboon microsatellite marker map, human microsatellite marker maps, and human genome maps to develop a chromosomal region expression array (CREA). The CREA was screened with heterologous liver cDNA from sib-pairs of contrasting HDL-C phenotypes on two different diets, and genes were prioritized for further study by expression profiles. Analysis of gene expression in this restricted chromosomal region, combined with HDL-C phenotypic information, yielded a list of candidate genes for the QTL regulating HDL-C in baboons. Our data demonstrate the power of this strategy for identifying candidate genes encoding QTLs for multigenic traits. This strategy is applicable to many species that serve as models for human diseases and can even be used with human subjects.