LINKAGE BETWEEN CHOLESTEROL 7-ALPHA-HYDROXYLASE AND HIGH PLASMA LOW-DENSITY-LIPOPROTEIN CHOLESTEROL CONCENTRATIONS

Interindividual differences in plasma low-density lipoprotein choleste rol (LDL-C) levels reflect both environmental variation and genetic po lymorphism, but the specific genes involved and their relative contrib utions to the variance in LDL-C are not known. In this study we invest igated the relationship between plasma LDL-C concentrations and three genes with pivotal roles in LDL metabolism: the low-density lipoprotei n receptor (LDLR), apolipoprotein B (APOB), and cholesterol 7 alpha-hy droxylase (CYP7), Analysis of 150 nuclear families indicated statistic ally significant linkage between plasma LDL-C concentrations and CYP7, but not LDLR or APOB. Further sibling pair analyses using individuals with high plasma LDL-C concentrations as probands indicated that the CYP7 locus was linked to high plasma LDL-C, but not to low plasma LDL- C concentrations. This finding was replicated in an independent sample . DNA sequencing revealed two linked polymorphisms in the 5' flanking region of CYP7. The allele defined by these polymorphisms was associat ed with increased plasma LDL-C concentrations, both in sibling pairs a nd in unrelated individuals. Taken together, these findings indicate t hat polymorphism in CYP7 contributes to heritable variation in plasma LDL-C concentrations. Common polymorphisms in LDLR and APOB account fo r little of the heritable variation in plasma LDL-C concentrations in the general population.