ROLE OF COMMON GENETIC POLYMORPHISMS IN THE LDL RECEPTOR GENE IN AFFECTING PLASMA-CHOLESTEROL LEVELS IN THE GENERAL-POPULATION

A large number of rare mutations in the low-density lipoprotein (LDL) receptor gene cause the autosomal dominant disorder familial hypercholesterolemia. In addition, a number of common DNA polymorphisms have been identified in the LDL receptor gene, but their significance in affecting plasma cholesterol levels in the general population has not been studied widely. We investigated the role of two common DNA polymorphisms, Ava II (exon 13) and Nco I (exon 18), at the LDL receptor locus in affecting plasma lipid profiles in normolipidemic Hispanics (n=385) and non-Hispanic whites (NHWs; n=543) from the San Luis Valley, Colorado. While the distribution of the Nco I polymorphism was comparable between Hispanics and NHWs, the allele frequencies at the Ava II restriction site differed significantly between the two ethnic groups (P<.001). The Ava II and Nco I polymorphisms were in linkage disequilibrium (P<.05) in both Hispanics and NHWs. Both polymorphisms revealed a gender-specific effect on total and LDL cholesterol (LDL-C) confined to women only in both ethnic groups. The Ava II polymorphism was associated significantly with total cholesterol and LDL-C in NHW women (P=.001 and P=.014) and in Hispanic women (P=.011 and P=.057). The effect of the Nco I polymorphism was significant on total cholesterol and LDL-C (P=.019 and P=.035) in Hispanic women only. Although a similar trend was observed in NHW women, the effect was not significant at the 5% level. There was a gene-dosage effect on total cholesterol and LDL-C levels among the Ava II and Nco I genotypes: these levels were low in the (-/-) genotype, intermediate in the (+/-) genotype, and high in the (+/+) genotype. The average effect of the Ava II (+) allele was to increase total cholesterol (LDL-C) by 6.52 mg/dL (4.95 mg/dL) in NHW women and 3.69 mg/dL (2.92 mg/dL) in Hispanic women; this polymorphism explained about 4% and 2% of the phenotypic variance in total cholesterol and LDL-C, respectively. The average effect of the Nco I (+) allele was to increase total cholesterol (LDL-C) by 3.66 mg/dL (3.07 mg/dL) in Hispanic women; this polymorphism explained 3.3% and 2.6% of the phenotypic variance in total cholesterol and LDL-C, respectively. When premenopausal and postmenopausal women were analyzed separately within each ethnic group, no evidence of physiological interaction was observed between the two LDL receptor polymorphisms and the menopausal status in affecting plasma lipid levels. After examination of an interaction effect between the LDL receptor/Ava II and apolipoprotein E polymorphisms, we found no evidence of interaction between these two genes in determining total cholesterol and LDL-C levels, indicating that the effects of these two genes on cholesterol levels are independent from each other. Thus, this study demonstrated a significant contribution of genetic variation at the LDL receptor locus in determining interindividual differences in plasma cholesterol levels in the general population.