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 hyperchol esterolemia. In addition, a number of common DNA polymorphisms have be en identified in the LDL receptor gene, but their significance in affe cting plasma cholesterol levels in the general population has not been studied widely. We investigated the role of two common DNA polymorphi sms, Ava II (exon 13) and Nco I (exon 18), at the LDL receptor locus i n affecting plasma lipid profiles in normolipidemic Hispanics (n=385) and non-Hispanic whites (NHWs; n=543) from the San Luis Valley, Colora do. While the distribution of the Nco I polymorphism was comparable be tween Hispanics and NHWs, the allele frequencies at the Ava II restric tion 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 gende r-specific effect on total and LDL cholesterol (LDL-C) confined to wom en only in both ethnic groups. The Ava II polymorphism was associated significantly with total cholesterol and LDL-C in NHW women (P=.001 an d 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 explaine d 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 Hisp anic women; this polymorphism explained 3.3% and 2.6% of the phenotypi c variance in total cholesterol and LDL-C, respectively. When premenop ausal and postmenopausal women were analyzed separately within each et hnic group, no evidence of physiological interaction was observed betw een the two LDL receptor polymorphisms and the menopausal status in af fecting plasma lipid levels. After examination of an interaction effec t between the LDL receptor/Ava II and apolipoprotein E polymorphisms, we found no evidence of interaction between these two genes in determi ning total cholesterol and LDL-C levels, indicating that the effects o f these two genes on cholesterol levels are independent from each othe r. Thus, this study demonstrated a significant contribution of genetic variation at the LDL receptor locus in determining interindividual di fferences in plasma cholesterol levels in the general population.