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Document Type

Article

Abstract

Many low-density lipoprotein (LDL) receptor mutations have been identified and characterized, demonstrating a high degree of allelic heterogeneity at this locus. The ability to identify mutant LDLreceptor genes for prenatal diagnosis of familial hypercholesterolemia (FH) or to study the role of the LDL-receptor gene in polygenic hypercholesterolemia requires the use of closely linked restriction fragment lenghth polymorphisms (RFLPs). In the present study nine different RFLPs (Taql, Stul, HincIl, HstEII, AvaIl, PvuIl, MsplA, MsplB, and Ncol) and a sequence variation at Arg450 were used to clarify the characteristics of the LDL-receptor gene in Koreans. A total of 978 LDLreceptor alleles from 244 members of 43 different pedigrees (15 nonnal and 28 FH pedigrees) and 245 individuals (187 nonnal and 58 FH) were analyzed. Frequencies of these polymorphisms did not differ significantly between controls and FH patients. Individually, seven sites-Taql, BstEII, AvaIl, MsplA, MspJB, Ncol and Arg45o-had heterozygosity indices ranging from 0.3610 to 0.4601, whereas the PvuIl site displayed low levels of polymorphism and Stul was monomorphic. Haplotypes were constructed for 215 individuals of 13 nonnal and 24 PH pedigrees using the nine polymorphisms. Of 512 (~ 29) possible combinations for the nine polymorphic sites, 39 unique haplotypes were detected. The frequency distribution of individual haplotypes ranged from 1/155 (0.65%) to 40/155 (25.8%). The four most common haplotypes accounted for 59.4% of those sampled. Statistical analysis of the haplotypes indicated marked linkage disequilibrium for these 10 sites and throughout the region containing the LDL-receptor gene. Owing to the high degree of linkage disequilibrium over the entire locus, not all RFLPs were informative. We rank each RFLP according to its infonnativeness and present a strategy for the optimal selection of RFLPs for pedigree analysis.

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