Polymorphic DNA haplotypes at the human low-density lipoprotein receptor gene locus in Koreans

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 LDL-receptor 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 cl osely linked restriction fragment lenghth polymorphisms (RFLPs). In the pre sent study nine different RFLPs (TaqI, StuI, HincII, BstEII, AvaII, PvuII, MspIA, MspIB, and NcoI) and a sequence variation at Arg(450), were used to clarify the characteristics of the LDL-receptor gene in Koreans. A total of 978 LDL-receptor alleles from 244 members of 43 different pedigrees (15 no rmal and 28 FH pedigrees) and 245 individuals (187 normal and 58 FH) were a nalyzed. Frequencies of these polymorphisms did not differ significantly be tween controls and FH patients. Individually, seven sites-TaqI, BstEII, Ava II, MspIA, MspIB, NcoI and Arg(450)-had heterozygosity indices ranging from 0.3610 to 0.4601, whereas the PvuII site displayed low levels of polymorph ism and StuI was monomorphic. Haplotypes were constructed for 215 individua ls of 13 normal and 24 FH pedigrees using the nine polymorphisms. Of 512 (= 2(9)) possible combinations for the nine polymorphic sites, 39 unique hapl otypes were detected. The frequency distribution of individual haplotypes r anged 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 haplotyp es indicated marked linkage disequilibrium for these 10 sites and throughou t the region containing the LDL-receptor gene. Owing to the high degree of Linkage disequilibrium over the entire locus, not all RFLPs were informativ e. We rank each RFLP according to its informativeness and present a strateg y for the optimal selection of RFLPs for pedigree analysis.