POLYMORPHIC HAPLOTYPES AND RECOMBINATION RATES AT THE LDL RECEPTOR GENE LOCUS IN SUBJECTS WITH AND WITHOUT FAMILIAL HYPERCHOLESTEROLEMIA WHO ARE FROM DIFFERENT POPULATIONS

RFLPs at the low-density lipoprotein (LDL) receptor locus for TaqI, St uI, HincII, AvaII, ApaLI (5' and 3'), PvuII, and NcoI were studied in Swiss and German families with familial hypercholesterolemia (FH). A t otal of 1,104 LDL receptor alleles were analyzed using Southern blotti ng and new PCR-based techniques for detection of the TaqI, StuI, HincI I, AvaII, NcoI RFLPs. Two hundred fifty-six independent haplotypes f r om 368 individuals of 61 unrelated Swiss families, as well as 114 inde pendent haplotypes from 184 subjects of 25 unrelated German families, were constructed. In 76 families, clinical diagnosis of FH was confirm ed by cosegregation analysis. Of the 43 unique haplotypes consisting o f seven RFLPs detected in the Swiss and Germans, only 9 were common in both population samples. Analysis of linkage disequilibrium revealed nonrandom associations between several of the investigated RFLPs. ApaL I (5'), NcoI, PvuII, TaqI, and AvaII or HincII were particularly infor mative (cumulative informativeness .85). Relative frequencies, heteroz ygosity indexes, and PICs of the RFLPs from the Swiss and Germans were compared with values calculated from reported haplotype data for Ital ians, Icelanders, North American Caucasians, South African Caucasians, and Japanese. Pairwise comparisons of population samples by common RF LPs demonstrated unexpected differences even between geographically ad jacent populations (e.g., the Swiss and Germans). Furthermore, genetic distances from the Germans to the other Caucasians were larger than t o the Japanese. An unexpected lack of correlation between linkage dise quilibria and physical distances was detected for the German and Japan ese data, possibly because of nonuniform recombination with excessivel y high rates between exon 13 and intron 15. Hence, the present study r evealed a striking variety of polymorphic haplotypes and heterogeneity of RFLP frequencies and recombination rates among the seven populatio n samples.