Haplotype associations of three DNA polymorphisms at the human low density lipoprotein receptor gene locus in familial hypercholesterolaemia.

The frequency and inheritance of three restriction fragment length polymorphisms (RFLPs) of the low density lipoprotein (LDL) receptor gene were investigated in 27 South African families with familial hypercholesterolaemia. Four haplotypes, defined by the enzymes PvuII, StuI, and NcoI, were found to segregate in this population. The frequency of the rare allele detected by NcoI was found to be 0.53 in 45 unrelated familial hypercholesterolaemic (FH) patients compared to 0.33 in 60 normal controls (p less than 0.005). In 71% of the families studied, a haplotype with common alleles for PvuII and StuI and the rare allele for NcoI cosegregated with the defective gene. In 20% of the families, a second haplotype with rare alleles for PvuII and StuI and common allele for NcoI segregated with FH. In these families the haplotypes unambiguously cosegregate with the disease and can therefore be used for early diagnosis of FH.