Four DNA polymorphisms in the LDL receptor gene: their genetic relationship and use in the study of variation at the LDL receptor locus.

We have studied four different restriction fragment length polymorphisms (RFLPs) for the LDL receptor gene, detected using the restriction enzymes StuI, PvuII, ApaLI, and NcoI, in normal subjects and in patients with familial hypercholesterolaemia (FH) from London. Significant linkage disequilibrium was detected between all four RFLPs. Used together they give a polymorphism information content (PIC) of greater than 0.7 which makes them useful for studying the inheritance of the LDL receptor gene in more than 70% of families with FH. The NcoI and ApaLI RFLPs were found to be the most useful, giving a combined PIC value of 0.6. The allele frequencies of all four polymorphisms were compared in the normal and FH groups and the frequency of the rarer N2 allele of the NcoI RFLP was found to be significantly higher in the FH group. This suggests that a mutation has occurred on the rare NcoI N2 allele and that it may be making a significant contribution to the defects causing FH in this patient group. We have also used these RFLPs to look for evidence that variation at the LDL receptor gene locus contributes to the determination of cholesterol levels in the normal population. People with different RFLP genotypes do not have significantly different levels of serum total or LDL cholesterol. At present we have no evidence that variation at this locus may be determining cholesterol levels in the non-FH population.