SixDNA polymorphisms inthelowdensity lipoprotein receptor gene:theirgenetic relationship andan example oftheir usefor identifying affected relatives ofpatients with familial hypercholesterolaemia

We havedetermined therelative allele frequency andestimated linkage disequilibriumbetweensixDNA polymorphismsofthelowdensity lipoprotein (LDL)receptorgene.Polymorphisms weredetected usingtheenzymesSfaNI, TaqI,StuI, HincII, AvaIl, andNcoIafter DNA amplification by thepolymerase chainreaction. Stronglinkage disequilibriumwasdetected betweenmanyofthe pairwisecomparisons inasampleof60 patients heterozygous forfamilial hypercholesterolaemia (FH).UsingtheenzymesHincII, NcoI,andSfaNI, 85% of patients wereheterozygous foratleast onepolymorphism andthuspotentially informative forcosegregation studies. Thepolymorphisms wereusedtofollow theinheritance ofthedefective allele of theLDL receptor geneintherelatives of apatient withFH.Assays ofLDL receptoractivity onlymphoblastoid celllines fromtwomembersofthefamilywas usedtoconfirmthattheproband, butnot thehypercholesterolaemic brother, hada defect intheLDL receptor. Inthefamily, noneofthechildren hadinherited the allele oftheLDL receptor geneinferred tobedefective. Theproblemsassociated with thiscosegregation approachto identify relatives ofpatients withaclinicaldiagnosis ofFH arediscussed. (JMedGenet1993;30:273-9)