A three-allelic polymorphic system in exon 12 of the LDL receptor gene is highly informative for segregation analysis of familial hypercholesterolemia in the Spanish population.

We have screened exon 12 of the low density lipoprotein (LDL) receptor gene from 46 familial hypercholesterolemia (FH) heterozygotes and 64 normolipidemic controls for two polymorphisms, HincII, which is caused by a T to C substitution at base 1773, and a C to T transition at base 1725, by using single strand conformation polymorphism (SSCP) analysis. Our results indicate that polymorphism at base 1725, previously reported as very rare from a Japanese sample, is quite frequent in the Spanish population and that it is closely linked to the presence of the HincII site (HincII+). Thus, both polymorphisms constitute a system of three alleles, typed HincII- C1725, HincII+ C1725, and HincII+ T1725, whose frequencies in the FH sample were 0.489, 0.347, and 0.164, respectively. No significant differences were found in the allele frequencies between the FH and control samples. This three-allelic polymorphic system provides a higher information content (PIC value) than the HincII RFLP alone (0.537 versus 0.373, respectively); therefore, it is an extremely useful marker for linkage analysis of FH in Caucasian populations.