A 3-ALLELIC POLYMORPHIC SYSTEM IN EXON-12 OF THE LDL RECEPTOR GENE ISHIGHLY 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 bas e 1725, by using single strand conformation polymorphism (SSCP) analys is. Our results indicate that polymorphism at base 1725, previously re ported as very rare from a Japanese sample, is quite frequent in the S panish 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(-) C-1725, HincII(+) C-1725, and HincI I(+) T-1725, whose frequencies in the FH sample were 0.489, 0.347, and 0.164, respectively. No significant differences were found in the all ele frequencies between the FH and control samples. This three-allelic polymorphic system provides a higher information content (PIG value) than the HincII RFLP alone (0.537 versus 0.373, respectively); therefo re, it is an extremely useful marker for linkage analysis of FH in Cau casian populations.