MUTATIONS OF LOW-DENSITY-LIPOPROTEIN-RECEPTOR GENE, VARIATION IN PLASMA-CHOLESTEROL, AND EXPRESSION OF CORONARY HEART-DISEASE IN HOMOZYGOUSFAMILIAL HYPERCHOLESTEROLEMIA

Variation in plasma-cholesterol concentration and the expression of co ronary heart disease in patients with homozygous familial hypercholest erolaemia (FH) is well documented, but the underlying reasons for vari ation are not clearly defined. Because FH is caused by mutations at th e low-density-lipoprotein-gene locus, we compared plasma-cholesterol c oncentrations in 21 FH homozygotes with either the greater than 10 kb deletion (promoter region and exon 1) (11 subjects) or the exon 3 miss ense (trp66-->gly) mutation (1 0 subjects) of the low-density-lipoprot ein gene. Subjects with the greater than 10 kb deletion had a higher m ean plasma-cholesterol concentration than those with the exon 3 mutati ons (26.7 vs 16.1 mmol/L; p=0.000006), and there was no overlap in ind ividual plasma-cholesterol concentrations between subjects in the two groups. Although the frequency of coronary heart disease was similar i n the two groups, age-of-onset was earlier in subjects with the greate r than 10 kb deletion (p=0.059). Also, coronary deaths were more frequ ent (p=0.044) and occurred at an earlier age (p=0.009) in subjects wit h the greater than 10 kb deletion. Our results provide evidence that t here is less variation in plasma-cholesterol concentrations among FH h omozygotes when they are subdivided into groups according to low-densi ty-lipoprotein-receptor-gene defect. Furthermore, differences in plasm a-cholesterol concentrations are reflected in the severity of coronary heart disease expression.