Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia.

Variation in plasma-cholesterol concentration and the expression of coronary heart disease in patients with homozygous familial hypercholesterolaemia (FH) is well documented, but the underlying reasons for variation are not clearly defined. Because FH is caused by mutations at the low-density-lipoprotein-gene locus, we compared plasma-cholesterol concentrations in 21 FH homozygotes with either the greater than 10 kb deletion (promoter region and exon 1) (11 subjects) or the exon 3 missense (trp66-->gly) mutation (10 subjects) of the low-density-lipoprotein gene. Subjects with the greater than 10 kb deletion had a higher mean plasma-cholesterol concentration than those with the exon 3 mutations (26.7 vs 16.1 mmol/L; p = 0.000006), and there was no overlap in individual plasma-cholesterol concentrations between subjects in the two groups. Although the frequency of coronary heart disease was similar in the two groups, age-of-onset was earlier in subjects with the greater than 10 kb deletion (p = 0.059). Also, coronary deaths were more frequent (p = 0.044) and occurred at an earlier age (p = 0.009) in subjects with the greater than 10 kb deletion. Our results provide evidence that there is less variation in plasma-cholesterol concentrations among FH homozygotes when they are subdivided into groups according to low-density-lipoprotein-receptor-gene defect. Furthermore, differences in plasma-cholesterol concentrations are reflected in the severity of coronary heart disease expression.