Familial hypercholesterolemia in Sweden : Genetic and metabolic studies

Abstract: Familial hypercholesterolemia (FH) is inherited as an autosomal codominant disease, usually caused by mutations in the LDL receptor (LDLR) gene. Heterozygous FH is a common disease with a prevalence of about 1/500 in most populations. Clinically, FH is characterized by elevated LDL cholesterol, tendon xanthomas and premature atherosclerosis. The number of reported mutations in the LDLR gene is very large, and the pattern of mutations differs in various populations. To characterize the distribution of genetic aberrations in Swedish FH patients, we investigated 150 unrelated Swedish FH patients for mutations in the LDLR gene and for the most common mutation (apoB 3500) causing familial ligand-defective apoB100 (FDB). Mutations in the LDLR gene considered to be the cause of disease were identified in 52 patients (35 %), representing 31 different mutations. Of these, four were nonsense mutations, 13 were missense mutations, 7 splice junction mutations, and four represented major rearrangements. In addition, two small deletions and one base exchange in the promoter region were identified. The mutation apoB 3500 was found in another three patients, making the total number of patients with detected mutations 55 (37%). Also, fifteen different types of polymorphic changes were detected. Thus, a large heterogeneity of mutations in the LDLR gene was found. The most frequent mutation was FH-HeIsinki (n=1 0), reflecting the admixture of Finnish immigrants in our country. We performed linkage analysis in four large FH families in which no mutations were detected in the initial investigation. Linkage to the LDLR locus was found in three of these families. Two of them were found to possess mutations in the coding region of the LDLR gene, while the third showed two intronic variants. In the fourth family, no evidence for linkage was demonstrated, suggesting that not yet unidentified gene(s) may be causative for their disease. One case of severe hypercholesterolemia was characterized and found to be caused by a splice acceptor mutation in the ARH gene, conclusive for the rare disease autosomal recessive hypercholesterolemia (ARH). An effective lipid-lowering treatment was applied, which eliminated the need for LDL apheresis. Earlier studies have shown that growth hormone (GH) can reduce plasma cholesterol and stimulate hepatic LDLR expression in humans. We characterized the effects of GH treatment on plasma LDL clearance and investigated the role of LDLR activity and stimulation of bile acid synthesis in healthy subjects and patients with FH. Our results showed that GH reduced plasma LDL cholesterol by inducing LDL clearance without increasing bile acid synthesis. A partially preserved LDLR expression was required to lower plasma LDL cholesterol, since no effect was seen in an LDLRdeficient homozygous FH patient.