LDLR gene’s promoter region hypermethylation in patients with familial hypercholesterolemia

Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein cholesterol (LDL-C) levels and a high risk of early coronary heart disease. Structural alterations in the LDLR, APOB, and PCSK9 genes were not found in 20–40% of patients diagnosed using the Dutch Lipid Clinic Network (DCLN) criteria. We hypothesized that methylation in canonical genes could explain the origin of the phenotype in these patients. This study included 62 DNA samples from patients with a clinical diagnosis of FH according to the DCLN criteria, who previously tested negative for structural alterations in the canonical genes, and 47 DNA samples from patients with normal blood lipids (control group). All DNA samples were tested for methylation in the CpG islands of the three genes. The prevalence of FH relative to each gene was determined in both groups and the respective prevalence ratios (PRs) were calculated. The methylation analysis of APOB and PCSK9 was negative in both groups, showing no relationship between methylation in these genes and the FH phenotype. As the LDLR gene has two CpG islands, we analyzed each island separately. The analysis of LDLR-island1 showed PR = 0.982 (CI 0.33–2.95; χ(2) = 0.001; p = 0.973), also suggesting no relationship between methylation and the FH phenotype. Analysis of LDLR-island2 showed a PR of 4.12 (CI 1.43–11.88; χ(2) = 13,921; p = 0.00019), indicating a possible association between methylation on this island and the FH phenotype.