ABSTRACT
Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect. The metabolite profile in plasma and urine suggested that their defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial splicing defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady state.
Subject(s)
Cholesterol/genetics , Farnesyl-Diphosphate Farnesyltransferase/genetics , Musculoskeletal Abnormalities/genetics , Child , Child, Preschool , Enhancer Elements, Genetic/genetics , Female , Humans , Infant , Male , Promoter Regions, Genetic/genetics , RNA Splicing/genetics , Smith-Lemli-Opitz Syndrome/genetics , Exome Sequencing/methodsABSTRACT
OBJECTIVE: The CC genotype of the C3435T polymorphism in ABCB1 is associated with increased P-glycoprotein expression, reduced low-density lipoprotein cholesterol (LDL-C) response to atorvastatin, and a reduced area-under-the-curve in pharmacokinetic studies. We sought to assess the relationship between 1) genotype and Atorvastatin efficacy, independently of variation in cholesterol metabolism and 2) genotype and myalgia. METHODS: High-risk vascular patients were genotyped and treated with atorvastatin 80 mg for 6 weeks. The lipid panel and percent LDL-C reduction with atorvastatin were related to C3435T genotype. Genotypes and allele frequency were assessed in patients with and without myalgia. RESULTS: A total of 117 patients were recruited and genotyped. Of these, 98 completed the study with adequate atorvastatin adherence, and 10 reported myalgia. T and C allele frequencies were 0.63 and 0.37, respectively. A 6-week course of atorvastatin (80 mg/day) reduced LDL-C by 58% ± 11% (mean ± SD). Patients with the CC genotype showed less LDL-C reduction with atorvastatin compared with the TT/TC genotype (53% vs 59%, respectively, P = .034), and this finding was independent of variation in cholesterol metabolism (P = .045 after correction for desmosterol and cholestanol/cholesterol ratio). The T allele was more frequent in patients with myalgia than those without (0.80 vs 0.62) and the C allele less frequent (0.20 vs 0.38, P = .043). CONCLUSION: In patients treated with atorvastatin, the CC genotype at the C3435T polymorphism in ABCB1 is associated with reduced atorvastatin efficacy independently of cholesterol metabolism. The T allele is more frequent and the C allele less frequent in patients with myalgia.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Heptanoic Acids/adverse effects , Heptanoic Acids/pharmacology , Muscular Diseases/chemically induced , Pain/chemically induced , Polymorphism, Single Nucleotide/genetics , Pyrroles/adverse effects , Pyrroles/pharmacology , Vascular Diseases/drug therapy , ATP Binding Cassette Transporter, Subfamily B , Aged , Atorvastatin , Cohort Studies , Female , Gene Frequency , Genotype , Heptanoic Acids/therapeutic use , Humans , Male , Middle Aged , Muscular Diseases/genetics , Pain/genetics , Pyrroles/therapeutic use , Risk , Vascular Diseases/geneticsABSTRACT
OBJECTIVE: Genetic loci predict <5% of variation in low-density lipoprotein cholesterol (LDL-C) response to statins. Cholestanol and desmosterol are plasma markers of cholesterol absorption and synthesis, respectively. Because statins lower LDL-C by inhibiting cholesterol synthesis, we studied the relationship between cholestanol and desmosterol and LDL-C response to atorvastatin. METHODS: High-risk patients were treated with 80 mg of atorvastatin for 6 weeks. LDL-C response to atorvastatin was related to baseline cholestanol to cholesterol ratio (CCR) and desmosterol. The following comparisons were used: (1) correlates of percentage LDL-C response, (2) baseline characteristics of hyperresponders versus hyporesponders, and (3) binary logistic regression analysis for predictors of achieved LDL-C <70 mg/dL. RESULTS: One hundred fifty-four patients were enrolled of which 118 completed the study with adequate adherence. Average LDL-C reduction was 57% ± 13% (mean ± SD). On univariate analysis, desmosterol and CCR correlated with percentage LDL-C reduction and multivariate modeling explained approximately 16% of the variation in response. Atorvastatin hyperresponders had higher mean desmosterol (P = 0.046) and lower CCR (P = 0.035) than hyporesponders. On logistic regression analysis for the outcome of achieved LDL-C of <70 mg/dL, baseline LDL-C and CCR were significant predictors; odds ratios were 0.932 and 0.979, respectively. CONCLUSIONS: CCR and desmosterol explain more variation in LDL-C response to statin than that reported with pharmacogenomics. CCR and desmosterol may guide lipid-lowering therapy.
