Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ("French Canadian mutation") of the LDL receptor gene.

Abstract

The 10-kb deletion ("French Canadian mutation") of the low-density lipoprotein (LDL) receptor gene is the most common mutation causing familial hypercholesterolemia among subjects of French Canadian descent. In affected subjects, it results in a null allele of the LDL receptor gene and provides a unique opportunity to examine single-allele regulation of this gene in humans. We sought to ascertain the response of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in subjects with the French Canadian mutation of the LDL receptor gene and to correlate this response with biochemical variables and the haplotype of the nondeletion LDL receptor allele. The prevalence of nonresponders to high doses of HMG CoA reductase inhibitors (denned as <15% decrease in LDL cholesterol [LDL-C] from baseline values after dietary intervention) was ascertained in 105 patients heterozygous for the 10-kb deletion after excluding first-degree relatives and those on combined lipid-lowering therapy or other lipid-lowering agents. Lipoprotein cholesterol levels were examined after a diet period (30% calories as fat) and after receiving HMG CoA reductase inhibitors as monotherapy for a minimum of 3 months. The mean reduction in total cholesterol was 45±23%, in LDL-C 33±15%, and in F amilial hypercholesterolemia (FH) is a genetic disorder characterized by elevated plasma levels of total cholesterol due to elevated low-density lipoprotein (LDL) cholesterol (LDL-C) and cutaneous lipid deposits (xanthelasmas, xanthomas, and corneal arcus) as well as the presence of premature coronary artery disease in probands and family members.1 ' 2 Mutations within the gene coding for the LDL receptor have been identified as the cause of FH.3 Multiple mutations have been described, 4 and five classes of phenotypes at the cellular level have been established. Class 1 defects do not produce LDL receptor protein (null allele); class 2 defects encode proteins that are blocked between the endoplasmic reticulum and the Golgi complex; class 3 defects encode proteins that do triglycerides 32±49% (all P<.005). There was a slight increase in high-density lipoprotein cholesterol of 8.5±18% (P>.05). Overall, 68.4% of patients had more than a 30% decrease in LDL-C levels and 23% had a decrease ranging from 15% to 30%; 8.6% of patients failed to respond, and some even showed an increase in their LDL-C levels (mean change, 1.2±11.9%). This response was independent of age, gender, triglycerides, or high-density lipoprotein cholesterol levels. There was no significant overall effect of the apolipoprotein E phenotype in predicting the degree of total cholesterol or LDL-C reduction. Haplotypes of the LDL receptor gene were determined with the use of five polymorphic markers. The 10-kb deletion is known to be present on a single haplotype, thus allowing the haplotype determination of the nondeletion allele. Analysis of the nondeletion allele of the LDL receptor did not reveal a difference between responders and nonresponders, suggesting that a defec...

Determinants of Variable Response to Statin Treatment in Patients With Refractory Familial Hypercholesterolemia

“…Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase catalyzes the rate-limiting step in cholesterol synthesis, namely, the conversion of HMG CoA to mevalonic acid (MVA), and its activity is rapidly regulated at the transcriptional, translational, and protein levels. 3 HMG CoA reductase inhibitors (statins) have been very effective in treating FH, but we 4 and others 5,6 have reported large variations in interindividual plasma cholesterol responses to statins, irrespective of the statin and dose used. Whether the nature of the LDL receptor mutation influences the degree of cholesterol lowering achieved by statins is controversial, with evidence for 5,7,8 and against 6,9 -12 this hypothesis.…”

“…3 HMG CoA reductase inhibitors (statins) have been very effective in treating FH, but we 4 and others 5,6 have reported large variations in interindividual plasma cholesterol responses to statins, irrespective of the statin and dose used. Whether the nature of the LDL receptor mutation influences the degree of cholesterol lowering achieved by statins is controversial, with evidence for 5,7,8 and against 6,9 -12 this hypothesis.…”

“…Whether the nature of the LDL receptor mutation influences the degree of cholesterol lowering achieved by statins is controversial, with evidence for 5,7,8 and against 6,9 -12 this hypothesis. However, the extent of variability documented by Karayan et al 6 in Ͼ100 patients, all with the same mutation, as well as in non-FH subjects without LDL receptor mutations suggests that other factors play a major role in determining the response to statins.…”

Stimulation of Liver-Directed Cholesterol Flux in Mice by Novel N-Acetylgalactosamine–Terminated Glycolipids With High Affinity for the Asialoglycoprotein Receptor

“…We conclude from these data that LCO-TyrGalNAc 3 is very effective in promoting cholesterol transport to hepatocytes and, thus, may be a promising alternative for hyperlipidemic individuals who do not respond sufficiently to current cholesterol-lowering therapies, such as familial hypercholesterolemic patients. 20,21 …”

The Effects of Rosuvastatin on the Serum Cortisol, Serum Lipid, and Serum Mevalonic Acid Levels in the Healthy Indian Male Population

“…HMG-CoA reductase inhibitors decrease plasma concentration and urinary excretion of MVA (23). Findings in familial hypercholesterolemia volunteers in South Africa treated with high doses of atorvastatin, simvastatin, or pravastatin showed that, compared with good responders, poor responders had a lower basal level and a smaller decrease of plasma MVA on statins (24). Marked reductions in plasma and urine MVA following rosuvastatin treatment for 14 days were observed (25).…”