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 (defined 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 triglycerides 32±49% (all 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 defect in the nondeletion allele of the LDL receptor may not be the cause of this phenomenon.