Gene-drug interaction: additive influence of mutant APOA1 and testosterone on plasma HDL-cholesterol

Abstract Objectives: Factors associated with decreased plasma high-density lipoprotein (HDL) cholesterol concentration, or hypoalphalipoproteinemia, include androgenic steroids and mutations in APOA1, encoding apolipoprotein (apo) A-I, the main structural protein of HDL. However, there is little information regarding the extent of plasma HDL lowering when exogenous testosterone is used in subjects with monogenic low HDL. Design and methods: A man with coronary heart disease (CHD) had been receiving exogenous testosterone post-orchidectomy. He had marked hypoalphalipoproteinemia, which was not responsive to diet or medication. To identify a possible genetic contribution to his biochemical phenotype, we sequenced the LCAT and APOA1 genes. Results: There were no sequence abnormalities in LCAT, but we found that he was a heterozygote for a novel APOA1 mutation in codon 107 (AAG->TGG), which predicted the replacement of lysine by tryptophan (K107W). Serial biochemical measurements over 11 years showed that plasma HDL cholesterol on either intramuscular or oral testosterone was 0.19 ± 0.06 mmol/L, while plasma HDL cholesterol on transdermal testosterone was significantly higher at 0.52 ± 0.18 mmol/L ( p = 0.015, unpaired t-test). Conclusions: The findings suggest that the low plasma HDL cholesterol associated with heterozygosity for mutant APOA1 can become extremely depressed during treatment with oral or intramuscular androgens. The findings also suggest that transdermal testosterone may perturb HDL to a lesser extent than other routes of delivery in such patients.