Background

The response in levels of very-low-density (VLDL) and low-density (LDL) lipoproteins varies substantially among hyperlipidemic patients during treatment with HMGCoA reductase inhibitors. Apolipoprotein E genotype and gender are known to contribute to the regulation of steady state levels of plasma lipoproteins. This study explores the effect of these and other potential determinants of the response of VLDL and LDL to treatment with reductase inhibitors.

Methods

Using mixed linear statistical models, the response of lipoprotein lipid values was studied in 142 hyperlipidemic individuals who were treated with reductase inhibitors. Patients received one or more of the following drugs individually for a total of 623 treatment observations: lovastatin, pravastatin, simvastatin, or atorvastatin. For evaluation of the effects of treatment in the aggregate, actual doses were expressed as equivalent doses of atorvastatin, using factors based on random assignment comparisons in 16 reported studies. The analysis factors considered were apolipoprotein E genotype, baseline average triglycerides >170 mg/dL (vs less), and gender.

Results

Presence of an apo epsilon4 allele was associated with a trend toward greater reduction of triglyceride levels and a diminished ability of the reductase inhibitors to reduce LDL cholesterol levels. Gender had only minimal effect on the response of either LDL cholesterol or triglycerides. However, the effect of elevated baseline triglycerides on the response of both triglycerides and LDL cholesterol was striking and was exerted in opposite directions. The triglyceride-lowering effect of reductase inhibitors was greater in patients with initial triglyceride levels above 170 mg/dL (P=0.0001). The effect was even greater in patients with initial triglyceride levels over 250 mg/dL (P=0.015). Conversely, for LDL cholesterol levels, elevated baseline triglycerides were associated with a significantly decreased response to the drugs (P=0.0015).

Conclusions

These findings indicate that baseline triglyceride levels are an important predictor of response of plasma lipoproteins to HMGCoA reductase inhibitors, perhaps reflecting fundamental differences in mechanism underlying the hyperlipidemic phenotype.

Short-acting β2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled β2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.