Physiogenomic analysis of CYP450 drug metabolism correlates dyslipidemia with pharmacogenetic functional status in psychiatric patients

Abstract

Aims: To investigate associations between novel human cytochrome P450 (CYP450) combinatory (multigene) and substrate-specific drug metabolism indices, and elements of metabolic syndrome, such as low density lipoprotein cholesterol (LDLc), high density lipoprotein cholesterol (HDLc), triglycerides and BMI, using physiogenomic analysis.

Methods: CYP2C9, CYP2C19 and CYP2D6 genotypes and clinical data were obtained for 150 consecutive, consenting hospital admissions with a diagnosis of major depressive disorder and who were treated with psychotropic medications. Data analysis compared clinical measures of LDLc, HDLc, triglyceride and BMI with novel combinatory and substrate-specific CYP450 drug metabolism indices.

Results: We found that a greater metabolic reserve index score is related to lower LDLc and higher HDLc, and that a greater metabolic alteration index score corresponds with higher LDLc and lower HLDc values. We also discovered that the sertraline drug-specific indices correlated with cholesterol and triglyceride values.

Conclusions: Overall, we demonstrated how a multigene approach to CYP450 genotype analysis yields more accurate and significant results than single-gene analyses. Ranking the individual with respect to the population represents a potential tool for assessing risk of dyslipidemia in major depressive disorder patients who are being treated with psychotropics. In addition, the drug-specific indices appear useful for modeling a variable of potential relevance to an individual's risk of drug-related dyslipidemia.

Figure 1. Physiogenomic plots correlating LDLc with the four CYP450 combinatory drug metabolism indices

Each plot contains three components: the distribution of the phenotype (bell curve), the index score of each individual patient (circles) and the LOESS fit of the index value as a function of phenotype (regression curve). In each of four panels the abscissa represents each patient’s LDLc. The ordinate indicates the index value for the LOESS curve. The p-value is derived from a linear analysis associating the index and clinical variable, and the n indicates the number of samples considered in the analysis. Correction for the comparisons of each index to five phenotypes in this study (LDLc, HDLc, LDLc:HDLc, triglycerides and BMI) requires multiplication of the respective p-value by a factor of five. LDLc: Low density lipoprotein cholesterol; LOESS: Locally weighted scatter plot smooth.

Figure 2. Physiogenomic plots correlating LDLc:HDLc ratio with the four CYP450 combinatory drug metabolism indices

Each plot contains three components: the distribution of the phenotype (bell curve), the index score of each individual patient (circles) and the LOESS fit of the index value as a function of phenotype (regression curve). In each of four panels, the abscissa represents each patient’s LDLc:HDLc ratio. The ordinate indicates the index value for the LOESS curve. The p-value is derived from a linear analysis associating the index and clinical variable, and the n indicates the number of samples considered in the analysis. Correction for the comparisons of each index to five phenotypes in this study (LDLc, HDLc, LDLc:HDLc, triglycerides and BMI) requires multiplication of the respective p-value by a factor of five. LOESS: Locally weighted scatter plot smooth.

Figure 3. Physiogenomic plots correlating LDLc:HDLc ratio with sertraline-specific CYP450 combinatory indices

Each plot contains three components: the distribution of the phenotype (bell curve), the index score of each individual patient (circles) and the LOESS fit of the index value as a function of phenotype (regression curve). The p-value is derived from a linear analysis associating the index and clinical variable, and the n indicates the number of samples considered in the analysis. (A) Shows the inverse correlation between sertraline metabolic reserve and LDLc:HDLc ratio, and (B) shows the direct relationship between sertraline metabolic alteration and LDLc:HDLc ratio. HDLc: High density lipoprotein cholesterol; LOESS: Locally weighted scatter plot smooth.