Ratios of Acetaminophen Metabolites Identify New Loci of Pharmacogenetic Relevance in a Genome-Wide Association Study

Abstract

Genome-wide association studies (GWAS) with non-targeted metabolomics have identified many genetic loci of biomedical interest. However, metabolites with a high degree of missingness, such as drug metabolites and xenobiotics, are often excluded from such studies due to a lack of statistical power and higher uncertainty in their quantification. Here we propose ratios between related drug metabolites as GWAS phenotypes that can drastically increase power to detect genetic associations between pairs of biochemically related molecules. As a proof-of-concept we conducted a GWAS with 520 individuals from the Qatar Biobank for who at least five of the nine available acetaminophen metabolites have been detected. We identified compelling evidence for genetic variance in acetaminophen glucuronidation and methylation by UGT2A15 and COMT, respectively. Based on the metabolite ratio association profiles of these two loci we hypothesized the chemical structure of one of their products or substrates as being 3-methoxyacetaminophen, which we then confirmed experimentally. Taken together, our study suggests a novel approach to analyze metabolites with a high degree of missingness in a GWAS setting with ratios, and it also demonstrates how pharmacological pathways can be mapped out using non-targeted metabolomics measurements in large population-based studies.

Investigating Paracetamol’s Role as a Potential Treatment for Parkinson’s Disease: Ab Initio Analysis of Dopamine, l-DOPA, Paracetamol, and NAPQI Interactions with Enzymes Involved in Dopamine Metabolism

“…Thus, for the three enzymes that should be inhibited in the periphery to boost l -DOPA therapy efficacy, we predict that paracetamol, NAPQI, or both will inhibit two of them (COMT and tyrosinase) while leaving the third (DDC) uninhibited and 3-hydroxyparacetamol will inhibit COMT (in agreement with experimental studies).…”

“…Paracetamol, 3-hydroxyparacetamol, l -DOPA, and DOPAC also form strong attractive interactions with asparagine. The strong attraction of 3-hydroxy-paracetamol for the COMT active site is in agreement with the experimental observations of Thareja et al 36 In their work they found that 3-methoxyparacetamol is produced in the location of the COMT enzyme; this molecule is made from 3-hydroxyparacetamol, suggesting that it is a substrate for COMT. For tyrosinase, both paracetamol and NAPQI have EBEs within 14% of that of the natural substrate l -DOPA, so they should both be competitive inhibitors for that active site.…”

“…Thus, to improve the efficacy of l -DOPA therapy, DDC, COMT, and tyrosinase may be inhibited in the periphery. The work of Thareja et al 36 suggests that the paracetamol metabolite 3-hydroxy-paracetamol (see Figure 1 ) may also function as a substrate of COMT, so we have examined that molecule here as well. All inhibition in this section is examined through the proxy value of the EBE, which is different from binding free energy but whose relative values are assumed to follow the same patterns as in vivo binding energies.…”