Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes

Abstract

Sex differences have been widely observed in human health. However, little is known about the underlying mechanism behind these observed sex differences. We hypothesize that sex-differentiated genetic effects are contributors of these phenotypic differences. Focusing on a collection of drug metabolism enzymes and transporters (DMET) genes, we discover sex-differentiated genetic regulatory mechanisms between these genes and human complex traits. Here, we show that sex-differentiated genetic effects were present at genome-level and at DMET gene regions for many human complex traits. These sex-differentiated regulatory mechanisms are reflected in the levels of gene expression and endogenous serum biomarkers. Through Mendelian Randomization analysis, we identify putative sex-differentiated causal effects in each sex separately. Furthermore, we identify and validate sex differential gene expression of a subset of DMET genes in human liver samples. We observe higher protein abundance and enzyme activity of CYP1A2 in male-derived liver microsomes, which leads to higher level of an active metabolite formation of clozapine, a commonly prescribed antipsychotic drug. Taken together, our results demonstrate the presence of sex-differentiated genetic effects on DMET gene regulation, which manifest in various phenotypic traits including disease risks and drug responses.

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“…It is a method to assess the presence of a shared causal variant in the region for two traits. Analysis was performed using the coloc R package with PPH4 > 0.5 as the threshold for the shared genetic effects between the two traits [ 48 , 49 ].…”

Sex-biased gene expression and gene-regulatory networks of sex-biased adverse event drug targets and drug metabolism genes

“…Previous studies have identified that many drug metabolism genes have sex-biased gene expression in the liver [14][15][16][17], so we chose to investigate sex-specific liver gene-regulatory networks to determine if there are potential gene regulation differences of drug metabolism genes between males and females in the liver.…”

“…Multiple studies have found sex differences in several pharmacokinetic metrics, such as the area under the curve of the plasma concentration of a drug versus time after dose or peak/maximum concentration [11]. Other studies have shown that many drug metabolism enzymes have differential gene expression and protein activity in male and female liver tissue [14][15][16]. Additionally, Oliva, et al showed that in the Genotype-Tissue Expression (GTEx) project (n = 16,245 RNA-sequencing samples across 44 human tissues), 37% of genes had sex-biased tissue-specific expression and that these genes were enriched in drug metabolism gene sets (i.e., Gene Ontology [GO] and Kyoto Encyclopedia of Genes and Genomes [KEGG] terms: "Xenobiotic Metabolism, Mitochondrial Genes and Fatty Acid Oxidation," " Cellular Response to Hormones and Drugs," "Drug Interaction and Response," and "Drug Interaction") [17].…”