Transcriptional Profiling of Human Liver Identifies Sex-Biased Genes Associated with Polygenic Dyslipidemia and Coronary Artery Disease

Abstract

Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Top biological functions and diseases significantly enriched in sex-biased genes include transcription, chromatin organization and modification, sexual reproduction, lipid metabolism and cardiovascular disease. Notably, sex-biased genes are enriched at loci associated with polygenic dyslipidemia and coronary artery disease in genome-wide association studies. Moreover, of the 8 sex-biased genes at these loci, 4 have been directly linked to monogenic disorders of lipid metabolism and show an expression profile in females (elevated expression of ABCA1, APOA5 and LDLR; reduced expression of LIPC) that is consistent with the lower female risk of coronary artery disease. Female-biased expression was also observed for CYP7A1, which is activated by drugs used to treat hypercholesterolemia. Several sex-biased drug-metabolizing enzyme genes were identified, including members of the CYP, UGT, GPX and ALDH families. Half of 879 mouse orthologs, including many genes of lipid metabolism and homeostasis, show growth hormone-regulated sex-biased expression in mouse liver, suggesting growth hormone might play a similar regulatory role in human liver. Finally, the evolutionary rate of protein coding regions for human-mouse orthologs, revealed by dN/dS ratio, is significantly higher for genes showing the same sex-bias in both species than for non-sex-biased genes. These findings establish that human hepatic sex differences are widespread and affect diverse cell metabolic processes, and may help explain sex differences in lipid profiles associated with sex differential risk of coronary artery disease.

Inflammation-Associated MicroRNA-130b Down-Regulates Cytochrome P450 Activities and Directly Targets CYP2C9

“…Numerous factors are known to influence expression and function of ADME genes. These include constant factors such as sex or genetic variation, and factors that change over time, including age, hormonal and circadian influences, or disease states, including cancer, cholestasis, and inflammation (Congiu et al, 2009;Zhang et al, 2011;Harvey and Morgan, 2014). Despite extensive research into the mechanisms of ADME variability, individualized prediction of pharmacokinetics as a cornerstone of personalized drug therapy remains difficult.…”

Expression Variability of Absorption, Distribution, Metabolism, Excretion–Related MicroRNAs in Human Liver: Influence of Nongenetic Factors and Association with Gene Expression

“…For example, CYP2D6 appears to be almost exclusively regulated by gene polymorphisms, whereas other enzymes including CYPs 1A2, 2C8, and 3A4 are less affected by genetic polymorphism but strongly inducible through transcriptional regulation by ligand-dependent receptors [e.g., aryl hydrocarbon receptor, pregnane X receptor (PXR), constitutive androstane receptor, peroxisome proliferator-activated receptor a (Plant, 2007;Yang et al, 2010;Thomas et al, 2013)]. Additional factors including sex and age (Yang et al, 2010;Zhang et al, 2011) as well as hepatic disease states such as cholestasis and inflammatory conditions (Morgan, 2009;Nies et al, 2009;Klein et al, 2010) can have marked influence on the expression and function of ADME genes.…”

Genome-Wide Analysis of Chromatin States Reveals Distinct Mechanisms of Sex-Dependent Gene Regulation in Male and Female Mouse Liver

“…Sex differences in gene expression are best characterized in the liver, where ϳ1,000 genes are expressed in a sex-biased manner, as seen in mice, rats, and humans (18)(19)(20). These sex differences affect diverse physiological processes, including hepatic steroid, lipid, and drug metabolism (21)(22)(23), and contribute to sex differences in cardiovascular disease risk, fatty liver disease, and the development of hepatocellular carcinoma (20,(24)(25)(26). Sex differences in liver gene expression are regulated by the temporal pattern of pituitary growth hormone (GH) secretion, which is sex dependent and programmed by androgen and estrogen exposure during the neonatal period (21).…”