Project description: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. A first set of randomized liver RNA pools (WS9) was generated by randomly distributing 112 male and 112 female liver RNA samples into 8 pools comprised of 14 male liver samples (pools M1 to M8), and 8 pools of 14 female liver samples each (pools F1 to F8). A second set of 16 pools (WS10) was prepared from the same set of 224 liver samples in the same way (pools M9 to M16 and F9 to F16). The 16 liver RNA pools of each sex were used in a total of 16 male vs. female two-color hybridization microarrays by pairing pool M1 and pool F1, pool M2 with pool F2, etc. Fluorescent labeling of RNA and hybridization of the Alexa 555-labeled and Alexa 647-labeled amplified RNA samples to Agilent Whole Human Genome oligonucleotide microarrays (4 x 44K format; Agilent Technology, Palo Alto, CA; catalog # G4112F) were carried out, with dye swaps to eliminate dye bias.

Project description: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.

Project description:BackgroundPrevious studies have demonstrated associations between cardiovascular disease and the expression of various messenger RNAs (mRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). This study aimed to investigate the differential expression of mRNAs, lncRNAs, and miRNAs between tissues from patients with coronary artery disease (CAD) and healthy controls, and to determine the interactions between these molecules in CAD.MethodsWe investigated the differential expression of competitive endogenous RNAs (ceRNAs) between patients with CAD and healthy controls by collecting data from Gene Expression Omnibus (GEO) microarrays. We also investigated the biological function of these differentially expressed ceRNAs by performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. We then created a protein-protein interaction (PPI) network to identify the hub genes. Biosystems and literature searches were also carried out to identify relevant signaling pathways and the potential function of the differentially expressed ceRNAs.ResultsWe identified 456 expression profiles for miRNAs, 16,325 mRNA expression profiles, and 2,869 lncRNA expression profiles. With regards to connectivity, GO and KEGG analyses (count ?9) identified the top 11 PPI network nodes in rank order. We also identified the top 15 significant nodes for the ceRNAs identified according to degree centrality (DC) (P<0.05). Collectively, our analyses confirmed that the differential expression of certain ceRNAs, and their respective signaling pathways were associated with CAD.ConclusionsData arising from 11 GO and KEGG pathways, the top 15 PPI network nodes with the best connectivity rank, and the top 15 ceRNA network nodes, as determined by DC rank in CAD population, indicated that the differential expression of these ceRNAs plays a key role in the CAD. Our findings highlight new molecular mechanisms for CAD and provide new options for the development of therapeutic targets.

Dataset Information

Clinical Perspectives of Genetic Analyses on Dyslipidemia and Coronary Artery Disease.

Publications

Clinical Perspectives of Genetic Analyses on Dyslipidemia and Coronary Artery Disease.

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