A novel Y-specific long non-coding RNA associated with cellular lipid accumulation in HepG2 cells and Atherosclerosis-related genes
- Molina, Elsa, Chew, Guat, Myers, Stephen, Clarence, Elyse, Eales, James, Tomaszewski, Maciej, Charchar, Fadi
- Authors: Molina, Elsa , Chew, Guat , Myers, Stephen , Clarence, Elyse , Eales, James , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. 1 (2017), p. 1-12
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.
- Authors: Molina, Elsa , Chew, Guat , Myers, Stephen , Clarence, Elyse , Eales, James , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 7, no. 1 (2017), p. 1-12
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentified. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream effect contributing to the chronic inflammatory process that underpin CAD. Our findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.
Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
- Morris, Andrew, Le, Thu, Wu, Haojia, Akbarov, Artur, van der Most, Peter, Hemani, Gibran, Smith, George, Mahajan, Anubha, Gaulton, Kyle, Nadkarni, Girish, Valladares-Salgado, Adan, Wacher-Rodarte, Niels, Mychaleckyj, Josyf, Dueker, Nicole, Guo, Xiuqing, Hai, Yang, Haessler, Jeffrey, Kamatani, Yoichiro, Stilp, Adrienne, Zhu, Gu, Cook, James, Arnlov, Johan, Blanton, Susan, de Borst, Martin, Bottinger, Erwin, Buchanan, Thomas, Cechova, Sylvia, Charchar, Fadi, Chu, Pei-Lun, Damman, Jeffrey, Eales, James, Gharavi, Ali, Giedraitis, Vilmantas, Heath, Andrew, Ipp, Eli, Kiryluk, Krzysztof, Kramer, Holly, Kubo, Michiaki, Larsson, Anders, Lindgren, Cecilia, Lu, Yingchang, Madden, Pamela, Montgomery, Grant, Papanicolaou, George, Raffel, Leslie, Sacco, Ralph, Sanchez, Elena, Stark, Holger, Sundstrom, Johan, Taylor, Kent, Xiang, Anny, Zivkovic, Aleksandra, Lind, Lars, Ingelsson, Erik, Martin, Nicholas, Whitfield, John, Cai, Jianwen, Laurie, Cathy, Okada, Yukinori, Matsuda, Koichi, Kooperberg, Charles, Chen, Yii-Der, Rundek, Tatjana, Rich, Stephen, Loos, Ruth, Parra, Esteban, Cruz, Miguel, Rotter, Jerome, Snieder, Harold, Tomaszewski, Maciej, Humphreys, Benjamin, Franceschini, Nora
- Authors: Morris, Andrew , Le, Thu , Wu, Haojia , Akbarov, Artur , van der Most, Peter , Hemani, Gibran , Smith, George , Mahajan, Anubha , Gaulton, Kyle , Nadkarni, Girish , Valladares-Salgado, Adan , Wacher-Rodarte, Niels , Mychaleckyj, Josyf , Dueker, Nicole , Guo, Xiuqing , Hai, Yang , Haessler, Jeffrey , Kamatani, Yoichiro , Stilp, Adrienne , Zhu, Gu , Cook, James , Arnlov, Johan , Blanton, Susan , de Borst, Martin , Bottinger, Erwin , Buchanan, Thomas , Cechova, Sylvia , Charchar, Fadi , Chu, Pei-Lun , Damman, Jeffrey , Eales, James , Gharavi, Ali , Giedraitis, Vilmantas , Heath, Andrew , Ipp, Eli , Kiryluk, Krzysztof , Kramer, Holly , Kubo, Michiaki , Larsson, Anders , Lindgren, Cecilia , Lu, Yingchang , Madden, Pamela , Montgomery, Grant , Papanicolaou, George , Raffel, Leslie , Sacco, Ralph , Sanchez, Elena , Stark, Holger , Sundstrom, Johan , Taylor, Kent , Xiang, Anny , Zivkovic, Aleksandra , Lind, Lars , Ingelsson, Erik , Martin, Nicholas , Whitfield, John , Cai, Jianwen , Laurie, Cathy , Okada, Yukinori , Matsuda, Koichi , Kooperberg, Charles , Chen, Yii-Der , Rundek, Tatjana , Rich, Stephen , Loos, Ruth , Parra, Esteban , Cruz, Miguel , Rotter, Jerome , Snieder, Harold , Tomaszewski, Maciej , Humphreys, Benjamin , Franceschini, Nora
- Date: 2019
- Type: Text , Journal article
- Relation: Nature Communications Vol. 10, no. 1 (2019), p. 1-14
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- Reviewed:
- Description: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
- Authors: Morris, Andrew , Le, Thu , Wu, Haojia , Akbarov, Artur , van der Most, Peter , Hemani, Gibran , Smith, George , Mahajan, Anubha , Gaulton, Kyle , Nadkarni, Girish , Valladares-Salgado, Adan , Wacher-Rodarte, Niels , Mychaleckyj, Josyf , Dueker, Nicole , Guo, Xiuqing , Hai, Yang , Haessler, Jeffrey , Kamatani, Yoichiro , Stilp, Adrienne , Zhu, Gu , Cook, James , Arnlov, Johan , Blanton, Susan , de Borst, Martin , Bottinger, Erwin , Buchanan, Thomas , Cechova, Sylvia , Charchar, Fadi , Chu, Pei-Lun , Damman, Jeffrey , Eales, James , Gharavi, Ali , Giedraitis, Vilmantas , Heath, Andrew , Ipp, Eli , Kiryluk, Krzysztof , Kramer, Holly , Kubo, Michiaki , Larsson, Anders , Lindgren, Cecilia , Lu, Yingchang , Madden, Pamela , Montgomery, Grant , Papanicolaou, George , Raffel, Leslie , Sacco, Ralph , Sanchez, Elena , Stark, Holger , Sundstrom, Johan , Taylor, Kent , Xiang, Anny , Zivkovic, Aleksandra , Lind, Lars , Ingelsson, Erik , Martin, Nicholas , Whitfield, John , Cai, Jianwen , Laurie, Cathy , Okada, Yukinori , Matsuda, Koichi , Kooperberg, Charles , Chen, Yii-Der , Rundek, Tatjana , Rich, Stephen , Loos, Ruth , Parra, Esteban , Cruz, Miguel , Rotter, Jerome , Snieder, Harold , Tomaszewski, Maciej , Humphreys, Benjamin , Franceschini, Nora
- Date: 2019
- Type: Text , Journal article
- Relation: Nature Communications Vol. 10, no. 1 (2019), p. 1-14
- Full Text:
- Reviewed:
- Description: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
The y chromosome : A blueprint for men's health?
- Maan, Akhlaq, Eales, James, Akbarov, Artur, Rowland, Joshua, Xu, Xiaoguang, Jobling, Mark, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Maan, Akhlaq , Eales, James , Akbarov, Artur , Rowland, Joshua , Xu, Xiaoguang , Jobling, Mark , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2017
- Type: Text , Journal article , Review
- Relation: European Journal of Human Genetics Vol. 25, no. 11 (2017), p. 1181-1188
- Full Text:
- Reviewed:
- Description: The Y chromosome has long been considered a genetic wasteland' on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component. Phylogenetic studies reveal that carriers of a common European lineage of the Y chromosome (haplogroup I) possess increased risk of coronary artery disease. This occurs amidst upregulation of inflammation and suppression of adaptive immunity in this Y lineage, as well as inferior outcomes in human immunodeficiency virus infection. From structural analysis and experimental data, the UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene is emerging as a promising candidate underlying the associations between Y-chromosome variants and the immunity-driven susceptibility to complex disease. This review synthesises the recent structural, experimental and clinical insights into the human Y chromosome in the context of men's susceptibility to disease (with a particular emphasis on cardiovascular disease) and provides an overview of the paradigm shift in the perception of the Y chromosome. © 2017 The Author(s).
- Authors: Maan, Akhlaq , Eales, James , Akbarov, Artur , Rowland, Joshua , Xu, Xiaoguang , Jobling, Mark , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2017
- Type: Text , Journal article , Review
- Relation: European Journal of Human Genetics Vol. 25, no. 11 (2017), p. 1181-1188
- Full Text:
- Reviewed:
- Description: The Y chromosome has long been considered a genetic wasteland' on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component. Phylogenetic studies reveal that carriers of a common European lineage of the Y chromosome (haplogroup I) possess increased risk of coronary artery disease. This occurs amidst upregulation of inflammation and suppression of adaptive immunity in this Y lineage, as well as inferior outcomes in human immunodeficiency virus infection. From structural analysis and experimental data, the UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene is emerging as a promising candidate underlying the associations between Y-chromosome variants and the immunity-driven susceptibility to complex disease. This review synthesises the recent structural, experimental and clinical insights into the human Y chromosome in the context of men's susceptibility to disease (with a particular emphasis on cardiovascular disease) and provides an overview of the paradigm shift in the perception of the Y chromosome. © 2017 The Author(s).
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