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Shifting Paradigm from Gene Expressions to Pathways Reveals Physiological Mechanisms in Blood Pressure Control in Causation

Genetics for blood pressure (BP) in human and animals has been partitioned into two separate specialties. However, this divide is mechanistically-misleading. BP physiology is mechanistically participated by products of quantitative trait loci (QTLs). The key to unlocking its mechanistic mystery lies...

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Autores principales: Deng, Alan Y., Menard, Annie, Deng, David W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9863686/
https://www.ncbi.nlm.nih.gov/pubmed/36674778
http://dx.doi.org/10.3390/ijms24021262
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author Deng, Alan Y.
Menard, Annie
Deng, David W.
author_facet Deng, Alan Y.
Menard, Annie
Deng, David W.
author_sort Deng, Alan Y.
collection PubMed
description Genetics for blood pressure (BP) in human and animals has been partitioned into two separate specialties. However, this divide is mechanistically-misleading. BP physiology is mechanistically participated by products of quantitative trait loci (QTLs). The key to unlocking its mechanistic mystery lies in the past with mammalian ancestors before humans existed. By pivoting from effects to causes, physiological mechanisms determining BP by six QTLs have been implicated. Our work relies on congenic knock-in genetics in vivo using rat models, and has reproduced the physiological outcome based on a QTL being molecularly equal to one gene. A gene dose for a QTL is irrelevant to physiological BP controls in causation. Together, QTLs join one another as a group in modularized Mendelian fashion to achieve polygenicity. Mechanistically, QTLs in the same module appear to function in a common pathway. Each is involved in a different step in the pathway toward polygenic hypertension. This work has implicated previously-concealed components of these pathways. This emerging concept is a departure from the human-centric precept that the level of QTL expressions, not physiology, would ultimately determine BP. The modularity/pathway paradigm breaks a unique conceptual ground for unravelling the physiological mechanisms of polygenic and quantitative traits like BP.
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spelling pubmed-98636862023-01-22 Shifting Paradigm from Gene Expressions to Pathways Reveals Physiological Mechanisms in Blood Pressure Control in Causation Deng, Alan Y. Menard, Annie Deng, David W. Int J Mol Sci Article Genetics for blood pressure (BP) in human and animals has been partitioned into two separate specialties. However, this divide is mechanistically-misleading. BP physiology is mechanistically participated by products of quantitative trait loci (QTLs). The key to unlocking its mechanistic mystery lies in the past with mammalian ancestors before humans existed. By pivoting from effects to causes, physiological mechanisms determining BP by six QTLs have been implicated. Our work relies on congenic knock-in genetics in vivo using rat models, and has reproduced the physiological outcome based on a QTL being molecularly equal to one gene. A gene dose for a QTL is irrelevant to physiological BP controls in causation. Together, QTLs join one another as a group in modularized Mendelian fashion to achieve polygenicity. Mechanistically, QTLs in the same module appear to function in a common pathway. Each is involved in a different step in the pathway toward polygenic hypertension. This work has implicated previously-concealed components of these pathways. This emerging concept is a departure from the human-centric precept that the level of QTL expressions, not physiology, would ultimately determine BP. The modularity/pathway paradigm breaks a unique conceptual ground for unravelling the physiological mechanisms of polygenic and quantitative traits like BP. MDPI 2023-01-09 /pmc/articles/PMC9863686/ /pubmed/36674778 http://dx.doi.org/10.3390/ijms24021262 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Deng, Alan Y.
Menard, Annie
Deng, David W.
Shifting Paradigm from Gene Expressions to Pathways Reveals Physiological Mechanisms in Blood Pressure Control in Causation
title Shifting Paradigm from Gene Expressions to Pathways Reveals Physiological Mechanisms in Blood Pressure Control in Causation
title_full Shifting Paradigm from Gene Expressions to Pathways Reveals Physiological Mechanisms in Blood Pressure Control in Causation
title_fullStr Shifting Paradigm from Gene Expressions to Pathways Reveals Physiological Mechanisms in Blood Pressure Control in Causation
title_full_unstemmed Shifting Paradigm from Gene Expressions to Pathways Reveals Physiological Mechanisms in Blood Pressure Control in Causation
title_short Shifting Paradigm from Gene Expressions to Pathways Reveals Physiological Mechanisms in Blood Pressure Control in Causation
title_sort shifting paradigm from gene expressions to pathways reveals physiological mechanisms in blood pressure control in causation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9863686/
https://www.ncbi.nlm.nih.gov/pubmed/36674778
http://dx.doi.org/10.3390/ijms24021262
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