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

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.