Stress Reactivity, Susceptibility to Hypertension, and Differential Expression of Genes in Hypertensive Compared to Normotensive Patients

Abstract

Although half of hypertensive patients have hypertensive parents, known hypertension-related human loci identified by genome-wide analysis explain only 3% of hypertension heredity. Therefore, mainstream transcriptome profiling of hypertensive subjects addresses differentially expressed genes (DEGs) specific to gender, age, and comorbidities in accordance with predictive preventive personalized participatory medicine treating patients according to their symptoms, individual lifestyle, and genetic background. Within this mainstream paradigm, here, we determined whether, among the known hypertension-related DEGs that we could find, there is any genome-wide hypertension theranostic molecular marker applicable to everyone, everywhere, anytime. Therefore, we sequenced the hippocampal transcriptome of tame and aggressive rats, corresponding to low and high stress reactivity, an increase of which raises hypertensive risk; we identified stress-reactivity-related rat DEGs and compared them with their known homologous hypertension-related animal DEGs. This yielded significant correlations between stress reactivity-related and hypertension-related fold changes (log2 values) of these DEG homologs. We found principal components, PC1 and PC2, corresponding to a half-difference and half-sum of these log2 values. Using the DEGs of hypertensive versus normotensive patients (as the control), we verified the correlations and principal components. This analysis highlighted downregulation of β-protocadherins and hemoglobin as whole-genome hypertension theranostic molecular markers associated with a wide vascular inner diameter and low blood viscosity, respectively.

Plant_SNP_TATA_Z-Tester: A Web Service That Unequivocally Estimates the Impact of Proximal Promoter Mutations on Plant Gene Expression

“…Within Tikhonov’s regularization [ 61 ], this correlation ( Figure 2 a) characterizes a similarity between the ill-posed inverse problem of evaluating the transcriptional outcome of mutations in plant proximal promoters ( Figure 1 ) and the analogous well-posed problem for humans, which has already been solved using our public Web service Human_SNP_TATA_Z-tester [ 28 ] (see in-depth description in the Supplementary Materials [ 18 , 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 62 , 63 , 64 , 65 , 66 , 67 ]). With this in mind, Figure 2 depicts how we adapted it step-by-step for comparing between wildtype and mutant variants of the plant promoter DNA sequences under study in their effects on gene expression, i.e., our new Web service Plant_SNP_TATA_Z-tester created in this work.…”

“…We processed DNA sequences by means of our public Web service Plant_SNP_TATA_Z-tester (e.g., Figure 3 a and Figure 6 ) created in this work, as depicted in Figure 2 . To this end, as its prototype, we used our previously developed Web service Human_SNP_TATA_Z-tester [ 28 ] (see description [ 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 62 , 63 , 64 , 65 , 66 , 67 ] in the Supplementary Materials ), and we expanded it only with Equation (2) in line with Tikhonov’s regularization [ 61 ].…”

“…( a ) The interchangeability of hsTBP ( x -axis) and atTBP ( y -axis) for transcription in vitro [ 45 ]. ( b ) Using Human_SNP_TATA_Z-tester [ 28 ] (see in-depth description in the Supplementary Materials [ 18 , 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 62 , 63 , 64 , 65 , 66 , 67 ]), we estimated the −ln(K D; hsTBP ) values of hsTBP affinity for the 90 bp DNA sequence of either the wildtype or the mutant variant of the Agrobacterium tumefaciens T-DNA TC7 promoter ( AtTC7 ) [ 54 ] from [ 45 ], as shown by arrow 1. ( c ) Statistically significant linear regression of the predicted K D;hsTBP values in relation to the F hsTBP values measured using hsTBP [ 45 ], as expressed by Equation (1) written above the dashed line.…”

“…It uses a step-by-step approximation [ 29 ]: (i) TBP slides along DNA [ 18 ]; (ii) TBP stops at the best TBP-binding site [ 30 , 31 ]; (iii) the TBP–promoter complex is fixed by the DNA bending at a right angle [ 32 ], as proven experimentally [ 33 ]. Subsequently, using Human_SNP_TATA_Z-tester, we analyzed 15243 SNPs, which yielded 3229 candidate SNP markers aggravating or relieving the development of human disorders, such as subfertility [ 28 , 34 ], obesity [ 35 ], hypertension [ 36 ], cognitive disorders [ 37 ], atherosclerosis [ 38 ], Alzheimer’s disease [ 39 , 40 ], hematopoietic disorders [ 41 ], and many others (for a review, see [ 42 ]). Lastly, from article to article, we selectively experimentally verified these predictions, as did some independent researchers (e.g., see [ 43 ]).…”

“…The supporting information can be downloaded at . References [ 18 , 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 62 , 63 , 64 , 65 , 66 , 67 ] are cited in the Supplementary Materials.…”