Abstract
(1) Background: The World Health Organization (WHO) regards atherosclerosis-related myocardial infarction and stroke as the main causes of death in humans. Susceptibility to atherogenesis-associated diseases is caused by single-nucleotide polymorphisms (SNPs). (2) Methods: Using our previously developed public web-service SNP_TATA_Comparator, we estimated statistical significance of the SNP-caused alterations in TATA-binding protein (TBP) binding affinity for 70 bp proximal promoter regions of the human genes clinically associated with diseases syntonic or dystonic with atherogenesis. Additionally, we did the same for several genes related to the maintenance of mitochondrial genome integrity, according to present-day active research aimed at retarding atherogenesis. (3) Results: In dbSNP, we found 1186 SNPs altering such affinity to the same extent as clinical SNP markers do (as estimated). Particularly, clinical SNP marker rs2276109 can prevent autoimmune diseases via reduced TBP affinity for the human MMP12 gene promoter and therefore macrophage elastase deficiency, which is a well-known physiological marker of accelerated atherogenesis that could be retarded nutritionally using dairy fermented by lactobacilli. (4) Conclusions: Our results uncovered SNPs near clinical SNP markers as the basis of neutral drift accelerating atherogenesis and SNPs of genes encoding proteins related to mitochondrial genome integrity and microRNA genes associated with instability of the atherosclerotic plaque as a basis of directional natural selection slowing atherogenesis. Their sum may be stabilizing the natural selection that sets the normal level of atherogenesis.
Highlights
Atherosclerosis is an inflammatory disorder of arteries that can lead to myocardial infarction and stroke (i.e., two most frequent causes of death in humans according to the World Health Organization (WHO) [1])
To verify the robustness of our Web service predictions in terms of the annual single-nucleotide polymorphisms (SNPs) count growth, using current dbSNP build No 151 [12], we analyzed 644 SNPs within 70 bp proximal promoters of 26 human genes, where clinical SNP markers are located according to our previous reviews of this topic [19,21,45], which are updated here (i.e., ACKR1, ADH7, APOA1, CETP, COMT, DHFR, ESR2, F3, F7, FGFR2, GCG, HBB, HBD, HSD17B1, HTR2C, IL1B, INS, LEP, MBL2, MLH1, MMP12, NOS2, RET, SOD1, TGFBR2, and TPI1), and we compared the results with those from build No 147 [12]
We will describe in depth only our predictions regarding human gene CETP, whose promoter contains the only clinically proven SNP marker of atherosclerosis, so that we review all our other predictions briefly in a similar way
Summary
Atherosclerosis is an inflammatory disorder of arteries that can lead to myocardial infarction and stroke (i.e., two most frequent causes of death in humans according to the World Health Organization (WHO) [1]). The current conventional view is that low-density lipoprotein accumulation near the vessel inner wall is the precondition for atherogenesis initiation [2] Monocytes surround such lipoprotein clusters to absorb them and differentiate into macrophage foam cells, which can separate and take away excess lipoproteins temporarily as well as return them with lipoproteins deficit for their homeostasis and so on until such cells die over time, thereby building these clusters up into fatty streaks [3]. Such streaks can gradually transform first into thrombogenic bands, into their fibrous agglomerates, and into atherosclerotic plaques, which can be calcified and become inflammation hotbeds within blood vessels [4]. The sequenced genome of an individual allows to increase his/her life expectancy via the slowing of his/her atherogenesis if this person chooses the living conditions and lifestyle that can minimize dietary fat, infectious diseases, extreme physical exertion, injuries, foreign substances in the blood, and the risks of comorbidities related to atherosclerosis
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