Candidate SNP Markers of Familial and Sporadic Alzheimer's Diseases Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters.

Petr Ponomarenko,Dmitry Zhechev,Mikhail P Ponomarenko,Dmitry A Rasskazov,Irina Chadaeva,Ludmila K Savinkova,Elena V Kashina,Irina Drachkova,Nikolay Kolchanov,Ekaterina Sharypova

doi:10.3389/fnagi.2017.00231

Abstract

While year after year, conditions, quality, and duration of human lives have been improving due to the progress in science, technology, education, and medicine, only eight diseases have been increasing in prevalence and shortening human lives because of premature deaths according to the retrospective official review on the state of US health, 1990-2010. These diseases are kidney cancer, chronic kidney diseases, liver cancer, diabetes, drug addiction, poisoning cases, consequences of falls, and Alzheimer's disease (AD) as one of the leading pathologies. There are familial AD of hereditary nature (~4% of cases) and sporadic AD of unclear etiology (remaining ~96% of cases; i.e., non-familial AD). Therefore, sporadic AD is no longer a purely medical problem, but rather a social challenge when someone asks oneself: “What can I do in my own adulthood to reduce the risk of sporadic AD at my old age to save the years of my lifespan from the destruction caused by it?” Here, we combine two computational approaches for regulatory SNPs: Web service SNP_TATA_Comparator for sequence analysis and a PubMed-based keyword search for articles on the biochemical markers of diseases. Our purpose was to try to find answers to the question: “What can be done in adulthood to reduce the risk of sporadic AD in old age to prevent the lifespan reduction caused by it?” As a result, we found 89 candidate SNP markers of familial and sporadic AD (e.g., rs562962093 is associated with sporadic AD in the elderly as a complication of stroke in adulthood, where natural marine diets can reduce risks of both diseases in case of the minor allele of this SNP). In addition, rs768454929, and rs761695685 correlate with sporadic AD as a comorbidity of short stature, where maximizing stature in childhood and adolescence as an integral indicator of health can minimize (or even eliminate) the risk of sporadic AD in the elderly. After validation by clinical protocols, these candidate SNP markers may become interesting to the general population [may help to choose a lifestyle (in childhood, adolescence, and adulthood) that can reduce the risks of sporadic AD, its comorbidities, and complications in the elderly].

Highlights

While year after year, conditions, quality, and duration of human lives have been improving due to the progress in science, technology, education, and medicine, only eight diseases have been increasing in prevalence and shortening human lives because of premature deaths according to the retrospective official review on the state of US health, 1990-2010 (Murray et al, 2013)
We extended the use of our Web service to unannotated SNPs near known biomedical SNP markers in TATA-binding protein (TBP)-binding sites of promoters in human genes, associated with hereditary diseases, which were taken from our previous review (Ponomarenko et al, 2015)
We analyzed 626 SNPs retrieved from the dbSNP database, v.147 (Sherry et al, 2001), within [−70; −20] promoter regions of either 34 human genes containing SNP markers of hereditary diseases whose effects on TBP’s binding to these promoters are clinically identified as described in our review (Ponomarenko et al, 2015), or five human genes—MAPT, APP, PSEN1, PSEN2, and APOE—associated with familial Alzheimer’s disease (AD), which were taken from another article (Iwata et al, 2014)

Summary

Introduction

Conditions, quality, and duration of human lives have been improving due to the progress in science, technology, education, and medicine, only eight diseases have been increasing in prevalence and shortening human lives because of premature deaths according to the retrospective official review on the state of US health, 1990-2010 (Murray et al, 2013). The majority of the known regulatory SNP markers alter the binding sites for TATA-binding protein (TBP) because of their fixed locations within the narrow region [−70; −20] upstream of the transcription start site of a proteincoding transcript (Ponomarenko et al, 2013) This sort of the SNP markers has been easier to detect due to the positive correlation between the expression level of the human gene containing them and the affinity of TBP for the promoter of this gene (Mogno et al, 2010). This especially high importance of the TBP binding to the promoter can be attributed to the fact that this is the very first obligatory molecular event in the course of the transcription initiation in eukaryotes (Muller et al, 2001; Martianov et al, 2002; Ponomarenko et al, 2013)

Methods

Results

Conclusion