Obesity-related known and candidate SNP markers can significantly change affinity of TATA-binding protein for human gene promoters

Abstract

BackgroundObesity affects quality of life and life expectancy and is associated with cardiovascular disorders, cancer, diabetes, reproductive disorders in women, prostate diseases in men, and congenital anomalies in children. The use of single nucleotide polymorphism (SNP) markers of diseases and drug responses (i.e., significant differences of personal genomes of patients from the reference human genome) can help physicians to improve treatment. Clinical research can validate SNP markers via genotyping of patients and demonstration that SNP alleles are significantly more frequent in patients than in healthy people. The search for biomedical SNP markers of interest can be accelerated by computer-based analysis of hundreds of millions of SNPs in the 1000 Genomes project because of selection of the most meaningful candidate SNP markers and elimination of neutral SNPs.ResultsWe cross-validated the output of two computer-based methods: DNA sequence analysis using Web service SNP_TATA_Comparator and keyword search for articles on comorbidities of obesity. Near the sites binding to TATA-binding protein (TBP) in human gene promoters, we found 22 obesity-related candidate SNP markers, including rs10895068 (male breast cancer in obesity); rs35036378 (reduced risk of obesity after ovariectomy); rs201739205 (reduced risk of obesity-related cancers due to weight loss by diet/exercise in obese postmenopausal women); rs183433761 (obesity resistance during a high-fat diet); rs367732974 and rs549591993 (both: cardiovascular complications in obese patients with type 2 diabetes mellitus); rs200487063 and rs34104384 (both: obesity-caused hypertension); rs35518301, rs72661131, and rs562962093 (all: obesity); and rs397509430, rs33980857, rs34598529, rs33931746, rs33981098, rs34500389, rs63750953, rs281864525, rs35518301, and rs34166473 (all: chronic inflammation in comorbidities of obesity). Using an electrophoretic mobility shift assay under nonequilibrium conditions, we empirically validated the statistical significance (α < 0.00025) of the differences in TBP affinity values between the minor and ancestral alleles of 4 out of the 22 SNPs: rs200487063, rs201381696, rs34104384, and rs183433761. We also measured half-life (t1/2), Gibbs free energy change (ΔG), and the association and dissociation rate constants, ka and kd, of the TBP-DNA complex for these SNPs.ConclusionsValidation of the 22 candidate SNP markers by proper clinical protocols appears to have a strong rationale and may advance postgenomic predictive preventive personalized medicine.

Candidate SNP markers of aggressiveness-related complications and comorbidities of genetic diseases are predicted by a significant change in the affinity of TATA-binding protein for human gene promoters

“…The human LEP gene (leptin; synonyms: obesity factor with acronym OB ) contains a candidate SNP marker (rs201381696) of obesity (reducing this gene’s expression) as well as candidate SNP markers (rs200487063 and rs34104384) of obesity-induced hypertension caused by overexpression of this gene as we have predicted in silico and verified in vitro in our previous work [66] (Table 4). …”

“…In addition, a clinical case review [143] revealed longer survival in aggressive leptin-deficient women with anorexia nervosa. On the basis of these data, we expanded our prediction [66] on the obesity-related candidate SNP markers rs201381696, rs200487063, and rs34104384 to our prognosis that these SNPs can also be candidate SNP markers of aggressiveness in obesity.…”

“…That is why we apply this approach to studies of unannotated SNPs detected by the 1000 Genomes project [11] which are less known at present. Recently, we predicted candidate SNP markers of complications of hereditary diseases in obesity [66], of autoimmune comorbidities of these diseases [67], and of circadian rhythm disorders [68]. …”

The papers presented at 7th Young Scientists School “Systems Biology and Bioinformatics” (SBB’15): Introductory Note

“…The paper by Arkova et al "Obesity-related known and candidate SNP markers can significantly change affinity of TATA-binding protein for human gene promoters" [10] (http://www.biomedcentral.com/1471-2164/16/S13/S5) presents an in silico analysis of 22 known nucleotide polymorphisms and arrived at functionally important conclusion about the mechanism of action for at least one of these DNA variants.…”

Candidate SNP Markers of Chronopathologies Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

“…Recently, we showed suitability of this Web service for prediction of candidate SNP markers of complications of Mendelian diseases in obesity [38] and of autoimmune complications of these diseases [39] as well as SNP markers that can either enhance or weaken biological activity of oncogene inhibitors during cancer chemotherapy [40] (hereinafter, we use the term “Mendelian disease” according to the notation in database Online Mendelian Inheritance in Man, OMIM® [28]).…”