Ard Siest1, Michael Y Tsai2 and Sophie PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/12711626 Visvikis-Siest1,3*AbstractBackground: Although numerous candidate gene and genome-wide association studies have been performed on blood pressure, a small number of regulating genetic variants having a limited effect have been identified. This phenomenon can partially be explained by possible gene-gene/epistasis interactions that were little investigated so far. Methods: We performed a pre-planned two-phase investigation: in phase 1, one hundred single nucleotide polymorphisms (SNPs) in 65 candidate genes were genotyped in 1,912 French unrelated adults in order to study their two-locus combined effects on blood pressure (BP) levels. In phase 2, the significant epistatic interactions observed in phase 1 were tested in an independent population gathering 1,755 unrelated European adults. Results: Among the 9 genetic variants significantly associated with systolic and diastolic BP in phase 1, some may act through altering the corresponding protein levels: SNPs rs5742910 (Padjusted0.03) and rs6046 (Padjusted =0.044) in F7 and rs1800469 (Padjusted 0.036) in TGFB1; whereas some may be functional through altering the corresponding protein structure: rs1800590 (Padjusted =0.028, SE=0.088) in LPL and rs2228570 (Padjusted 9.48?0-4) in VDR. The two epistatic interactions found for systolic and diastolic BP in the discovery phase: VCAM1 (rs1041163) * APOB (rs1367117), and SCGB1A1 (rs3741240) * LPL (rs1800590), were tested in the replication population and we observed significant interactions on DBP. In silico analyses 4-Bromo-5-nitro-1H-indazole yielded putative functional properties of the SNPs involved in these epistatic interactions trough the PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/24083752 alteration of corresponding protein structures. Conclusions: These findings support the hypothesis that different pathways and then ijms17122034 different genes may act synergistically in order to modify BP. This could highlight novel pathophysiologic mechanisms underlying hypertension. Keywords: Blood pressure, Epistasis, Single nucleotide polymorphism, EpidemiologyBackground Blood pressure (BP) is a continuous, consistent and modifiable risk factor for cardiovascular diseases (CVD) such as ischemic heart disease (IHD) and stroke which are major causes of mortality and morbidity worldwide [1]: population-based studies showed that 972 million adults were hypertensive in 2005 and it is predicted to increase by about 60 to 1.56 billion in 2025 [2]. Existing evidence suggests that BP heritability ranges between 30-60 [3]. Despite the identification of specific causal genes involved in the regulatory pathways of rare familial forms of hypertension (HT) [4], both BP and* Correspondence: Sophie.visvikis-siest@inserm.fr 1 "Cardiovascular Genetics" Research Unit, EA-4373, University of Lorraine, 30 rue Lionnois ?54000, Nancy, France 3 Department of Internal Medicine and Geriatrics, CHU Nancy-Brabois, France Full list of author information is available Methyl 3-fluoro-2-thiophenecarboxylate at the end of the articleHT are still considered polygenic traits involving a large number of metabolic pathways [5]. The complex architecture of BP regulation may account for the numerous discrepancies found among studies of the genetic background of HT. Inflammation, blood coagulation cascade, cellular adhesion molecules and lipid metabolism all appear to have significant roles [6-8]. While aspects of BP regulation may be the product of an inflammation stimulus [6,9], thrombin is also known to induce several intracellular pathways [7], to modulate vascular tone [7,10.