title: Pleiotropic Effect of a High Resolution Mapped Blood Pressure QTL on Tumorigenesis.
abstract: This study is focused on a translationally significant, genome-wide-association-study (GWAS) locus for cardiovascular disease (QT-interval) on human chromosome 17. We have previously validated and high resolution mapped the homologous genomic segment of this human locus to <42.5 kb on rat chromosome 10. This <42.5 kb segment in rats regulates both QT-interval and blood pressure and contains a single protein-coding gene, rififylin (Rffl). The expression of Rffl in the hearts and kidneys is differential between Dahl S and S.LEW congenic rats, which are the strains used for mapping this locus. Our previous study points to altered rate of endocytic recycling as the underlying mechanism, through which Rffl operates to control both QT-interval and blood pressure. Interestingly, Rffl also contributes to tumorigenesis by repressing caspases and tumor suppressor genes. Moreover, the expression of Methyl-CpG Binding Domain Protein 2 (Mbd2) in the hearts and kidneys is also higher in the S.LEW congenic strain than the background (control) Dahl S strain. Mbd2 can repress methylated tumor suppressor genes. These data suggest that the S.LEW congenic strain could be more susceptible to tumorigenesis. To test this hypothesis, the S and S.LEW strains were compared for susceptibility to azoxymethane-induced colon tumors. The number of colon tumors was significantly higher in the S.LEW congenic strain compared with the S rat. Transcriptomic analysis confirmed that the chemical carcinogenesis pathway was significantly up-regulated in the congenic strain. These studies provide evidence for a GWAS-validated genomic segment on rat chromosome 10 as being important for the regulation of cardiovascular function and tumorigenesis.
authors.affiliation: Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States of America.
authors.forename: Xi
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States of America.
authors.forename: Harshal
authors.initials: H
authors.lastname: Waghulde
authors.affiliation: Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States of America.
authors.forename: Blair
authors.initials: B
authors.lastname: Mell
authors.affiliation: Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States of America.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Smedlund
authors.affiliation: Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States of America.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Vazquez
authors.affiliation: Program in Physiological Genomics, Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States of America.
authors.forename: Bina
authors.initials: B
authors.lastname: Joe
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001794:Blood Pressure / Q000235:genetics*; D001795:Blood Pressure Determination; D063646:Carcinogenesis / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D051381:Rats; D020303:Rats, Inbred Dahl; D011917:Rats, Inbred Lew; D013045:Species Specificity; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C502761:Rffl protein, mouse; D044767:Ubiquitin-Protein Ligases