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.

... are credited. 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

... resolution mapped the homologous genomic segment of this human locus to <42.5 kb on rat chromosome 10. This was done by generating and characterizing S.LEW congenic rats with chromosomal segments from the normotensive Lewis (LEW) rat introgressed onto the genetic background of the hypertensive Dahl salt-sensitive (S) rat [ 2 7 ]. The locus in rats regulates both QT-interval and blood pressure and contains a single protein-coding gene, rififylin ( Rffl ) [ 7 ]. While there are no exonic variants, 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 [ 7 , 8 ]. Our study points to the altered rate of endocytic recycling as the underlying mechanism, through which Rffl operates to control both cardiac QT-intervals and blood pressure [ 7 ]. The functions of Rffl (rififylin) are: (a) rififylin is an endosome associated ubiquitin ligase; (b) rififylin is also known as caspases-8- and -10-associated RING

... congenic strains by transferring chromosomal segments from the normotensive Lewis (LEW) rat onto the genetic background of the hypertensive Dahl S rat. In one of the S.LEW congenic strains, which contains LEW alleles within the <42.5 kb BP QTL region, blood pressure was significantly increased and QT-intervals were significantly shorter compared with the S rat [ 7 ]. This BP QTL in rats contains only a single protein-coding gene, rififylin ( Rffl ). The expression of Rffl was significantly higher in the hearts and kidneys of the S.LEW congenic strain compared with S and the overexpression of Rffl is known to delay endocytic recycling, which has been functionally linked to hypertension [ 7 , 8 ]. Intriguingly, Rffl plays an important role in the regulation of tumorigenesis by mediating tumor suppressor genes and regulating the tumor cell migration [ 9 11 ]. Further, the previous microarray study showed that Methyl-CpG Binding Domain Protein 2 ( Mbd2 ), which functions as a transcription

... Rffl as a candidate gene, the evidence is weak. The microarray dataset did not reveal any differential expression of Rffl between the colons of S and S.LEW congenic strain, although evaluation through real-time PCR showed a higher expression of Rffl in the congenic strain compared with S. The data was however not statistically significant (data not shown). Therefore, it is possible that other variant/s within the congenic segment independently influence the expression of Mbd2 . The studies above

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Gene: RFFL - ring finger and FYVE-like domain containing E3 ubiquitin protein ligase - (NCBI)

Protein : 1y02

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