TY - JOUR
T1 - Characterization of biological pathways associated with a 1.37 Mbp genomic region protective of hypertension in Dahl S rats
AU - Cowley, Allen W.
AU - Moreno, Carol
AU - Jacob, Howard J.
AU - Peterson, Christine B.
AU - Stingo, Francesco C.
AU - Ahn, Kwang Woo
AU - Liu, Pengyuan
AU - Vannucci, Marina
AU - Laud, Purushottam W.
AU - Reddy, Prajwal
AU - Lazar, Jozef
AU - Evans, Louise
AU - Yang, Chun
AU - Kurth, Theresa
AU - Liang, Mingyu
PY - 2014/6/1
Y1 - 2014/6/1
N2 - The goal of the present study was to narrow a region of chromosome 13 to only several genes and then apply unbiased statistical approaches to identify molecular networks and biological pathways relevant to blood-pressure salt sensitivity in Dahl salt-sensitive (SS) rats. The analysis of 13 overlapping subcongenic strains identified a 1.37 Mbp region on chromosome 13 that influenced the mean arterial blood pressure by at least 25 mmHg in SS rats fed a high-salt diet. DNA sequencing and analysis filled genomic gaps and provided identification of five genes in this region, Rfwd2, Fam5b, Astn1, Pappa2, and Tnr. A cross-platform normalization of transcriptome data sets obtained from our previously published Affymetrix GeneChip dataset and newly acquired RNA-seq data from renal outer medullary tissue provided 90 observations for each gene. Two Bayesian methods were used to analyze the data: 1) a linear model analysis to assess 243 biological pathways for their likelihood to discriminate blood pressure levels across experimental groups and 2) a Bayesian graphical modeling of pathways to discover genes with potential relationships to the candidate genes in this region. As none of these five genes are known to be involved in hypertension, this unbiased approach has provided useful clues to be experimentally explored. Of these five genes, Rfwd2, the gene most strongly expressed in the renal outer medulla, was notably associated with pathways that can affect blood pressure via renal transcellular Na+ and K+ electrochemical gradients and tubular Na+ transport, mitochondrial TCA cycle and cell energetics, and circadian rhythms.
AB - The goal of the present study was to narrow a region of chromosome 13 to only several genes and then apply unbiased statistical approaches to identify molecular networks and biological pathways relevant to blood-pressure salt sensitivity in Dahl salt-sensitive (SS) rats. The analysis of 13 overlapping subcongenic strains identified a 1.37 Mbp region on chromosome 13 that influenced the mean arterial blood pressure by at least 25 mmHg in SS rats fed a high-salt diet. DNA sequencing and analysis filled genomic gaps and provided identification of five genes in this region, Rfwd2, Fam5b, Astn1, Pappa2, and Tnr. A cross-platform normalization of transcriptome data sets obtained from our previously published Affymetrix GeneChip dataset and newly acquired RNA-seq data from renal outer medullary tissue provided 90 observations for each gene. Two Bayesian methods were used to analyze the data: 1) a linear model analysis to assess 243 biological pathways for their likelihood to discriminate blood pressure levels across experimental groups and 2) a Bayesian graphical modeling of pathways to discover genes with potential relationships to the candidate genes in this region. As none of these five genes are known to be involved in hypertension, this unbiased approach has provided useful clues to be experimentally explored. Of these five genes, Rfwd2, the gene most strongly expressed in the renal outer medulla, was notably associated with pathways that can affect blood pressure via renal transcellular Na+ and K+ electrochemical gradients and tubular Na+ transport, mitochondrial TCA cycle and cell energetics, and circadian rhythms.
KW - Bayesian analysis
KW - Chromosome 13
KW - Dahl S rats
KW - Pathway analysis
KW - Salt-sensitive hypertension
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U2 - 10.1152/physiolgenomics.00179.2013
DO - 10.1152/physiolgenomics.00179.2013
M3 - Article
C2 - 24714719
AN - SCOPUS:84901718506
SN - 1094-8341
VL - 46
SP - 398
EP - 410
JO - Physiological genomics
JF - Physiological genomics
IS - 11
ER -