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Characterization of biological pathways associated with a 1.37 Mbp genomic region protective of hypertension in Dahl S rats. Physiol Genomics 2014 Jun 01;46(11):398-410 PMID: 24714719 PMCID: PMC4042181

Pubmed ID

24714719

Abstract

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.

Author List

Cowley AW Jr, Moreno C, Jacob HJ, Peterson CB, Stingo FC, Ahn KW, Liu P, Vannucci M, Laud PW, Reddy P, Lazar J, Evans L, Yang C, Kurth T, Liang M

Authors

Kwang Woo Ahn PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Allen W. Cowley Jr PhD Professor in the Physiology department at Medical College of Wisconsin
Purushottam W. Laud PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Mingyu Liang PhD Center Director, Professor in the Physiology department at Medical College of Wisconsin
Pengyuan Liu PhD Adjunct Associate Professor in the Physiology department at Medical College of Wisconsin




Scopus

2-s2.0-84901718506   9 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Arterial Pressure
Bayes Theorem
Circadian Rhythm
Citric Acid Cycle
Gene Expression Profiling
Genome
Hypertension
Male
Mitochondria
Potassium
Rats
Rats, Inbred Dahl
Sequence Analysis, DNA
Signal Transduction
Sodium
Sodium Chloride, Dietary
jenkins-FCD Prod-300 626508253d14e4184314fb9f66322a03a5906796