Characterization of biological pathways associated with a 1.37 Mbp genomic region protective of hypertension in Dahl S rats.
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.
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; acowley@mcw.edu.
Allen W
AW
Cowley
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin;
Carol
C
Moreno
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin;
Howard J
HJ
Jacob
Department of Statistics, Rice University, Houston, Texas.
Christine B
CB
Peterson
Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas; and.
Francesco C
FC
Stingo
Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin;
Kwang Woo
KW
Ahn
Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin;
Pengyuan
P
Liu
Department of Statistics, Rice University, Houston, Texas.
Marina
M
Vannucci
Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin;
Purushottam W
PW
Laud
Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin;
Prajwal
P
Reddy
Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin;
Jozef
J
Lazar
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
Louise
L
Evans
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
Chun
C
Yang
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
Theresa
T
Kurth
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
Mingyu
M
Liang
D000818:Animals; D062186:Arterial Pressure / Q000235:genetics; D001499:Bayes Theorem; D002940:Circadian Rhythm / Q000235:genetics; D002952:Citric Acid Cycle / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D016678:Genome / Q000235:genetics*; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000235:genetics; D011188:Potassium / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D017422:Sequence Analysis, DNA / Q000379:methods; D015398:Signal Transduction / Q000235:genetics*; D012964:Sodium / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000378:metabolism
D017673:Sodium Chloride, Dietary; D012964:Sodium; D011188:Potassium
Bayesian analysis; Dahl S rats; chromosome 13; pathway analysis; salt-sensitive hypertension