Transcriptional profiling with a blood pressure QTL interval-specific oligonucleotide array.

Although the evidence for a genetic predisposition to human essential hypertension is compelling, the genetic control of blood pressure (BP) is poorly understood. The Dahl salt-sensitive (S) rat is a model for studying the genetic component of BP. Using this model, we previously reported the identification of 16 different genomic regions that contain one or more BP quantitative trait loci (QTLs). The proximal region of rat chromosome 1 contains multiple BP QTLs. Of these, we have localized the BP QTL1b region to a 13.5-cM (20.92 Mb) region. Interestingly, five additional independent studies in rats and four independent studies in humans have reported genetic linkage for BP control by regions homologous to QTL1b. To view the overall renal transcriptional topography of the positional candidate genes for this QTL, we sought a comparative gene expression profiling between a congenic strain containing QTL1b and control S rats by employing 1) a saturated QTL1b interval-specific oligonucleotide array and 2) a whole genome cDNA microarray representing 20,465 unique genes that are positioned outside the QTL. Results indicated that 17 of the 231 positional candidate genes for this QTL are differentially expressed between the two strains tested. Surprisingly, >1,500 genes outside of QTL1b were differentially expressed between the two rat strains. Integrating the results from the two approaches revealed at least one complex network of transcriptional control initiated by the positional candidate Nr2f2. This network appears to account for the majority of gene expression differences occurring outside of the QTL interval. Further substitution mapping is currently underway to test the validity of each of these differentially expressed positional candidate genes. These results demonstrate the importance of using a saturated oligonucleotide array for identifying and prioritizing differentially expressed positional candidate genes of a BP QTL.

[1]  N. Lee,et al.  Genomic approaches for reconstructing gene networks. , 2005, Pharmacogenomics.

[2]  Juan F Medrano,et al.  Real-time PCR for mRNA quantitation. , 2005, BioTechniques.

[3]  A. Dominiczak,et al.  Reduction of Gstm1 Expression in the Stroke-Prone Spontaneously Hypertension Rat Contributes to Increased Oxidative Stress , 2005, Hypertension.

[4]  D. Ganten,et al.  Identification of Hypertension-Related Genes Through an Integrated Genomic-Transcriptomic Approach , 2005, Circulation research.

[5]  M. Fornage,et al.  Combined Genealogical, Mapping, and Expression Approaches to Identify Spontaneously Hypertensive Rat Hypertension Candidate Genes , 2005, Hypertension.

[6]  E. Petretto,et al.  Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease , 2005, Nature Genetics.

[7]  J. Dutil,et al.  Combining congenic coverage with gene profiling in search of candidates for blood pressure quantitative trait loci in Dahl rats. , 2004, Hypertension research : official journal of the Japanese Society of Hypertension.

[8]  Y. Yazaki,et al.  Isolation of a Chromosome 1 Region Affecting Blood Pressure and Vascular Disease Traits in the Stroke-Prone Rat Model , 2003, Hypertension.

[9]  Douglas A. Hosack,et al.  Identifying biological themes within lists of genes with EASE , 2003, Genome Biology.

[10]  M. Tsai,et al.  Molecular mechanism of chicken ovalbumin upstream promoter-transcription factor (COUP-TF) actions. , 2003, The Keio journal of medicine.

[11]  T. Nabika,et al.  Exaggerated response to restraint stress in rats congenic for the chromosome 1 blood pressure quantitative trait locus , 2003, Clinical and experimental pharmacology & physiology.

[12]  M. Garrett,et al.  Defining the blood pressure QTL on Chromosome 7 in Dahl rats by a 177-kb congenic segment containing Cyp11b1 , 2003, Mammalian Genome.

[13]  A. Chakravarti,et al.  Erythrocyte Sodium-Lithium Countertransport and Blood Pressure: A Genome-Wide Linkage Study , 2003, Hypertension.

[14]  A. Dominiczak,et al.  Microarray Analysis of Rat Chromosome 2 Congenic Strains , 2003, Hypertension.

[15]  N. Hübner,et al.  Interaction between blood pressure quantitative trait loci in rats in which trait variation at chromosome 1 is conditional upon a specific allele at chromosome 10. , 2003, Human molecular genetics.

[16]  Yoav Benjamini,et al.  Identifying differentially expressed genes using false discovery rate controlling procedures , 2003, Bioinform..

[17]  M. Olivier,et al.  Insights into Dahl salt-sensitive hypertension revealed by temporal patterns of renal medullary gene expression. , 2003, Physiological genomics.

[18]  D. Ganten,et al.  Congenic strains confirm the presence of salt-sensitivity QTLs on chromosome 1 in the Sabra rat model of hypertension. , 2003, Physiological genomics.

[19]  Alexander E. Kel,et al.  TRANSFAC®: transcriptional regulation, from patterns to profiles , 2003, Nucleic Acids Res..

[20]  T. Kurtz,et al.  Gene expression profiling in hypertension research: a critical perspective. , 2003, Hypertension.

[21]  F. Cohen,et al.  Expression profiling of the schizont and trophozoite stages of Plasmodium falciparum with a long-oligonucleotide microarray , 2003, Genome Biology.

[22]  John Quackenbush,et al.  Assessing unmodified 70-mer oligonucleotide probe performance on glass-slide microarrays , 2003, Genome Biology.

[23]  M. Garrett,et al.  Identification of blood pressure quantitative trait loci that differentiate two hypertensive strains , 2002, Journal of hypertension.

[24]  Jerry Li,et al.  Within the fold: assessing differential expression measures and reproducibility in microarray assays , 2002, Genome Biology.

[25]  John Quackenbush,et al.  Identification of Src transformation fingerprint in human colon cancer , 2002, Oncogene.

[26]  N. Samani,et al.  Kidney Specificity of Rat Chromosome 1 Blood Pressure Quantitative Trait Locus Region , 2002, Hypertension.

[27]  J. Crabbe,et al.  Congenic Mapping of Alcohol and Pentobarbital Withdrawal Liability Loci to a <1 Centimorgan Interval of Murine Chromosome 4: Identification of Mpdz as a Candidate Gene , 2002, The Journal of Neuroscience.

[28]  H. Jacob,et al.  Renal medullary genes in salt-sensitive hypertension: a chromosomal substitution and cDNA microarray study. , 2002, Physiological genomics.

[29]  S. Dudoit,et al.  Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. , 2002, Nucleic acids research.

[30]  G. Peltz,et al.  Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus. , 2001, Immunity.

[31]  L. Schild,et al.  Trafficking and cell surface stability of ENaC. , 2001, American journal of physiology. Renal physiology.

[32]  K. Moremen,et al.  Overexpression of the Golgi-localized enzyme alpha-mannosidase IIx in Chinese hamster ovary cells results in the conversion of hexamannosyl-N-acetylchitobiose to tetramannosyl-N-acetylchitobiose in the N-glycan-processing pathway. , 2001, European journal of biochemistry.

[33]  J. Liu,et al.  High-resolution mapping of the blood pressure QTL on chromosome 7 using Dahl rat congenic strains. , 2001, Genomics.

[34]  M. Garrett,et al.  Multiple blood pressure QTL on rat chromosome 1 defined by Dahl rat congenic strains. , 2001, Physiological genomics.

[35]  G. Peltz,et al.  Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma , 2000, Nature Immunology.

[36]  H. Jacob,et al.  New target regions for human hypertension via comparative genomics. , 2000, Genome research.

[37]  J P Rapp,et al.  Genetic analysis of inherited hypertension in the rat. , 2000, Physiological reviews.

[38]  N. Schork,et al.  Mapping of a blood pressure quantitative trait locus to chromosome 15q in a Chinese population. , 1999, Human molecular genetics.

[39]  N. Hübner,et al.  Congenic substitution mapping excludes Sa as a candidate gene locus for a blood pressure quantitative trait locus on rat chromosome 1. , 1999, Hypertension.

[40]  T. Niu,et al.  An extreme-sib-pair genome scan for genes regulating blood pressure. , 1999, American journal of human genetics.

[41]  E. Boerwinkle,et al.  Genome-wide linkage analyses of systolic blood pressure using highly discordant siblings. , 1999, Circulation.

[42]  James Scott,et al.  Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats , 1999, Nature Genetics.

[43]  M. Tsai,et al.  Chick ovalbumin upstream promoter-transcription factors (COUP-TFs): coming of age. , 1997, Endocrine reviews.

[44]  S. Eto,et al.  Structure and transcriptional regulation of human alpha-mannosidase IIX (alpha-mannosidase II isotype) gene. , 1996, European journal of biochemistry.

[45]  J. Rapp,et al.  Development and characteristics of inbred strains of Dahl salt-sensitive and salt-resistant rats. , 1985, Hypertension.