The collection of maladies including obesity, dyslipidemia, insulin resistance and hypertension is referred to as the metabolic syndrome and is a major risk factor for cardiovascular disease. Its incidence continues to rise, in part as a result of the epidemic increase in obesity. The Lyon Hypertensive (LH) rat is a powerful inbred model for dissecting the genetic contributions of the human metabolic syndrome, with high body weight, cholesterol, triglycerides, and insulin/glucose ratios, and salt-sensitive hypertension. Interestingly, the Lyon normotensive (LN) control strain, concurrently selected from the same SD colony, is genetically quite similar (85%) to the LH, but phenotypically very distinct. Genetic linkage mapping in an LH x LN intercross identified 3 clusters of Quantitative Traits Loci (QTL) on rat chromosome (RNO) 17 for multiple features of the metabolic syndrome in the LH rat and 3 QTL for blood pressure on RNO17, 2, and 13. We hypothesize that the LH chromosome 17 has genes contributing to all major traits of the metabolic syndrome, and that there are QTL interactions between QTL on RNO 17 and between RNO 17, 2, and 13. To identify at least one of these genes, we propose a combined traditional positional cloning, in silico mapping, and QTL (phenotype and gene expression) mapping to identify causal genes and pathways leading to the metabolic syndrome. We will: 1: Validate the QTL regions for RNO17 in the LH and LN strains. The close genetic identity of the LH and LN strains allows for rapid generation and characterization of a consomic LH-17LN strain and congenic substrains. These strains will be used to narrow the QTL regions and to determine which phenotypes are due to multiple QTL, interacting QTL, or pleiotropic effects of a single gene within a QTL. 2: Investigate interactions between trans-acting and cis-acting haplotypes on traits underlying the metabolic syndrome. We will perform an F2 intercross between LH and LN to determine the interactions between QTL on RNO17, 2, and 13, and regulatory networks causing the phenotypes we observe in the LH. The offspring will be comprehensively studied by phenotyping, SNP genotyping, and gene expression profiling for combined phenotype (p) QTL and expression (e) QTL mapping. 3: Refine the QTL on RNO17 through SNP fine-mapping and experimental validation in congenic rats. For each candidate region, we will fine-map the haplotypes by additional SNP typing to narrow and define minimal QTL intervals. All genetic variation will be determined in these minimal regions to identify candidate genes and sequence variants. These regions will be experimentally validated in the congenics. 4: Validate functional variants through rat transgenic rescue. For the strongest candidate with evidence of functional sequence variants identified in the above aims, we will develop a transgenic rat, either introducing the LN allele into the LH rat or the LH allele into the LH-17LN.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL089895-04S1
Application #
8411732
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2008-06-01
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$186,391
Indirect Cost
$62,953
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Atanur, Santosh S; Diaz, Ana Garcia; Maratou, Klio et al. (2013) Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat. Cell 154:691-703
Park, Sungmi; Lu, Ko-Ting; Liu, Xuebo et al. (2013) Allele-specific expression of angiotensinogen in human subcutaneous adipose tissue. Hypertension 62:41-7
Gilibert, Sophie; Bataillard, Alain; Nussberger, Juerg et al. (2009) Implication of chromosome 13 on hypertension and associated disorders in Lyon hypertensive rats. J Hypertens 27:1186-93
Gilibert, S; Kwitek, A E; Hubner, N et al. (2008) Effects of chromosome 17 on features of the metabolic syndrome in the Lyon hypertensive rat. Physiol Genomics 33:212-7