A substantial genetic contribution underlies steady state peripheral blood counts. Notably, baseline hematological parameters are significant, independent risk factors for early mortality, heart disease and stroke in the general population, and for disease severity in sickle cell disease and thalassemia. In preliminary quantitative trait locus/loci (QTL) analyses in mice, we have identified specific chromosomal regions influencing multiple baseline hematological parameters, including red blood cell (RBC) count, hemoglobin (Hgb) and hematocrit (Hct) levels, and mean corpuscular volume (MCV). Based on these preliminary studies, we hypothesize that novel genes which significantly impact normal hematopoiesis exist and propose an unbiased approach to begin unraveling this genetic network, focusing on erythropoietic traits.
The specific aims are to:
Aim 1. Analyze F2 intercrosses to identify chromosome regions influencing baseline hematological traits. We will (a) add additional F2 animals and polymorphic markers to narrow existing QTL intervals identified for RBC count, Hgb, Hct, MCV, and MCH QTL;and (b) establish and analyze three new crosses to identify additional QTL, generating at least 500 F2 animals in each.
Aim 2. Narrow QTL intervals using genomic, statistical, and bioinformatic approaches. We will utilize genomic and in silico approaches to narrow QTL intervals. In silico analyses will include combined cross analysis, a statistical method developed by Co-Pi Dr. Gary Churchill, and haplotype analysis.
Aim 3. Identify and analyze candidate genes. We will pursue candidate gene analysis for the most robust QTL identified in Aims 1 and 2. Furthermore, we will make available publicly all QTL intervals identified, allowing any investigator to immediately pursue candidate gene analysis in animal models and in human populations by association studies. Relevance to Public Health: Genes regulating peripheral blood traits profoundly influence disease outcome in man. Identifying the primary genetic determinants of baseline peripheral blood traits will enhance our understanding of blood formation and provide novel diagnostic and therapeutic targets for hematological and cardiovascular pathologies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085480-03
Application #
7589833
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Luksenburg, Harvey
Project Start
2007-04-06
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
3
Fiscal Year
2009
Total Cost
$435,000
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Rivera, Alicia; Zee, Robert Y L; Alper, Seth L et al. (2013) Strain-specific variations in cation content and transport in mouse erythrocytes. Physiol Genomics 45:343-50
Peters, Luanne L; Shavit, Jordan A; Lambert, Amy J et al. (2010) Sequence variation at multiple loci influences red cell hemoglobin concentration. Blood 116:e139-49