Atherosclerosis is the major cause of morbidity and mortality in the western world. Studies of atherosclerosis in human subjects are complicated by non- Mendelian inheritance, genetic heterogeneity, a late age of onset, incomplete penetrance, and environmental influences. However, recent advances, including our improved ability to delineate the abnormal physiology related to insulin resistance and associated metabolic syndrome, the ability to assess preclinical physiological and structural aspects of the atherosclerotic process, the discovery of highly polymorphic molecular genetic markers, the development of new strategies for analysis of complex traits, and the relevant statistic programs have put the identification of genes making even modest contributions to the disease within reach. As a consequence, the rate limiting step in gene identification is the study of families in sufficient physiologic detail and in adequate sample size to match the power of the genetic marker and analytic technology. The goal of Project 2 is to utilize our experience in detailed extensive family phenotyping to identify specific genes and regions within the human genome contributing to intermediate phenotypes for atherosclerosis with particular emphasis on structural changes in the vessel wall, defined by a ultrasound assessment of carotid intimal medial thickness (IMT), and insulin resistance and components of the associated metabolic syndrome. A systematic mapping approach is particular appropriate since there are so many potential candidate genes for the various components of the atherosclerosis process. We therefore propose a two stage design consisting of an initial whole genome scan with a 10cM map, followed by fine mapping in selected regions, then confirming the linkage in an independent sample, using highly polymorphic molecular markers in 2 sets of approximately 112 each of extensively phenotyped Mexican-American families with a total of over 1800 sibpairs. The regions for fine mapping will be selected on the basis of the significance level of the linkage analyses, existence of known candidate genes or mouse syntenic regions. The confirmed linkages will be further examined by candidate gene association and stratified analyses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL060030-02
Application #
6341031
Study Section
Project Start
2000-08-20
Project End
2001-07-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$350,116
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Jo Hodonsky, Chani; Schurmann, Claudia; Schick, Ursula M et al. (2018) Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE Study. Am J Hematol :
Kerr, Kathleen F; Avery, Christy L; Lin, Henry J et al. (2017) Genome-wide association study of heart rate and its variability in Hispanic/Latino cohorts. Heart Rhythm 14:1675-1684
Kuo, Jane Z; Wong, Tien Y; Rotter, Jerome I (2014) Challenges in elucidating the genetics of diabetic retinopathy. JAMA Ophthalmol 132:96-107
Langfelder, Peter; Castellani, Lawrence W; Zhou, Zhiqiang et al. (2012) A systems genetic analysis of high density lipoprotein metabolism and network preservation across mouse models. Biochim Biophys Acta 1821:435-47
Ranganathan, Gouri; Unal, Resat; Pokrovskaya, Irina D et al. (2012) The lipoprotein lipase (LPL) S447X gain of function variant involves increased mRNA translation. Atherosclerosis 221:143-7
Goodarzi, Mark O; Lehman, Donna M; Taylor, Kent D et al. (2007) SORCS1: a novel human type 2 diabetes susceptibility gene suggested by the mouse. Diabetes 56:1922-9
Davis, Richard C; Jin, Angela; Rosales, Melenie et al. (2007) A genome-wide set of congenic mouse strains derived from CAST/Ei on a C57BL/6 background. Genomics 90:306-13
Li, Xiaohui; Quinones, Manuel J; Wang, Dai et al. (2006) Genetic effects on obesity assessed by bivariate genome scan: the Mexican-American coronary artery disease study. Obesity (Silver Spring) 14:1192-200
Estrada-Smith, Daria; Collins, Alan R; Wang, Xuping et al. (2006) Impact of chromosome 2 obesity loci on cardiovascular complications of insulin resistance in LDL receptor-deficient C57BL/6 mice. Diabetes 55:2265-71
Goodarzi, Mark O; Quinones, Manuel J; Azziz, Ricardo et al. (2005) Polycystic ovary syndrome in Mexican-Americans: prevalence and association with the severity of insulin resistance. Fertil Steril 84:766-9

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