The long-term goal of this project is to understand genetic susceptibility to cardiovascular disease (CVD) and non-insulin dependent diabetes mellitus (NIDDM) in Japanese-American kindreds by characterizing the genetic basis of the risk factors of the metabolic syndrome (insulin resistance syndrome). During the first four years of the project, three specific aims are being addressed, as follow: 1) to determine if variation in the diameter of the major low-density lipoprotein subclass (LDL size) is inherited as a single gene trait in Japanese-American families, and to determine if LDL size is associated with risk factors of the syndrome; 2) to characterize the inheritance of lipoprotein (a) and apolipoprotein (a) isoforms in Japanese Americans; and 3) to establish a repository of white blood cells and plasma aliquots for genetic studies.
These aims will be accomplished by the end of the initial 4-year project period, based on data from 400 study participants, including pedigree information, extensive laboratory results, medical history questionnaire data and nutritional data. The project proposed here will enhance these studies by recruiting and sampling approximately 350 additional relatives of local, married-in Japanese-American spouses, with 3 new specific aims: 1) to identify genetic influences on the risk factors that characterize the syndrome (including fasting insulin, proinsulin, C-peptide and glucose; body weight and waist circumference; lipoproteins; blood pressure; fibrinogen, factor VII and plasminogen activator inhibitor-1) using statistical genetic analysis approaches, including univariate complex segregation analysis, factor analysis, and quantitative multivariate genetic analysis; 2) to test for genetic linkage between specific candidate genes involved in lipid metabolism, carbohydrate metabolism, blood pressure, obesity, and hemostasis with genetically influenced risk factors of the metabolic syndrome in Japanese-Americans, using established linkage analysis approaches in sibships and in kindreds; and 3) when the DNA repository has been completed (750 samples by the end of year 4), to apply to the NHLBI Mammalian Genotyping Service to perform a whole genome screen to identify new genes involved in susceptibility to the metabolic syndrome. The investigators state that the studies proposed in this renewal application represent effective ways to characterize genetic susceptibility to the metabolic syndrome and subsequent risk of cardiovascular disease and non-insulin-dependent diabetes among Japanese-American families, and may lead to targeted intervention strategies to prevent these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050268-09
Application #
6537071
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Sholinsky, Phyliss
Project Start
1994-01-01
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2004-05-31
Support Year
9
Fiscal Year
2002
Total Cost
$246,410
Indirect Cost
Name
University of Washington
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Pierce, Brandon L; Austin, Melissa A; Crane, Paul K et al. (2007) Measuring dietary acculturation in Japanese Americans with the use of confirmatory factor analysis of food-frequency data. Am J Clin Nutr 86:496-503
Hutter, Carolyn M; Austin, Melissa A; Farin, Federico M et al. (2006) Association of endothelial lipase gene (LIPG) haplotypes with high-density lipoprotein cholesterol subfractions and apolipoprotein AI plasma levels in Japanese Americans. Atherosclerosis 185:78-86
Austin, M A; Zhang, C; Humphries, S E et al. (2004) Heritability of C-reactive protein and association with apolipoprotein E genotypes in Japanese Americans. Ann Hum Genet 68:179-88
Austin, Melissa A; Talmud, Philippa J; Farin, Federico M et al. (2004) Association of apolipoprotein A5 variants with LDL particle size and triglyceride in Japanese Americans. Biochim Biophys Acta 1688:1-9
Austin, Melissa A; Edwards, Karen L; McNeely, Marguerite J et al. (2004) Heritability of multivariate factors of the metabolic syndrome in nondiabetic Japanese americans. Diabetes 53:1166-9
Austin, M A; Rodriguez, B L; McKnight, B et al. (2000) Low-density lipoprotein particle size, triglycerides, and high-density lipoprotein cholesterol as risk factors for coronary heart disease in older Japanese-American men. Am J Cardiol 86:412-6
Austin, M A (1996) Genetic epidemiology of dyslipidaemia and atherosclerosis. Ann Med 28:459-63