Using a sample of 105 families identified and studied in Seattle in the early 1970s, the overall objectives of this project are 1) to determine prospectively the role of elevated plasma triglyceride (TG) as a risk factor for 20-year coronary heart disease (CHD) mortality in familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG), the familial forms of hypertriglyceridemia, and 2) to perform genetic epidemiologic studies of recently identified lipoprotein risk factors for CHD, including Atherogenic Lipoprotein Phenotypes (ALP) based on subclasses of low-density lipoproteins (LDL), Lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B plasma levels, and apo E isoforms.
The specific aims of this study are: 1) To determine if 20-year CHD mortality and all-cause mortality are increased in siblings and offspring of probands from families with FCHL and FHTG, compared to a group of married-in spouse controls, and determine if elevated plasma TG at baseline predicts 20-year CHD mortality in these family members; 2) Based on new blood samples from these same families, to investigate the inheritance of LAP phenotypes, to examine the association of elevated plasma Lp(a) and apo B levels with parental CHD mortality, and to investigate the association of lipid levels with apo E isoforms; 3) To establish a repository of frozen white blood cells and plasma aliquots for future genetic studies. These hypotheses will be addressed by determining the vital status of 1009 family members in the 105 families, carefully classifying the cause of death as CHD or not for deceased family members, and by obtaining a new blood samples from 3-generations of these families, including both local and non-local relatives. New personal and family history medical questionnaires will also be completed for each participant. This project will provide valuable new data on the role of triglyceride as a risk factor for CHD and on the genetic epidemiology of lipoprotein risk factors, using the only existing sample of families with hypertriglyceridemia that can be studied prospectively.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Epidemiology and Disease Control Subcommittee 2 (EDC)
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University of Washington
Schools of Public Health
United States
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Hutter, Carolyn M; Austin, Melissa A; Humphries, Steve E (2004) Familial hypercholesterolemia, peripheral arterial disease, and stroke: a HuGE minireview. Am J Epidemiol 160:430-5
Austin, Melissa A; Hutter, Carolyn M; Zimmern, Ron L et al. (2004) Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol 160:421-9
Austin, Melissa A; Hutter, Carolyn M; Zimmern, Ron L et al. (2004) Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 160:407-20
Ayyobi, Amir F; McGladdery, Sandra H; McNeely, Marguerite J et al. (2003) Small, dense LDL and elevated apolipoprotein B are the common characteristics for the three major lipid phenotypes of familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 23:1289-94
Austin, Melissa A; Edwards, Karen L; Monks, Stephanie A et al. (2003) Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia. J Lipid Res 44:2161-8
Austin, Melissa A; Zimmern, Ron L; Humphries, Steve E (2002) High ""population attributable fraction"" for coronary heart disease mortality among relatives in monogenic familial hypercholesterolemia. Genet Med 4:275-8
McNeely, M J; Edwards, K L; Marcovina, S M et al. (2001) Lipoprotein and apolipoprotein abnormalities in familial combined hyperlipidemia: a 20-year prospective study. Atherosclerosis 159:471-81
Kim, H; Marcovina, S M; Edwards, K L et al. (2001) Lipoprotein(a) as a risk factor for maternal cardiovascular disease mortality in kindreds with familial combined hyperlipidemia or familial hypertriglyceridemia. Clin Genet 60:188-97
Kamigaki, A S; Siscovick, D S; Schwartz, S M et al. (2001) Low density lipoprotein particle size and risk of early-onset myocardial infarction in women. Am J Epidemiol 153:939-45
Austin, M A (2000) Triglyceride, small, dense low-density lipoprotein, and the atherogenic lipoprotein phenotype. Curr Atheroscler Rep 2:200-7

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