BACKGROUND:

Heart disease, with coronary heart disease as the main form, and stroke are respectively the first and third most common causes of death in the Unites States. Hypertension, diabetes, hyperlipidemia, and cigarette smoking have been demonstrated to be major risk factors for coronary heart disease and stroke. The first three risk factors have all been suggested to be determined in some degree by genetic factors.

In 1975 the National Heart and Lung Institute convened a Task Force on Genetic Factors in Atherosclerotic Disease to review what was known in the field and to identify fruitful research priorities for future study. The Task Force recommended utilizing existing genealogical files, sampling and studying large kindreds from a general population, evaluating both genetic and modifying factors, and encouraging collaborative studies by epidemiologists, biostatisticians and population geneticists.

The Utah population was well suited for a study of coronary prone pedigrees. The high birth rate and polygamy in ancestral founders of the state produced very large pedigrees. Pedigrees were relatively easy to find and trace with available genealogical records.

DESIGN NARRATIVE:

A computer data base of Utah residents was developed which included 1.2 million persons in genealogical files, 240,000 persons in death certificate files and 120,000 persons in Health Family Tree questionnaire files. Over 1,400 persons who were members of 21 coronary prone pedigrees were clinically screened.

Death certificate files were used to identify early coronary deaths which were defined as before age 55 in men and before age 65 in women. Mail and phone contacts were made to the surviving offspring, spouses, or siblings of the deceased proband to determine risk factor profiles for probands and close relatives. Hospital charts were also abstracted to assess risk factor profiles for probands. Clinical screening of the relatives of coronary probands were conducted using a detailed protocol assessing all standard coronary risk factors. Fasting blood tests were obtained for total cholesterol, triglycerides, high density lipoprotein, apo B, apo A-1, and apo E. At clinical screening, information was obtained on relationships, dates and places of vital events for the index person, spouse, offspring, siblings, parents, aunts and uncles, grandparents, grand aunts and uncles, and great-grandparents. Information was obtained on blood pressure, height, weight, electrocardiograms, physician's history and physical examination.

Information was also collected on tobacco and alcohol use, hospitalization, medication usage, socioeconomic status, Type A personality, physical activity, and reproductive history.

Beginning in 1983 the investigators expanded the collection of computerized detailed family histories from the families of high school students participating in the Health Family Trees, a required health education course. Using the Health Family Trees, siblings were identified in which two or more siblings had early coronary heart disease. The information from the Health Family Trees was validated by contacting affected relatives and by collecting hospital data. These individuals then attended clinic screening. Detailed biochemical analyses of blood samples from these individuals were compared to find abnormalities that occured in both siblings with coronary heart disease and to identify specific subtypes of inherited early coronary disease. Testing for genetic linkage of DNA markers for apolipoproteins with these specific abnormalities was also done. Healthy age-sex matched controls with at least three siblings and no coronary heart disease in siblings or parents served as controls.