A Population Perspective for Genetics Research and Applications to Control Cardiovascular Disease in Utah

Summary

A sample of high risk families with early coronary heart disease (CHD) and hypertension (HBP) has been objectively ascertained from the general Utah population for both research efforts and public health applications regarding genetic predisposition to cardiovascular disease. Death certificates linked to population genealogical data were used to ascertain large multigenerational pedigrees. Detailed “health family tree” questionnaires obtained from the parents of 40 000 high school students have been used more recently to ascertain sibships with two or more affected siblings with either early hypertension or early coronary heart disease. Detailed biochemical and genetic studies have been performed for 4000 participants from 2500 families evaluated over the past 14 years at the Cardiovascular Genetics Research Clinic.

For both coronary heart disease and hypertension, familial aggregation is strong and due mostly to genetic factors rather than shared family environment. As expected, lipid abnormalities were up to five times more common among coronary siblings than in the general population, but hypertensive siblings also showed up to four times more frequent lipid abnormalities than the general population. Familial dyslipidemic hypertension (FDH) was defined as two or more siblings having both hypertension and lipid abnormalities before age 60. About 12 % of persons with hypertension have this disorder and also have increased risk of coronary heart disease. Persons with FDH often have elevated fasting insulin levels and either familial combined hyperlipidemia or central obesity. Persons with a point mutation for lipoprotein lipase seem to have more hypertension and lipid abnormalities and may help explain a subset of FDH. Understanding and diagnosing FDH has practical application since it leads to better diagnosis and treatment of lipid abnormalities both in index cases with hypertension and in their close relatives who share their risk.

Segregation analysis in hypertensive families has detected seven recessive “intermediate phenotypes” with high heritability and some association with hypertension. These include urinary kallikrein excretion, sodium-lithium countertransport, intraerythrocytic sodium concentration, number of erythrocytic sites of the sodium potassium ATPase pump, a relative fat pattern index, knee width, and possibly fasting plasma insulin levels. A seven year prospective study found several variables were independent predictors of the future occurrence of hypertension, including the high sodium-lithium countertransport genotype, a positive family history, uric acid, phosphate, systolic blood pressure, change in diastolic blood pressure during bicycle exercise, change in diastolic blood pressure during handgrip exercise, and scapular skinfold thickness.

Three approaches to genetic linkage studies have been illustrated by a test for genetic linkage of recessive high sodium-lithium countertransport with the antiporter gene of the sodium hydrogen exchange system. No cosegregation was found in extended pedigrees, no increased sharing of alleles was found between hypertensive siblings, and there was no correlation between similar SLC levels in siblings and increased sharing of alleles. These three approaches will be used in further tests for genetic linkage of traits related to hypertension.

Characterization of families with two or more living siblings with early CHD revealed several common syndromes: familial combined hyperlipidemia (FCHL) in 36 %, familial dyslipidemic hypertension (FDH) in 21 %, low high density lipoprotein (HDL)-cholesterol in 15 % (with considerable overlap of FDH with FCHL and low HDL); high Lp(a) in 16 %, high homocyst(e)ine in 6 %, familial hypercholesterolemia (FH) in 3 % and type III hyperlipidemia in 3 %.

A prototype for helping high risk families is sponsored by the U.S. Centers for Disease Control and has been given the title MED PED (Tracing Medical Pedigrees to Foster More Early Diagnoses and Prevent Early Deaths). The goal is to find and help all persons in Utah with FH. Index cases with confirmed FH are collected from physicians and laboratories, high risk relatives are identified and screened for FH, and a computer registry tracks the results of screening and treatment. Coordinated efforts in population genetics can lead to effective research and help initiate public health measures to help families with high risk of cardiovascular disease.

Supported by two grants (HL24855-11 and HL21088-14) from the National Heart, Lung and Blood Institute, Bethesda, MD, USA and a cooperative agreement with the U.S. Centers for Disease Control, Atlanta, GA, USA. Public helath applications to control cardiovascular disease in high risk families is a joint project with the Bureau of Chronic Disease Control of the Utah Department of Health