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Molecular Genetics of Hypertension and its Complications

Donna K. Arnett, Ph.D.
University of Minnesota

Hypertension affects 25-55% of middle age Americans across various ethnic subgroups, making it a public health issue of considerable magnitude. Despite the ready availability of treatment, only 27% of hypertensive Americans ages 18-74 have systolic or diastolic blood pressures below 140/90 mmHg, and even fewer older Americans are at this goal blood pressure. Although prevention of hypertension is a national priority, we do not yet know how to effectively target preventive measures. Identification of the genes contributing to interindividual blood pressure variation and hypertension may allow for primordial prevention of hypertension, development of new, more efficacious treatments, and tailoring of particular treatments to patients who are most likely to respond.

Studies consistently demonstrate familial aggregation of hypertension, and indicate most of the between-person variation in blood pressure is explained by shared genetic factors with smaller contributions from shared environmental factors. Previous studies identifying individual hypertension genes demonstrate rare syndromic conditions (e.g., Liddle's syndrome) or association of candidate genes with hypertension (e.g., adducin, angiotensinogen). However most association studies have yielded modest or nonsignificant associations with hypertension, most likely because of the complex, dynamic interrelationship of multiple physiological pathways contributing to blood pressure regulation. Despite some successes, the identity and characteristics of the individual genes contributing to blood pressure and the occurrence of hypertension in the population-at-large remain poorly defined.

One method to identify genes contributing to hypertension is to examine intermediate phenotypes of hypertension, such as left ventricular (LV) hypertrophy or renal dysfunction. LV hypertrophy profoundly affects morbidity and mortality from cardiovascular diseases, including myocardial infarction, congestive heart failure, and stroke. LV hypertrophy is a common disorder, occurring in 16% of Whites, 33-43% of African Americans, and 22 to 60% of hypertensives. That LV hypertrophy is familial is emerging from several lines of research. Data from twin studies as well as the Framingham Heart Study report the heritability of LV mass to be 22-59%, independent of the effects of body size, blood pressure, gender, and age. Recent results from the HyperGEN (Hypertension Genetic Epidemiologic Network) study support that LV mass is heritable (26% in Whites and 70% in African Americans). Findings also indicate significant linkage of LV mass and functional measures of LV function to several chromosomal regions in Whites and African Americans which contain genes coding for sarcomeric proteins and calcineurin. Collectively, these results indicate that measures of LV hypertrophy may provide access to understanding the genetics of the hypertension and/or its complications.

Similarly to LV hypertrophy, impaired renal function may also serve as a tool for the identification of genes contributing to hypertension. Recent data from the HyperGEN study report evidence for linkage of creatinine clearance--an estimate of renal function--on chromosome 3 (LOD = 3.61 at 214.6 cM, 3q27) in African Americans. Our best evidence for linkage in Caucasians was on chromosome 6 (LOD = 2.36 at 102.8 cM). Positional candidate genes contained in and around the region on chromosome 3 that may contribute to renal function include enoyl-CoA hydratase/3 hydroxyacyl-CoA dehydrogenase (EHHADH) and apolipoprotein D (ApoD). These findings suggest there may be influential genetic regions on the variability of creatinine clearance among hypertensives.

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