Hereditary Determinants of Human Hypertension

摘要

Essential hypertension is characterized by chronically elevated blood pressure with no specific underlying medical cause. Data on family history of affected individuals coupled with disease concordance rate in twins has established that both genetic and environmental factors determine susceptibility to hypertension. The heritability of hypertension is often cited in the range of ≈30% to 60%, with multiple contributory genes; additionally, ethnic and genetic heterogeneity participate in variable clinical presentation and drug response in hypertension, rendering genetic study of this disease a challenging task. Human population and animal studies have implicated several important etiologic pathways contributing to the clinical presentation of essential hypertension that enable functional candidate gene association studies, in addition to more comprehensive genome wide linkage or association studies. Recent results also suggest a complex genetic architecture for hypertension and its associated risk traits, including evidence for pleiotropy (one gene→multiple traits), epistasis (gene-by-gene interaction), and on occasion molecular heterosis (a more extreme phenotype for heterozygotes than either homozygote class). Here we highlight recent findings on the genetics of hypertension that may lead to new approaches for investigating the pathogenesis, diagnosis, treatment, and prognosis of the disease.Although blood pressure displays substantial heritability, typically reported at ≈30% to 60%,1 hypertension is likely to be a heterogeneous phenotype (trait). Applying the concept of “intermediate phenotypes”2,3 might enhance risk assessment for the development of future hypertension and its consequences, thus enabling more timely diagnosis and management of even “prehypertensive” individuals. Such intermediate phenotypes may be influenced earlier and more proximately by the genome than are ultimate disease/clinical traits such as hypertension, and therefore may assist in discovery of hypertension-predisposition loci.2,3Intermediate traits in physical, physiological/hemodynamic,4 autonomic/sympathetic,5–8 metabolic,9 inflammatory,9 oxidative,5 endothelial,10,11 and renal12 pathways displayed significant heritability, typically exceeding that reported for blood …