Genetics of blood pressure, hypertensive complications, and antihypertensive drug responses.
Hypertension is the most prevalent, treatable risk factor for diseases of the heart, brain and kidneys. In this review, we discuss advances in understanding of the genetics of blood pressure regulation, the development of hypertensive complications and the pharmacodynamics of antihypertensive drug responses. Discovery of single gene mutations that cause hypertension or hypotension in humans suggests that the common final pathway for regulation of blood pressure level is via alterations in renal sodium handling. Based on a working hypothesis that common genetic variations contributing to blood pressure variation in the population may also act on this same pathway, we summarize supporting evidence emerging from linkage and selected association studies of candidate genes--including those encoding components of the renin-angiotensin-aldosterone system, the epithelial sodium channel, adrenoceptors, G protein subunits, and other cellular signaling mediators and modifiers. We proceed to distinguish ischemic target organ complications due to arteriolosclerotic changes of the microvasculature from those due to atherosclerosis involving larger conduit and capacitance arteries. Using the example of subcortical white matter ischemia of the brain, we propose that interindividual variation in the arteriolosclerotic complications is more likely than atherosclerotic complications to be related to the same genetic (and environmental) mechanisms that contribute to hypertension. We conclude by summarizing the state-of-the-art of antihypertensive pharmacogenetics, which has succeeded in rejecting the null hypothesis that genetic variation does not influence blood pressure or protective target organ responses to drug therapy. In each of the three areas covered in this review, we indicate the many remaining obstacles to the routine clinical use of genetic measurements in the diagnosis, evaluation and treatment of hypertension.
Turner
Stephen T
ST
Division of Hypertension, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN, USA. turner.stephen@mayo.edu
Boerwinkle
Eric
E
D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000235:genetics*; D002545:Brain Ischemia / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D015995:Prevalence
D000959:Antihypertensive Agents