EVIDENCE FOR SINGLE-GENE CONTRIBUTIONS TO HYPERTENSION AND LIPID DISTURBANCES - DEFINITION, GENETICS, AND CLINICAL-SIGNIFICANCE

Several large family studies are reviewed to identify results suggesti ng single gene traits contributing to the occurrence of hypertension i n humans. Segregation analysis in families has suggested major gene ef fects for several highly heritable traits associated with hypertension . These include recessively segregating high sodium-lithium countertra nsport (major gene H-2=34%), additively segregating low urinary kallik rein excretion (major gene H-2=51%), and recessively segregating hyper insulinemia (major gene H-2=33%). In some families, hypertension and m etabolic abnormalities (dyslipidemia, hyperinsulinemia, and obesity) s eem to be related to several candidate genes studied but not conclusiv ely proven (LPL deficiency mutations, dense LDL subfractions, or NIDDM with hyperinsulinemia). More recently, DNA markers have identified ge nes promoting hypertension. Glucocorticoid-remediable aldosteronism (G RA) promotes a rare but unusual form of hypertension that is unrespons ive to ordinary medications but very responsive to glucocorticoid medi cations. GRA has been found in hypertensive persons with a specific mu tation of the 11 beta-hydroxylase gene on chromosome 8q21. Many person s with essential hypertension carry a common ''susceptibility gene'' a t the angiotensinogen locus (chromosome 1q4) identified using linkage studies in siblings, association studies, and in studies of preeclamps ia and hypertension in pregnant women. These first two well-establishe d genetic loci promoting human hypertension represent two ends of a br oad spectrum. The rare ''determinant'' gene for GRA by itself seems to produce severe hypertension and early strokes. The angiotensinogen (A GT) ''susceptibility'' gene is very common (30% of Utah Caucasians) an d seems to predispose to hypertension but probably requires other gene tic and environmental influences to be fully expressed. An understandi ng of other genetic and environmental factors that interact with genet ic traits like angiotensinogen and kallikrein will probably identify p atients in whom specific environmental interventions (such as sodium r estriction or potassium supplementation) or specific types of medicati ons will facilitate targeted prevention and treatment of hypertension and its complications.