LINKAGE OF THE ANGIOTENSINOGEN GENE TO ESSENTIAL-HYPERTENSION

Background. The renin-angiotensin system is a powerful presser system with a major influence on salt and water homeostasis. Angiotensinogen (also called renin substrate) is a key component of this system; it is cleaved by renin to yield angiotensin I, which is then cleaved by ang iotensin-converting enzyme to yield angiotensin II, The observation th at plasma angiotensinogen levels correlate with blood pressure and tra ck through families suggests that angiotensinogen may have a role in e ssential hypertension. We therefore investigated whether there is link age between the angiotensinogen gene on chromosome 1q42-43 and essenti al hypertension. Methods. Samples of DNA from 63 white European famili es in which two or more members had essential hypertension were tested for linkage of the angiotensinogen gene to this disorder. Affected co usins, nephews, nieces, and half-siblings were included when possible. To test for linkage, we used as a marker a dinucleotide-repeat sequen ce flanking this gene, and we employed the affected-pedigree-member me thod of linkage analysis. Two molecular variants of the angiotensinoge n gene, one encoding threonine instead of methionine at position 235 ( M235T) and the other encoding methionine rather than threonine at posi tion 174 (T174M), were also tested for possible association with essen tial hypertension. Results. We found significant linkage (t = 5.00, P< 0.001) and association (chi-square = 53.3, P<0.001) of the angiotensin ogen-gene locus to essential hypertension in the 63 multiplex families . This linkage was consistently maintained in the subgroup of subjects with diastolic pressure above 100 mm Hg and in the subgroups classifi ed according to sex. It has been proposed previously that T174M and M2 35T are associated with essential hypertension. However, we found no a ssociation in our population between either polymorphism and this diso rder.Conclusions. This study provides strong and consistent support fo r the linkage to essential hypertension of regions within or close to the angiotensinogen gene. Precisely how mutations in this region may r esult in hypertension remains to be determined.