A MOLECULAR VARIANT OF ANGIOTENSINOGEN IS ASSOCIATED WITH DIABETIC NEPHROPATHY IN IDDM

Recent studies have suggested that an inherited predisposition to esse ntial hypertension may increase susceptibility to nephropathy for pati ents with IDDM. Essential hypertension has been linked to the angioten sinogen (AGT) gene in genetic linkage studies in American and European populations, A molecular variant (M235T), which has a functional effe ct, has been described with highest plasma AGT levels being associated with the TT genotype. In a case-control study, me have evaluated the role of this functional genetic marker in patients with IDDM and nephr opathy and in IDDM patients without nephropathy. We studied 195 IDDM p atients, of whom 95 had established diabetic nephropathy; the remainin g 100 patients, who had no evidence of microalbuminuria, served as con trol subjects. All patients were whites born in Northern Ireland. The point mutation in the AGT gene was analyzed using restriction typing. The background frequency of the M235T variant was assessed in 80 healt hy blood donors, and the TT genotype was present in 9%. This genotype occurred in 8% of control IDDM patients without nephropathy and 19% of IDDM patients with nephropathy (P = 0.025). The odds ratio for diabet ic nephropathy associated with the TT genotype was 2.7 (95% CI 1.04-7. 52). There was no relationship between blood pressure and AGT genotype s in the control group. We cannot exclude the possibility that the obs erved association in the nephropathy group is due to an association be tween AGT genotype and hypertension, This evidence may help to explain the predisposition to diabetic nephropathy afforded by hypertension a cid merits further investigation.