Association studies between the HSD11B2 gene (encoding human 11betahydroxysteroid dehydrogenase type 2), type 1 diabetes mellitus and diabetic nephropathy

Objective: Mutations in the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2) explain the syndrome of apparent mineralocorticoid excess where cortisol acts as a mineralocorticoid. A microsatellite marker within the HSD11B2 gene associates with salt sensitivity and hypertension - phenotypes characterising diabetic nephropathy. Here, we evaluate the HSD11B2 gene as a susceptibility locus for diabetic nephropathy. Design: 150 patients with type 1 diabetes and nephropathy (DN), 145 patients with type 1 diabetes with a long duration of non-nephropathy (LDNN) and 151 normal controls were studied. Methods: We determined allele frequencies for the (CA), repeat marker within intron 1 of the HSD11B2 gene. Duration of type 1 diabetes, diabetic status and renal function were recorded. Results: 11 alleles (13 8 - 15 8) for the marker were observed. Allele 15 2 was significantly increased in controls compared with LDNN (70.5% vs 57.6%, P-c <0.05 where P-c is the P value corrected for multiple comparisons) but no difference was observed between DN and LDNN subjects. Allele 154 was significantly increased in the LDNN compared with the DN subjects (15.9% vs 7.0%, P-c <0.01) but no difference was observed between DN and controls. A greater proportion of subjects carried at least 1 allele <152 in DN compared with control subjects (47.3% vs 28.5%, P-c <0.01), but no difference was observed in LDNN compared with control and DN subjects. Conclusions: Weak associations arc reported between the HSD11B2 gene, type 1 diabetes mellitus and nephropathy. The increased frequency of HSD11B2 short alleles in the diabetic groups may reflect reduced renal 11beta-hydroxysteroid dehydrogcnase type 2 (11beta-HSD2) activity and may, in part, explain the enhanced salt sensitivity observed in patients with type 1 diabetes.