Angiotensin-converting enzyme and angiotensin II receptor subtype 2 genotypes in type 1 diabetes and severe hypoglycaemia requiring emergency treatment: a case cohort study.

Aims: In type 1 diabetes, individual susceptibility to severe hypoglycaemia is likely to be influenced by genetic factors. We have previously reported an association of the deletion (D-) allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the A-allele of the angiotensin II receptor subtype 2 (AT2R) 1675 G>A polymorphism with risk of severe hypoglycaemia in such patients. The aim of this study was to test the hypothesis that these alleles are more frequent in patients suffering from the most severe episodes of hypoglycaemia requiring medical emergency treatment.

Methods: The case cohort study consisted of 108 cases of type 1 diabetic patients with severe hypoglycaemia requiring medical emergency treatment during a 1-year period and 262 consecutive controls without such events. ACE I/D and AT2R 1675G>A genotype distributions were compared between cases and controls.

Results: The proportion of D-allele carriers was higher amongst cases than controls (83 vs. 73%; P=0.032). In contrast, AT2R genotype distribution was similar in cases and controls. In a multiple regression analysis, D-allele carriage remained a significant risk factor for being a case [odds ratio: 1.9 (1.0-3.6)] together with male sex, impaired symptomatic awareness of hypoglycaemia and presence of nephropathy.

Conclusion: The D-allele of the ACE gene is associated with severe hypoglycaemia requiring emergency treatment in type 1 diabetic patients with preserved spontaneous ACE activity. This supports the association between high ACE activity and occurrence of severe hypoglycaemia.