The relationship between ACE genotype and risk of severe hypoglycaemia in a large population-based cohort of children and adolescents with type 1 diabetes

Abstract

Aims/hypothesis Genetic factors may account for familial clustering related to diabetes complications. Studies have shown a significant relationship between the presence of the deletion (D) allele of the gene encoding ACE and risk of severe hypoglycaemia. This large prospective cohort study assesses this relationship in a large sample of children and adolescents with type 1 diabetes. Subjects and methods We studied 585 children and adolescents (mean age 11.9±4 years, 48.4% males). The frequency of severe hypoglycaemia (an event leading to loss of consciousness or seizure) was prospectively assessed over the 13-year period 1992-2004. Patients were seen with their parents every 3 months and data recorded at each visit. The ACE gene was detected using PCR. Results In our cohort of 585 children, 186 (31.8%) had at least one episode of severe hypoglycaemia, and of these 28.0% had the II genotype, 48.9% had the ID genotype and 23.1% had the DD genotype. This was in agreement with the Hardy-Weinberg proportion. A total of 477 severe hypoglycaemic episodes was recorded with a total of 3,404 person-years of follow-up, giving a total incidence of 14 per 100 patient-years. No significant increase in risk for DD genotype (incidence rate ratio=0.97, 95% CI 0.61-1.55) relative to II genotype was observed. Conclusions/interpretation This large prospective study concludes that the presence of the D allele of the ACE gene does not predict a significantly higher risk of severe hypoglycaemia in type 1 diabetic children and adolescents.

Hypoglycemia, S-ACE and ACE genotypes in a Danish nationwide population of children and adolescents with type 1 diabetes

“…In their following prospective study, they could not demonstrate an independent risk for the ACE gene for severe hypoglycemia, but confirmed that correction for serum ACE activity eliminated the effect of ACE genotype (12). In the present study, we could not demonstrate any isolated association of hypoglycemia to ACE genotype, which is also in accordance with recent findings of Bulsara et al in children and adolescents with T1DM (9). Furthermore, no association of the ACE genotype could be found neither in hypoglycemia in T2DM (20) nor in hypoglycemia awareness in T1DM (21).…”

“…The condition of limited substrate availability seen in hypoglycemia -leading to cerebral glucose deficiency in T1DM -has been compared to endurance performance in athletes. As (i) the D-allele in the Angiotensin Converting Enzyme (ACE) gene polymorphism has been found less common in endurance athletes (5) and (ii) the ACE genotype has been associated with the level of serum-ACE (S-ACE) -the ACE-DD genotype conferring highest S-ACE level (6-8) -the ACE gene and serum ACE levels have been studied in the relation to hypoglycemia in adult T1DM patients (9)(10)(11)(12)(13). It has, by three groups, been demonstrated that high levels of S-ACE predispose to the risk of hypoglycemia (10)(11)(12)(13)(14), however; some inconsistency relates to the risk of the ACE genotype from the same studies.…”

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

“…This study in an Australian cohort on type 1 diabetic children failed to reproduce the influence of the I/D polymorphism on SH [14]. The discrepancy is likely to be explained by a shorter duration of diabetes and preserved hypoglycaemic defence mechanisms in the childhood cohort [14]. Furthermore, hypoglycaemic events were less well documented in this study.…”

“…Only one other study has assessed the relationship between ACE genotype and SH in type 1 diabetes. This study in an Australian cohort on type 1 diabetic children failed to reproduce the influence of the I/D polymorphism on SH [14]. The discrepancy is likely to be explained by a shorter duration of diabetes and preserved hypoglycaemic defence mechanisms in the childhood cohort [14].…”

Impaired Awareness of Hypoglycemia in a Population-Based Sample of Children and Adolescents With Type 1 Diabetes

“…Princess Margaret Hospital is the only pediatric diabetes referral center for the population of Western Australia, and almost all children with type 1 diabetes in the state are registered and treated here. Previous studies have shown that this center has a case ascertainment close to 100% (8,9). All patients have had ongoing prospective documentation from diagnosis, at 3-month intervals, of hypoglycemic events, diabetic ketoacidosis, and glycemic control measured by A1C.…”