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Clinical Science (2007) 113, (467–472) (Printed in Great Britain)

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Is the influence of variation in the ACE gene on the prospective risk of Type 2 diabetes in middle-aged men modified by obesity?

Amal MUTHUMALA*, David R. GABLE*, Jutta PALMEN*, Jackie A. COOPER*, Jeffrey W. STEPHENS†, George J. MILLER‡ and Steve E. HUMPHRIES*

*Centre For Cardiovascular Genetics, Royal Free and UCL Medical School, The Rayne Institute, 5 University Street, London WC1E 6JF, U.K., †Diabetes Research Group, The Medical School, University of Swansea, Swansea SA2 8PP, U.K., and ‡Medical Research Council Cardiovascular Group, Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, U.K.

Key words: angiotenin II, angiotensin-converting enzyme gene (ACE gene), body mass index (BMI), gene–environment interaction, inflammatory state, obesity, Type 2 diabetes.

Abbreviations: Ang, angiotensin; ACE, Ang-converting enzyme; ARB, AngII receptor blocker; BMI, body mass index; BP, blood pressure; CI, confidence interval; CRP, C-reactive protein; D, deletion; HR, hazard ratio; I, insertion; NPHSII, Second Northwick Park Heart Study; OR, odds ratio; SBP, systolic BP; SNP, single nucleotide polymorphism; T2DM, Type 2 diabetes; UDACS, University College London Diabetes and Cardiovascular Disease Study.

Correspondence: Dr Amal Muthumala (email a.muthumala@ucl.ac.uk).

There is strong evidence for the presence of a functional renin–angiotensin system in diabetogenic tissues, and ACE (angiotensin-converting enzyme) inhibitors may improve glucose metabolism in those individuals at high risk of developing T2DM (Type 2 diabetes). In the present study, we tested the hypothesis that subjects with genetically lower plasma and tissue ACE activity, because of their ACE [I/D (insertion/deletion)] genotype, would have a lower risk of T2DM in 2642 healthy middle-aged Caucasian men (mean age, 56 years) followed-up for 15 years. Obesity was the strongest predictor of T2DM, with an HR (95% CI) [hazard ratio (95% confidence interval)] of 3.74 (2.66-5.26) (P<0.0001). Overall there was no association between ACE genotype (II homozygotes, n=623; and D allele carriers, n=2019) and risk of T2DM, and although in lean men there was no genotype difference in risk in D allele carriers compared with II homozygotes [adjusted HR=0.75 (95% CI, 0.46–1.22)], in obese (body mass index >30 kg/m²) men the risk of T2DM was higher [adjusted HR=4.26 (95% CI, 1.30–13.93)] with a genotype–obesity interaction of P=0.01. A similar pattern of risk was seen by re-analysis of a previously published case-control study, where D allele carriers had a non-significant 1.30 (0.97–1.74)-fold higher risk of developing T2DM than II homozygotes when non-obese, but a 1.79 (1.17–2.72) (P=0.007)-fold higher risk when obese. Further prospective studies are needed to confirm these findings. The ACE D allele may worsen glucose metabolism, which could raise the prospective T2DM risk in obese men, but not in lean men. In obesity, adipose tissue undergoes inflammatory infiltration and the subsequent higher levels of pro-inflammatory angiotensin II may explain this association.

Received 10 May 2007/28 June 2007; accepted 12 July 2007

Published as Immediate Publication 12 July 2007, doi:10.1042/CS20070158

© The Authors Journal compilation © 2007 Biochemical Society