Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression

M-L Ancelin,I Chaudieu,J Scali,K Ritchie,I Carrière,J Ryan

doi:10.1038/tp.2013.95

Abstract

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic–pituitary–adrenocortical (HPA) axis, which shows hyperactivity in depressed patients. ACE could thus be a promising candidate gene for late-life depression but this has not been examined previously. Depression was assessed in 1005 persons aged at least 65 years, at baseline and over the 10-year follow-up. A clinical level of depression (DEP) was defined as having a score of ⩾16 on the Centre for Epidemiology Studies-Depression scale or a diagnosis of current major depression based on the Mini International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) in the ACE gene were genotyped and diurnal cortisol secretion, as an index of HPA axis activity, was measured. Multivariable analyses were adjusted for socio-demographic and vascular factors, cognitive impairment, and apolipoprotein E. Strong significant associations were found between all seven SNPs and DEP and, in particular, first-onset DEP in persons without a past history of depression (P-values ranging from 0.005 to 0.0004). These associations remained significant after correction for multiple testing. The genotypes that were associated with an increased risk of DEP were also significantly associated with an increase in cortisol secretion under stress conditions. Variants of the ACE gene influence cortisol secretion and appear as susceptibility factors for late-life depression in the elderly population. Whether this could represent a common pathophysiological mechanism linking HPA axis and late-life depression remains to be explored.

Highlights

Angiotensin-converting enzyme (ACE) converts inactive angiotensin I, into a potent vasoconstrictor and aggravator of endothelial dysfunction, angiotensin II, and degrades the vasodilatator bradykinin, both of which are important in the maintenance of blood pressure.[1]
Experimental studies have shown that angiotensin II and ACE can interfere with the secretion of pituitary hormones such as corticotropin (ACTH) and potentiates the stimulatory effects of corticotropin-releasing hormone (CRH), contributing to the stress-related activation of the hypothalamic– pituitary–adrenocortical (HPA) axis.[2,3]
As the first prospective study to examine the association between variants in the ACE gene and clinical levels of depression in the Abbreviations: ApoE, apolipoprotein E; CES-D, Center for Epidemiologic Studies-Depression Scale; MMSE, Mini-Mental State Examination. aCorresponds to current major depression or a CES-D scoreX16. bAdjusted for age and gender. cw[2] test. dA history of angina pectoris, myocardial infarction, stroke, cardiovascular surgery, arteritis. eFasting glycemia levels[47] mmol l À 1 or treated (n 1⁄4 1001 as four subjects had missing data)

Summary

Introduction

Angiotensin-converting enzyme (ACE) converts inactive angiotensin I, into a potent vasoconstrictor and aggravator of endothelial dysfunction, angiotensin II, and degrades the vasodilatator bradykinin, both of which are important in the maintenance of blood pressure.[1]. Prior genetic association studies of ACE variants and depression have revealed inconsistent results. The most widely studied has been the insertion/deletion (I/D) polymorphism resulting from the presence/absence of a 287-bp fragment in intron 16 of the ACE gene. This variant was discovered through its association with ACE plasma levels,[7] but does not appear to be functionally significant[8] and meta-analyses fail to find consistent support for its association with depression.[9,10] given that the ACE gene is in a region of highly conserved linkage disequilibrium, current opinion favors the presence of other functional polymorphisms in ACE.[1,11]

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