Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism

Abstract

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, which shows hyperactivity in the majority of patients with major depression. The ACE gene, known to be associated with cardiovascular disorders, which in turn are accompanied with an increased susceptibility for depression, is therefore a promising candidate gene for affective disorders. We investigated the genetic association between 35 single-nucleotide polymorphisms (SNPs) and an insertion/deletion (I/D)-polymorphism in the ACE gene and the susceptibility for unipolar major depression together with the genetic association with ACE serum activity and functional parameters of the HPA system. Two independent case/control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated. A case/control sample was screened to detect genetic associations with unipolar major depression. In addition, a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression. In the screening sample, two SNPs within the ACE gene were significantly associated with unipolar major depression. The association with unipolar major depression of one SNP (rs4291) located in the promoter region of the ACE gene was confirmed in our replication sample. The T-allele of this SNP was associated with depression and depressed T-allele carriers showed higher ACE serum activity and HPA-axis hyperactivity. Variants of the ACE gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE activity and HPA-axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease.

Association of polymorphisms in the angiotensin-converting enzyme gene with syndromal panic attacks

“…6 The replication of significant SNPs was performed in a second German sample from the University of Mü nster, consisting of patients with panic disorder with and without agoraphobia (n = 169) and blood donors as controls (n = 334) matched for gender and age (sample 2, Mü nster). Genotyping was performed as described in Baghai et al 2 In the discovery sample, we found nominal associations in five intronic SNPs: rs4311 (P = 0.001), rs4329 (P = 0.02), rs4333 (P = 0.01), rs4344 (P = 0.01) and rs4353 (P = 0.04). rs4291, the promoter polymorphism found to be associated with unipolar depression in two independent samples, did not show a significant association with panic disorder (P = 0.08).…”

“…All five SNPs were in linkage disequili- brium (LD) and located in the 3 0 region of the second LD block within the ACE gene, identified as described in Baghai and co-workers, which spans the promoter region as well as all coding regions for ACE isoforms 1 and 2. 2,7 Only for rs4311, the P-value was still significant after Bonferroni correction for multiple testing (Table 1). All five SNPs entered the replication and significant P-values after Bonferroni correction were found for rs4311 and rs4333 (Table 1); rs4329 (P = 0.04), rs4344 (P = 0.01), rs4353 (P = 0.04) were nominally associated in sample 2.…”

“…1 Recently, a functional role of polymorphisms in the ACE gene was reported in unipolar depression. 2 The implication of ACE in anxiety disorders is unclear so far, but its close relation to cardiovascular and respiratory control may suggest a role in the etiology of panic attacks. Three previous genetic association studies focused on the insertion/deletion polymorphism in the ACE gene in patients with panic disorder.…”

“…A Japanese study failed to detect an effect, whereas two European studies reported a significant association of the less active I allele with panic disorder mainly in the male subgroup of panic patients. [3][4][5] To further elucidate the role of the ACE in the genetic vulnerability for panic attacks, we first genotyped the 24 single nucleotide polymorphisms (SNPs) covering the ACE gene region (710 kb) reported in Baghai et al (2006), in 175 patients with syndromal panic attacks (including panic disorder with and without agoraphobia 87.7%, social and special phobia 13.3%), who were recruited from our Anxiety Disorders Outpatient Clinic, versus 445 healthy controls matched for ethnicity, age and sex (sample 1, Max Planck Institute for Psychiatry (MPI)). Patients and controls underwent a thorough clinical and laboratory examination.…”

“…While the variant rs4291 associated with unipolar depression was not significantly associated with panic disorders, all of the five SNPs associated with panic disorder were also nominally associated with unipolar depression. 2 The ACE gene may thus be an example for a genetic or locus overlap between anxiety and depression.…”