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

ACE influences the HPA-system and contributes to substance P degradation. Therefore, the ACE gene is a candidate gene for the susceptibility to affective disorders.

We tried to clarify whether variants of 35 SNPs and an I/D-polymorphism within the ACE gene contribute to susceptibility for unipolar major depression and to functional parameters such as ACE and HPA axis activity.

We investigated two independent samples with a total of 843 unrelated unipolar depressed patients and 1479 psychiatrically healthy controls. 35 SNPs were genotyped within the ACE gene region. A replication sample was used to confirm the detected associations and to further investigate functional and clinical consequences of the genetic variants associated with depression. ACE serum activity, HPA axis activity and clinical outcome were studied.

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 activity.

Variants of rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE and HPA axis activity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease.