Association between a functional polymorphism in the renin-angiotensin system and completed suicide

Abstract

Suicide has been suggested to involve disturbances in the stress response system and to be related to genetics. The renin-angiotensin system (RAS) has been shown to affect the stress response, and several functional polymorphisms in RAS-related genes have been predicted to alter protein function. We hypothesized that the dysregulation of RAS was involved in suicide, and examined the association between completed suicides and four functional polymorphisms of RAS-related genes: the angiotensinogen M235T, angiotensin-converting enzyme (ACE) insertion(I)/deletion(D), angiotensin type-1 receptor A1166C, and G-protein-beta3 C825T gene polymorphisms. The I allele of the ACE I/D polymorphism was found to be more frequent in completed suicides than in controls (P = 0.014). The I allele was also found to be more frequent in male completed suicides (P = 0.022) than in male controls, while this was not the case in females. These results suggest that the alteration of RAS function caused by the genetic polymorphism is involved in the susceptibility to suicide in males.

Angiotensin-Converting Enzyme Polymorphism and Completed Suicide: An Association in Caucasians and Evidence for a Link with a Method of Self-Injury

“…This is similar to recent findings among Japanese men [5] . One difference between our observations and the previous study [5] is that Hishimoto et al reported an association with the ACE II genotype (i.e. a recessive effect), whereas our results suggest that a codominant model is more appropriate.…”

“…a recessive effect), whereas our results suggest that a codominant model is more appropriate. However, reanalysis of genotype distribution reported by these authors [5] showed that the data are consistent both with a codominant and recessive model of inheritance (p = 0.6 in both cases). Analysis of the OR per single ACE I allele under a codominant model using the data of Hishimoto et al yielded an OR = 1.45 (CI = 1.06-1.98).…”

“…This study had a power of 0.7 to detect at ␣ = 0.05 an increase in the frequency of the ACE II genotype among suicides versus controls associated with the OR similar to that reported by Hishimoto et al [5] .…”

“…Given the pronounced and well-documented functional significance of the ACE polymorphism [6] , the most straightforward interpretation of the reported associations is that a lower activity of ACE enzyme found in the II homozygotes increases the risk for suicide [5] . However, these conclusions are not consistent with a recent study of Sparks et al [17] , who also found an association between ACE genotype and suicide but in the reverse direction, i.e., it was the DD genotype which was found to be the risk factor for suicide.…”

“…The study by Hishimoto et al [5] was intriguing, but it should be regarded as preliminary due to marginal statistical significance of the reported association (p = 0.03) and lack of correction for multiple comparisons (4 loci, i.e. 12 genotypes, were analyzed in each sex).…”