The lack of association between angiotensin‐converting enzyme gene insertion/deletion polymorphism and nicotine dependence in multiple sclerosis

Abstract

ObjectiveBlood‐borne angiotensin II is generated from angiotensinogen via cleavage by renin and angiotensin‐converting enzyme (ACE), an enzymatic cascade known as the renin–angiotensin system (RAS). Several lines of evidence indicate that ACE, beyond its classical role of mediating blood pressure regulation, might contribute to the etiology of substance addictions by influencing dopaminergic signaling. A functional insertion/deletion (I/D) polymorphism of the ACE gene was associated with risk for being a smoker among individuals with depression and with smoking severity in studies comprising patients with depression and healthy controls. Several reports have described significantly increased ACE activity in cerebrospinal fluid and serum among MS patients. Furthermore, in our previous work with MS patients from Croatian and Slovenian populations, we demonstrated that the ACE‐I/D polymorphism contributes to an elevated MS risk among male patients. Here we investigated whether the ACE‐I/D polymorphism might influence smoking behavior among patients with MS.Patients and MethodsGenotyping was performed in 521 patients (males/females: 139/382) using polymerase chain reaction.ResultsWe revealed no significant differences in ACE genotype and allele frequencies between smokers and nonsmokers and no significant association between the ACE‐I/D polymorphism and either pack‐year smoking history or number of cigarettes smoked daily (p > .05, respectively).ConclusionThe ACE‐I/D polymorphism does not contribute either to risk for nicotine dependence or to smoking severity among MS patients. In the context of reports on the ACE‐I/D polymorphism and nicotine dependence among healthy controls and patients with depression, we may speculate that the mechanism by which this polymorphism influences nicotine dependence risk differs in MS compared to depression, although not compared to a healthy population. In addition to angiotensin II, other potential ACE substrates, such as substance P and neurotensin, which also influence dopaminergic neurotransmission (and are proposed to be associated with MS), may deserve study in future.

Association between the ACE‑I/D polymorphism and nicotine dependence amongst patients with lung cancer

“…The ACE-I/D polymorphism had a significant impact on the risk of nicotine dependence in male patients in this patient group, where the presence of the ACE-I allele contributed to a greater risk of being a smoker. These findings are not consistent with any of the previous reports on the potential relevance of the ACE-I/D polymorphism in the etiology of nicotine dependence (26)(27)(28)(29), highlighting the presence of a mechanism by which the ACE-I/D polymorphism contributed to the risk of nicotine dependence in lung cancer which differs from that than in other diseases and/or conditions.…”

“…For example, there is a significantly greater risk of being a smoker observed amongst ACE-DD homozygous individuals suffering from depression in the German population (27) and amongst heterozygous (ID) females with schizophrenia in the Croatian population (29). Conversely, studies consisting of healthy subjects from the Czech Republic and German populations (26,27) and multiple sclerosis patients from the Croatian population (28) found no evidence of an association between the ACE-I/D polymorphism and the risk of smoking. The ACE-I/D polymorphic variant may also serve a role in smoking severity; the ACE-DD homozygous genotype was shown to contribute to an increase in the number of cigarettes smoked per day amongst patients suffering from depression, as well as an increase in the pack-years of smoking history amongst healthy individuals in the German population (27).…”

“…A functional insertion/deletion (I/D) polymorphism (rs1799752) in intron 16 of the ACE gene (17q23), which is characterized by the presence or absence of a 287 bp Alu repetitive sequence, accounts for ~50% of the ACE levels (24) and is the most widely-studied RAS-related polymorphic variant, and the only RAS-related polymorphism investigated in the etiology of nicotine dependence (25)(26)(27)(28)(29). To date, several studies have addressed the potential relevance of the ACE-I/D polymorphism in the etiology of nicotine dependence, but the results have been inconsistent (25)(26)(27)(28)(29). For example, there is a significantly greater risk of being a smoker observed amongst ACE-DD homozygous individuals suffering from depression in the German population (27) and amongst heterozygous (ID) females with schizophrenia in the Croatian population (29).…”