Angiotensin-converting enzyme gene insertion/deletion polymorphism is not associated with schizophrenia in a Croatian population

Abstract

Because angiotensin-converting enzyme (ACE) plays an important role in dopamine system functioning in the brain and the insertion/deletion (I/D) polymorphism of a 287 nucleotide fragment of the ACE gene correlates with enzyme activity, several studies have investigated the role of the ACE I/D polymorphism in psychiatric diseases (Segman et al., 2002;Crescenti et al., 2009). Two recent studies have yielded contradictory results: the D allele was identified as a protective factor in a Spanish population, whereas a protective effect toward schizophrenia and bipolar disorder was attributed to the I allele in a Turkish population (Crescenti et al., 2009;Kucukali et al., 2010).We tested whether the risk of schizophrenia was associated with the ACE I/D polymorphism in a Croatian population, and examined its possible impact on schizophrenia symptom severity.Our study group included 211 Croatian patients (115 men, 96 women) with schizophrenia (n = 187) and schizoaffective disorder (n = 24), and 270 healthy blood donors (135 men, 135 women). Regarding clinical diagnosis, trained psychiatrists conducted the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Axis I disorders. The controls underwent no specific examination for psychiatric status but, according to the practice of blood donation in Croatia, they were free of chronic diseases or regular medication. All participants gave informed consent for the analysis. The study was approved by the Ethics Committee of the School of Medicine, University of Rijeka, Rijeka, Croatia. Genotyping was performed by PCR as previously described (Rigat et al., 1992). To exclude mistyping of the heterozygotes as DD homozygotes, all DD genotype samples were confirmed with insertion-specific PCR (Shanmugan et al., 1993).The significance of differences in the genotype and allele frequencies between patients and controls was determined using the w 2 -test. Potential correlation between Positive and Negative Symptom Scale (PANSS) scores and I/D polymorphism was tested using linear regression analysis (stepwise selection), adjusted for age at PANSS assessment and sex, in patients with schizophrenia. PANSS evaluation was performed during the last hospitalization due to a psychotic episode. P-values of less than 0.01 were considered statistically significant.Allelic and genotypic frequencies of I/D polymorphisms were consistent with Hardy-Weinberg equilibrium and were not significantly different between groups. Allele frequencies were 230 (D) and 192 (I) in the patient group and 285 (D) and 255 (I) in the control group. Genotype frequencies were 0.299 (DD = 63), 0.493 (ID = 104), and 0.208 (II = 44) in the patient group and 0.274 (DD = 74), 0.507 (ID = 137), and 0.219 (II = 59) in the control group. Therefore, our data did not support results from Spanish or Turkish samples. However, after adjusting for sex and age at PANSS assessment, we observed a significant correlation between the ACE genotype and psychopathology evaluated by PANSS. Increa...

Relationship between major depressive disorder and ACE gene I/D polymorphism in a Turkish population

“…A meta-analysis evaluating the data of several studies indicated that there was no association between schizophrenia and ACE I/D polymorphism 25 , and the same result was supported in a study with the Croatian population 26 , in consistent with our study results. While it was reported that bipolar disorder was not associated with I/D polymorphism 27 , another study suggested that it was associated with I/D genotype in the Asian race 28 .…”

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

“…In line with gender‐specific differences in the effect of the ACE‐I/D polymorphism in various conditions and/or diseases, such as blood pressure (among healthy individuals) (Avila‐Vanzzini et al., 2015), hypertension (Higaki et al., 2000; Sipahi, Budak, Şen, Ay1, & Şener, 2006), schizophrenia (Mazaheri, 2015; Nadalin, Buretić‐Tomljanović, Ristić, Jonovska, & Tomljanović, 2015; Nadalin et al., 2012), as well as MS (Lovrečić et al., 2006), and according to observations of gender–gene interaction in risk for nicotine dependence in general population (Beuten, Payne, Ma, & Li, 2006; Beuten et al., 2005; Nedic et al., 2010; Tochigi et al., 2007) and specific diseases (i.e., schizophrenia) (Nadalin, Buretić‐Tomljanović, Rebić, Pleša, & Šendula Jengić, 2016) association analyses between ACE‐I/D polymorphism and smoking habits were performed separately among male and female patients. Furthermore, there is also evidence that estrogen may influence dopaminergic neurotransmission, since it has been observed that estrogen treatment reduces dopamine receptor D2 levels in several rat brain regions (Chavez et al., 2010).…”

ACE I/D genotype-related increase in ACE plasma activity is a better predictor for schizophrenia diagnosis than the genotype alone

“…Interestingly, 7 out of the 9 previous studies investigating the I/D polymorphism correlation with SCZ were negative (Arinami et al, 1996;Ouyang et al, 2001;Segman et al, 2002;Golimbet et al, 2005;Baskan et al, 2010;Nadalin et al, 2012;Song and Lee, 2014), while of the remaining 2 of the 9 studies, one reported significantly lower D-allele frequency in SCZ (Crescenti et al, 2009) and the other reported significantly lower I/I genotypes (Kucukali et al, 2010). Taken together, our results are consistent with the majority of previous studies, as we also did not find any significant association between I/D genotypes alone and SCZ diagnosis.…”