The schematic representation of the study selection process is shown in Figure 1. Out of 61 studies retrieved from the databases after excluding duplicate and not relevant studies, the full-texts of 16 studies and another study identified by hand searching were assessed for eligibility
(a total of 17 full-texts). After checking the full-texts, three studies were recognized as meta-analyses and consequently they were excluded. But checking the references of previous meta-analyses related to the subject, two other studies [20,21] were added that we didn’t find their full-text; since they had previously included in other meta-analyses, and since all the required data were extracted from other meta-analyses. In conclusion, 16 studies were included in the meta-analysis.
Some important characteristics of the studies involved in the present meta-analysis are shown in Table 1. The studies were published from 1999 to 2018. Twelve studies reported their research in Caucasian ethnicity [21-32] and four studies [9,20,33,34] in Asian ethnicity. Among Caucasian ethnicity, four studies [23,25,26,31] were conducted in Arab population, four studies [21,24,27,28] enrolled European population, while the remaining four studies [22,29,30,32] evaluated other populations (Pakistani, Iranian and Turkish populations). The meta-analysis included 3003 psoriatic patients and 3689 controls. With regard to the controls source, nine studies [9,20,23-26,32-34] enrolled hospital-based patients, two studies [28,29] were population-based, and five studies [21,22,27,30,31] enrolled controls of unknown origin. In most of the considered studies, the ratio of patients affected by different psoriasis subtypes was not reported [9,20,21,30,32-34], while only 5 and 4 studies were conducted in groups of patients affected predominantly by psoriasis vulgaris [22,24,25,27,31] and psoriatic arthritis [23,26,28,29], respectively. In all studies the used genotyping method was polymerase chain reaction (PCR). In two out of 16 studies, the genotype frequencies of controls [26,27] didn’t follow HWE.
Forest plot of the psoriasis susceptibility related to ACE I/D polymorphisms based on five genetic models is identified in Figure 2. The pooled ORs of D versus I, DD versus II, ID versus II, ID + DD versus II, and DD versus II + ID models were 0.96 [95%CI: 0.82, 1.12; P=0.58; I2=74% (Pheterogeneity (Ph)<0.00001)], 0.99 [95%CI: 0.73, 1.36; P=0.96; I2=71% (Ph<0.0001)], 0.81 [95%CI: 0.72, 0.91; P=0.0003; I2=42% (Ph=0.04)], 0.91 [95%CI: 0.73, 1.13; P=0.40; I2=64% (Ph=0.0003)], and 1.05 [95%CI: 0.85, 1.30; P=0.68; I2=61% (Ph=0.0007)], respectively. Therefore, the presence of ID genotype had a significant slight protective effect against psoriasis development.
The results of psoriasis susceptibility related to ACE I/D polymorphisms on the basis of different considered variables are shown in Table 2. With regard to ethnicity, the analyses showed that there was no risk of psoriasis related to ACE I/D polymorphisms in East Asian populations, but the presence of ID genotype had a slight protective effect against the disease [OR = 0.82; 95%CI: 0.69, 0.97]. Based on three models of DD versus II, ID versus II, and ID + DD versus II the pooled OR was 0.69 (95%CI: 0.52, 0.91), 0.66 (95%CI: 0.50, 0.85), and 0.67 (95%CI: 0.52, 0.86), respectively. Such results showed that DD and ID genotypes had protective roles in psoriatic arthritis, unless this was not valid for psoriasis vulgaris type. The ID genotype had a significantly decreased susceptibility to psoriasis in studies conducted in hospital-based populations based on heterozygote model (OR=0.77, 95%CI: 0.67, 0.90). Caucasian population was evaluated in three groups, Arab, European and the other group. The other group consisted of Iran, Pakistan and Turkey. With regard to the Caucasian population, the ID genotype had a significant protective role in psoriasis if compared with other genotypes in non-Arab and non-European population (the other group) (OR= 0.73, 95%CI: 0.58, 0.92).
Out of 16 studies included in the meta-analysis, two studies [26,27] were excluded since P-value of HWE for controls was less than 0.05 (Table 3). Notwithstanding, the new analysis showed that the results were unchanged with just a decreased susceptibility to psoriasis among patients carrying ID genotype (OR=0.80, 95%CI: 0.71, 0.90). In addition, other analyses - one study removed and cumulative analysis- didn’t change the result of previous overall analysis and therefore they showed the stability of the previous overall result.
The alleles and genotypes distribution of ACE I/D polymorphism on the basis of the differences in patient’s characteristics are shown in Table 4. In detail, only three studies [20-22] considered gender, six studies [9,20,22,23,25,28] reported family history for psoriasis, eight studies [9,22-25,27-29,33] considered the age at the onset, one study  reported type of psoriasis, and three studies [31,9,28] reported severity of the disease. The results showed significant difference between ACE polymorphisms in patients with family history (familial) versus those without family history (sporadic) for the disease [OR=1.44; 95%CI: 1.24, 1.67; P<0.001]. When considering psoriasis severity (grouped among severe or mild disease), a significant difference was obtained [OR=0.70; 95%CI: 0.55, 0.88; P=0.002]. Therefore, the II genotype was significantly more represented in familial patients than in sporadic patients and the DD genotype was more frequent in severe than in mild psoriasis. There was no significant difference in terms of gender, age at the onset, and type of psoriasis among groups of patients.
The evaluation of quality for each study is shown in Table 1. Unfortunately, the full-text of two studies [20,21] was not available for the quality assessment. In detail, eight studies had high quality (score ≥7).
We checked publication bias for overall analysis using both Egger’s and Begg’s tests (Figure 3). The results showed that both tests didn’t reveal the existence of publication bias between the studies in each model analyses (P>0.05).