The gene coding for angiotensin-converting enzyme (ACE) has been reported to be associated with the development of psoriasis.
The gene coding for angiotensin-converting enzyme (ACE) has been reported to be associated with the development of psoriasis.
To evaluate the association of psoriasis risk and ACE polymorphisms.
We carried out a retrieval of studies that explored associations between ACE polymorphism and psoriasis, and analysed the genotype frequencies.
In total, 8 studies with 1242 patients and 1646 controls were included. The genotype frequencies in all studies were in Hardy–Weinberg equilibrium. After pooling all studies, the results indicated that the I/I genotype was associated with risk of psoriasis (OR = 1.41, 95% CI 1.11–1.80, P = 0.005), whereas the I/D genotype may decrease the risk of psoriasis (OR = 0.71, 95% CI 0.56–0.90, P = 0.005) in Asian, but not in white populations.
Our study suggests that ACE polymorphism are associated with the risk of psoriasis in Asians, especially the I/I genotype and I allele. Further studies are needed to confirm our results.
Psoriasis is an autoimmune disease characterized by scaly patches covering the top layer of the epidermis. Although various treatments can help to relieve the symptoms of the disease, patients often experience recurrences and remissions throughout their lives. A number of environmental agents may cause an exacerbation of psoriasis, including infections, medications, stress, alcohol consumption and smoking.[2-4] Some studies have indicated that a combination of genetic predisposition, immune disorder and lifestyle agents may ultimately lead to the occurrence of disease, but the cause of psoriasis is still unclear. A series of epidemiological investigations showed that the risk in a sibling of a patient with the disease is about 10%, which is higher than the risk in the general population. Most gene variants involve susceptibility loci, including the various psoriasis susceptibility genes (PSORS1-13), the gene for interleukin 12B and the gene for angiotensin-converting enzyme (ACE).[7-9]
A previous study showed that ACE is essential for control of normal extracellular volume and arterial vasoconstriction, and these are affected by expression of the ACE gene, which is located on chromosome 17. An insertion/deletion (I/D) polymorphism has been identified, which generates three genotypes: D/D, I/D and I/I. It is thought that the D allele may increase the risk for developing type 2 diabetes, hypertension and late-onset Alzheimer disease. Several studies have also investigated the involvement of ACE alleles and genotypes in psoriasis,[9, 12-18] but results have been conflicting. In the present study, we assessed the association of ACE gene polymorphisms with psoriasis susceptibility using a meta-analysis.
We retrieved studies that explored associations between ACE gene polymorphism and psoriasis. A systematic search was carried out using MEDLINE (from 1966 to March 2012), the Cochrane Library, Google Scholar, and Chinese databases such as the China National Knowledge Infrastructure (CNKI), Weipu, Wanfang. The MeSH keywords and free text words used for this research were: ACE, polymorphism(s) OR allele(s), variation OR genotype(s) AND psoriasis OR psoriatic disease.
We also performed hand searches of articles and reviews on this topic, and conducted a manual search of references listed in published original and review articles. All database searches were restricted to human subjects without language limitation.
Studies were included in our study if they met the following criteria: (i) type of the study design described in the original articles had to be a case–control study; (ii) the data collected must have included gender and age, and studies must have identified all age groups; (iii) one or more of the alleles, such as I or D, must be mentioned; (iv) and genotype frequencies in the control group must have complied with Hardy–Weinberg equilibrium (HWE).
The titles and abstracts of retrieved documents were screened. Studies were excluded if they did not meet the eligibility criteria or were duplicated. The full text was obtained and evaluated for those articles that were included in further analyses. The following information was extracted from each study: author name, date of publication, study type, and characteristics of the study population (including ethnicity, total sample size, and number of cases and controls).
The asymptotic Pearson χ² test was used to calculate whether the genotype distribution of the control group in each study met HWE. We analysed the data using Stata software (version 11.0; Stata Corp., College Station, TX, USA). Associations between ACE gene polymorphisms and psoriasis were analysed by means of odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The decision to use a random-effects or fixed-effects model was based on the clinical heterogeneity between the included studies. The heterogeneity between studies was evaluated using forest plots and χ² test and I2 tests. In general, Q statistics were used to test the homogeneity of the effect sizes, and homogeneity was accepted if the P-value was > 0.05. The I2 test was generally used to test the size of the heterogeneity, with studies considered heterogeneous at I2 > 50% and homogeneous at I2 < 50%. In our study, the potential publication bias was tested using the funnel plot and Egger test.
In total, 40 studies were initially identified, of which 12 studies with overlapping data, 5 animal studies, 10 review articles and 5 uncontrolled studies were excluded, leaving 9 studies that met the inclusion criteria (Table 1). By means of the HWE equation, genotype frequencies in the included studies were compared. The genotype frequency in one study (Veletza et al.) was not in HWE. Therefore, we only pooled and analysed the other 8 studies, which were all case–control studies (3 from Asia and 5 from Europe and North Africa) that included 1242 cases with psoriasis and 1646 controls In addition, several studies explored the relationships of alleles/genotypes with age at disease onset, gender and presence of family history (Table 2).
|Author||Year||Country||Ethnicity||Subjects, n (M/F)||Comments|
|Liu et al.||2007||China||Asian||88 (46/42)||95 (50/45)||I/D may not be a genetic risk of psoriasis in Chinese populations|
|Chang et al.||2006||Taiwan||Asian||312 (235/77)||615 (330/285)||I allele may be a risk factor for development of psoriasis in Taiwan Chinese|
|Ozkur et al.||2004||Turkey||White||86 (44/42)||154 (81/73)||I allele may be a risk factor for development of psoriasis in psoriatic families|
|Weger et al.||2007||Austria||White||207 (147/60)||182 (119/63)||I/I may affect susceptibility to early-onset psoriasis in white Austrians|
|Coto-Segura et al.||2009||Spain||White||268 (142/126)||272 (147/125)||ACE polymorphism is not likely to be associated with psoriasis|
|Veletza et al.||2008||Greece||White||128 (77/51)||113 (matched to cases)||I/D genotype and D allele were more common in patients with early-onset psoriasis|
|Vasku V et al.||1999||Czech Republic||White||200 (104/96)||208 (142/66)||No differences|
|Nagui NA et al.||2007||Egypt||White||30 (15/15)||20 (9/11)||I allele may be a risk factor in individuals from psoriatic families; D/D may affect susceptibility to severe psoriasis|
|Al-Awadhi et al.||2007||Kuwait||Asian||51 (19/32)||100 (35/65)||I/I genotype may confer susceptibility to the development of late-onset psoriatic arthritis|
|Author and study groups||Cases||Controls|
|Liu et al.|
|Chang et al.|
|Ozkur et al.|
|Weger et al.|
|Coto-Segura et al.|
|Al-Awadhi et al.|
|Vasku V et al.|
|Nagui NA et al.|
Pooling the data from the eight studies, we found that the I allele was not associated with psoriasis risk in the overall analysis using the fixed-effects model (OR = 1.09, 95% CI 0.98–1.22, P = 0.11) (Table 3). However, in subgroup analysis by ethnicity, the I allele increased the risk for psoriasis in Asian (OR = 1.19, 95% CI 1.01–1.42, P = 0.06), but not in white populations (OR = 1.04, 95% CI 0.90–1.19, P = 0.60) (Table 3, Fig. 1a).
|Comparison||Subgroup||Fixed-effects model||Random-effects model||Heterogeneity|
|OR||95% CI||P||OR||95% CI||P||I2,%||P|
|D/D vs. others||Overall||1.02||0.85–1.25||0.86||1.02||0.85–1.21||0.86||0||0.72|
|I/D vs. others||Overall||0.82||0.71–0.96||0.01||0.83||0.71–0.97||0.02||7.3||0.37|
|I/I vs. others||Overall||1.28||1.07–1.52||<0.01||1.26||1.04–1.53||0.02||9.8||0.35|
|D vs. I||Overall||0.91||0.82–1.02||0.11||0.92||0.81–1.04||0.17||14.2||0.32|
|I vs. D||Overall||1.09||0.98–1.22||0.11||1.09||0.96–1.23||0.17||14.2||0.32|
Analysis of ACE genotypes found that there was no difference between cases and controls for the three genotypes overall, but for Asians, presence of the homozygous genotype I/I indicated an increased risk of psoriasis (OR = 1.41, 95% CI 1.11–1.80, P < 0.01) compared with the other genotypes, and the heterozygous I/D genotype had a slight protective effect against psoriasis (OR = 0.71, 95% CI 0.56–0.90, P < 0.01). (Table 3, Fig. 1b,c).
No significant difference was found for the alleles or genotypes when comparing gender, onset of psoriasis (early vs. late), or presence/absence of a family history of psoriasis (data not shown).
To evaluate the sensitivity of our study, we compared the fixed-effects with the random-effects models, and found no difference for either alleles or genotypes.
A funnel plot and the Egger test were used to evaluate the publication bias of the included studies. The funnel plot was symmetrical, with no apparent evidence of publication bias (Fig. 2). The Egger test did not show any significant difference for each allele and genotype group, again suggesting that the probability of publication bias was low (t = 0.53, P = 0.62).
ACE plays an important role in normal cutaneous homeostasis and wound healing. It may be a crucial regulatory factor in controlling cutaneous inflammatory response, and may be involved in the survival of skin fibroblasts, melanocytes, endothelial cells and keratinocytes.[21, 22] ACE performs these functions by converting angiotensin I to angiotensin II, and degrading the potent vasodilator peptides bradykinin and kallidin. It has been suggested that the kallikrein–kinin system plays a crucial role in the pathogenesis of psoriasis. Generally, the average ACE activity level in people with the D/D genotype is approximately twice that of those with the I/I genotype, and the I/D genotype is intermediate between these two. Thus, it is likely that the reduction in ACE levels in people with the I/I genotype might increase bradykinin, trigger an inflammatory response, and induce the development of psoriasis. Some studies have shown that psoriasis is a polygenic disease, and the known susceptibility genes such as PSORS1-13 and ACE are associated with the disease.[7, 24]
Although many studies have investigated the association between ACE gene polymorphisms and susceptibility to psoriasis, the results are still controversial. Liu et al. did not find significant differences in the distribution of ACE gene polymorphisms between patients with psoriasis and controls, whereas Chang et al. reported that the I allele may be a risk factor for development of psoriasis in Taiwanese populations. The large difference between two studies on the same ethnic group may be a result of the small sample size used by Liu et al. In addition, the patients originated from northern China, and three types of psoriasis were involved. Thus, the different types of psoriasis and the different environmental factors may also partly explain the inconsistent results between these two studies. Similar to the Chang et al. study, Ozkur et al. and Nagui et al. reported that the presence of the I allele was higher in participants with a family history of psoriasis. Weger et al. found that the I/I genotype may affect susceptibility to early-onset psoriasis in a white Austrian population; however, in two large sample studies, ACE gene polymorphisms were considered unlikely to be associated with psoriasis.[16, 17] These discrepancies suggest that differences in ACE gene polymorphisms might contribute to the variability between reports for different populations in the same ethnic group. Nagui et al. found that the D allele and the D/D genotype were higher in different psoriasis subtypes characterized by early or severe psoriasis. Differences in the environment of the population studied and in the laboratory detection method used for ACE genotyping might be a limitations in these latter two studies.
In our study, we assessed the data for the distribution of ACE alleles and genotypes, and then pooled the genetic data from 1242 cases and 1646 controls in Asia, Europe and North Africa. Our overall results for psoriasis showed no significant association with ACE alleles and genotypes; however there was a trend toward an association with two genotypes (I/D and I/I) and with the I allele in Asians, indicating that these might be genetic risk factors for susceptibility to psoriasis in this population.
There are several potential limitations in our study. Firstly, the quality of our study depended on the quality of the data from the included studies, but the final number of original publications in our meta-analysis was only eight, which was insufficient for a comprehensive analysis. The number of ethnic groups was also limited, with no black African groups included. Secondly, although we tested for publication bias in the included studies, using funnel plots, and found no significant publication bias, this represents only a possible trend, and the results of these studies should be interpreted with caution because the number of included studies is small. Consequently, further studies with the large sample will be necessary in follow-up studies to properly assess the relationship between ACE gene polymorphisms and the risk of psoriasis. Finally, our study focused only on the correlation between ACE gene polymorphisms and psoriasis; we did not assess the relationship between ACE gene polymorphisms and disease extent, because the included studies generally did not report such data.
The present study shows that ACE gene polymorphisms may be associated with psoriasis. For Asians, the I/I genotype and the I allele were associated with increased susceptibility to psoriasis, whereas the I/D genotype seemed to have a protective role. However, these results need to be confirmed by larger sample studies.
We are particularly grateful to Professor V. Vašků (Department of Dermatovenerology, Faculty of Medicine, Masaryk University, Czech Republic) and Dr A. Hay (Faculty of Medicine, Cairo University, Egypt) for their help with the original documents and data. We kindly thank the editors and reviewers for their useful comments.
To demonstrate knowledge of angiotensin-converting enzyme (ACE) gene polymorphisms and recent evidence for the susceptibility gene in relation to psoriasis.
Which of the following genes is not involved in susceptibility to psoriasis?
The angiotensin-converting enzyme (ACE) gene is located on which of the following chromosomes?
Which of the following is not a physiological function of angiotensin-converting enzyme (ACE)?
Which of the following genotypes results in the highest angiotensin-converting enzyme (ACE) activity level?
Which of the following alleles in the angiotensin-converting enzyme genotype may increase the susceptibility to psoriasis in Asians?
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