Journal of the Renin-Angiotensin- Aldosterone System
2015, Vol. 16(1) 195 –202
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Introduction
Psoriasis is a chronic inflammatory skin disorder character- ized by keratinocyte hyperproliferation and increased blood flow induced by the stimulation of tissue-resident immune cells by markedly altered cutaneous cytokine profiles.1,2 Vitiligo is a progressive depigmenting disorder character- ized by the loss of functional melanocytes from the epider- mis and affects 1–2% of the world population.3 Rheumatoid arthritis (RA) is a chronic inflammatory disease of predom- inantly synovial joints that causes significant morbidity and shortens life expectancy.4 Although the etiology of these diseases is not fully understood, interactions between a sus- ceptible genetic background and environmental factors have been suggested.5
Angiotensin-converting enzyme (ACE) converts angio- tensin I into angiotensin II and inactivates bradykinin via the kallikrein–kininogen system.6 Angiotensin II is the main effector molecule of the renin–angiotensin–system (RAS), is pleiotropic, and is a mediator of the development and progression of diseases.7 Furthermore, angiotensin II is
a potent pro-inflammatory modulator that augments and perpetuates the immune response.7 The ACE gene, located on chromosome 17q23, contains an insertion (I)/deletion (D) polymorphism within intron 16 that may contain or lack a 287 bp repeat sequence.8 The DD genotype is associ- ated with approximately a two-fold higher tissue and plasma concentration of ACE than the II genotype.8 Thus, it seems possible that the D allele could play a role in the pathogenesis of autoimmune diseases.
The angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to rheumatoid arthritis, vitiligo and psoriasis: A meta-analysis
Gwan Gyu Song
1, Sang-Cheol Bae
2, Jae-Hoon Kim
1and Young Ho Lee
1Abstract
Introduction: The purpose of this study was to examine whether the insertion (I) and deletion (D) of angiotensin- converting enzyme (ACE) polymorphism confers susceptibility to psoriasis, vitiligo and rheumatoid arthritis (RA).
Materials and methods: A meta-analysis was conducted on the association between the ACE I/D polymorphisms and psoriasis, vitiligo and RA.
Results: Fifteen studies comprising five on psoriasis, five on vitiligo and five on RA were available for the meta-analysis consisting of 2094 cases and 2871 controls. Meta-analysis of the DD+ID genotype showed significant associations with psoriasis (odds ratio (OR) 0.753, 95% confidence interval (CI) 0.601–0.921, p = 0.006). Meta-analysis showed no associa- tion between vitiligo and the ACE I/D polymorphism. Meta-analysis of the DD+ID genotype showed an association with RA (OR 2.199, 95% CI 1.379–3.506, p = 0.001). Ethnicity-specific meta-analysis of the D allele showed no association with psoriasis in Europeans, and vitiligo in South Asians. However, subgroup analysis by ethnicity revealed a significant association between the D allele and RA in Arab populations (OR 2.697, 95% CI 1.803–4.034, p = 1.3 × 10−5).
Conclusions: Our meta-analysis demonstrates that the ACE I/D polymorphism is associated with susceptibility to RA, especially in Arab populations.
Keywords
Angiotensin-converting enzyme, meta-analysis, polymorphism, psoriasis, vitiligo, rheumatoid arthritis
Date received: 29 October 2012; accepted: 09 August 2014
1 Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
2 Division of Rheumatology, Department of Internal Medicine, The Hospital for Rheumatic Diseases, Hanyang University Medical Center, Seoul, Korea
Corresponding author:
Young Ho Lee, Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea.
Email: [email protected]
Original Article
The ACE I/D polymorphism has been studied in the con- text of autoimmune disease. However, published results on the genetic association for the ACE I/D polymorphism are controversial and inconclusive.9–22 This may be due to small sample sizes, low statistical power, and/or clinical heterogeneity. In order to overcome the limitations of indi- vidual studies, resolve inconsistencies and reduce the like- lihood that random errors are responsible for false-positive or false-negative associations, we employed meta-analysis to further characterize the association. In the present study,23–25 we used meta-analysis to investigate whether the ACE I/D polymorphism contributes to susceptibility to pso- riasis, vitiligo and RA.
Materials and methods
Identification of eligible studies and data extraction
A literature search was conducted for studies that examined the association between the ACE I/D polymorphism and psoriasis, vitiligo and RA. We utilized the MEDLINE and EMBASE citation indices to identify articles in which the ACE I/D polymorphism was determined in patients and controls (up to October 2012). In addition, all references mentioned in the identified articles were reviewed to iden- tify studies not indexed by MEDLINE and EMBASE. The following keywords and subject terms were searched:
‘angiotensin-converting enzyme’, ‘ACE’, ‘psoriasis’, ‘viti- ligo’, ‘rheumatoid arthritis’, and ‘RA’. Studies were included in the analysis if they: (1) were case control stud- ies; (2) contained original data; and (3) contained sufficient data to calculate odds ratios (ORs). No language restriction was applied. We excluded the following: (1) studies con- taining overlapping data; (2) studies in which the number of null and wild genotypes or alleles could not be ascer- tained; and (3) studies in which family members had been studied because their analysis was based on linkage consid- erations. The following information was extracted from each identified study: author, year of publication, ethnicity of the study population, demographics, numbers of cases and controls and the frequencies of the genotypes and alleles of the ACE I/D polymorphism.
Evaluation of publication bias and study quality
Funnel plots are used to detect publication bias, but they require a range of studies of varying sizes and subjective judgments, and thus, we evaluated publication bias using Egger’s linear regression test.26 The Egger’s linear regres- sion test measures funnel plot asymmetry on a natural loga- rithmic scale of ORs. The chi-square test was used to determine whether observed genotype frequencies in con- trols conformed to Hardy–Weinberg (H-W) expectations.
Evaluation of statistical associations
We performed meta-analyses using: (1) the allelic contrast (D vs. I); (2) the recessive (DD vs. ID + II); (3) the domi- nant (DD + ID vs. II); and (4) the homozygote contrast (DD vs. II) models. Point estimates of risks, ORs and 95% con- fidence intervals (CIs) were estimated for each study. In addition, within- and between-study variations and hetero- geneities were assessed using Cochran’s Q-statistic.
Cochran’s Q-statistic test assesses the null hypothesis that all studies evaluated the same effect. The effect of hetero- geneity was quantified using I2, with a range between 0 and 100%, and represents the proportion of between-study vari- ability attributable to heterogeneity rather than chance.27 I2 values of 25%, 50% and 75% were nominally assigned as low, moderate and high estimates. The fixed effects model assumes that a genetic factor has a similar effect on disease susceptibility across all studies investigated and that observed variations among studies are caused by chance alone.28 The random effects model assumes that different studies show substantial diversity and assesses both within- study sampling error and between-study variance.29 When study groups are homogeneous, the two models are similar.
If the study groups lack homogeneity, the random effects model usually provides wider CIs than the fixed effects model.
The random effects model is most appropriate in the pres- ence of significant between-study heterogeneity.29 Statistical manipulations were undertaken using a Comprehensive Meta-Analysis computer program (Biosta, Englewood, NJ, USA). The power of each study was computed as the prob- ability of detecting an association between the ACE polymor- phism and vasculitis using a significance level of 0.05 and assuming an OR of 1.5 (small effect size). Power analysis was performed using the statistical program G*Power (http://www.psycho.uni-duesseldorf.de/aap/projects/gpower).
Results
Studies included in the meta-analysis
Twenty studies were identified by electronic and manual searches and 15 were selected for a full-text review based on title and abstract details.9–22,30 One study was excluded because it contained duplicate data.30 One eligible study contained data on two different RA groups, and these were treated independently.21 Thus, a total of 15 separate com- parisons met our inclusion criteria.9–22 These studies com- prised five each on psoriasis, vitiligo and RA. They consisted of four European, three East Asian, three Arab, three Turkish and two South Asian studies. In total the stud- ies included 2094 cases and 2871 controls. Selected details of the individual studies are summarized in Table 1. The statistical power of these 15 studies ranged from 16.4% to 86.1%. One of the studies had a statistical power exceeding 80%.12
Table 1. Details of the individual studies included in the meta-analysis. AuthorCountryEthnicityDiseaseNumbersD allele (%)AssociationH-W equilibrium p-valuePowera (%) CaseControlCaseControlOR95% CIp-value Coto-Segura et al., 20099SpainEuropeanPsoriasis 268 27262.760.81.0810.8461.3820.5340.05064.2 Weger et al., 200710AustriaEuropeanPsoriasis 207 18248.355.20.7580.5711.0050.0540.65350.5 Al-Awadhi et al., 200711KuwaitArabPsoriasis 51 10067.663.51.2020.7251.9910.4750.77023.3 Chang et al., 200712TaiwanEast AsianPsoriasis 312 61527.631.80.8170.6601.0100.0620.87386.1 Ozkur et al., 200413TurkeyTurkishPsoriasis 86 15462.859.40.8200.5851.1510.2520.37834.1 Tippisetty et al., 201114IndiaSouth AsianVitiligo 272 20548.340.00.8550.6071.2030.3680.00758.9 Pehlivan et al., 200915TurkeyTurkishVitiligo 48 5055.257.00.9300.5291.6350.8010.66316.8 Dwivedi et al., 200816IndiaSouth AsianVitiligo 125 15638.843.62.5611.3744.7710.0030.65838.9 Akhtar et al., 200517UKEuropeanVitiligo 106 17449.553.42.7991.6514.7470.0000.82938.7 Jin et al., 200418KoreaEast AsianVitiligo 120 42948.339.31.0230.7311.4330.8930.14564.9 Yigit et al., 201219TurkeyTurkishRA 110 14651.436.00.9730.6931.3660.874<0.00136.0 Uppal et al., 200720KuwaitArabRA 60 3574.252.91.0810.8461.3820.5340.13116.4 Ahmed et al., 201222EgyptArabRA 66 6676.553.80.7580.5711.0050.0540.12921.0 Ghelani et al.-1, 201121UKEuropeanRA 135 14055.955.41.2020.7251.9910.4750.35138.2 Ghelani et al.-2, 201221UKEast AsianRA 128 14742.242.91.1530.7851.6920.4680.17738.2 Total2094287149.745.41.1600.9751.3810.094 RA: rheumatoid arthritis; OR: odds ratio; CI: confidence interval; H-W: Hardy–Weinberg. aPower calculations assume α = 0.05, OR = 1.5.
Meta-analysis of the association between the ACE I/D polymorphism and psoriasis, vitiligo and RA
Meta-analysis was performed on each patient with psoria- sis, vitiligo or RA. A summary of the meta-analysis find- ings of the relation between the ACE I/D polymorphism and the diseases is provided in Table 2. Meta-analysis of the DD+ID genotype showed significant association with pso- riasis (OR 0.753, 95% CI 0.601–0.921, p = 0.006), whereas no such relation was found for the D allele, the DD geno- type or the DD vs. II genotype (Table 2; Figure 1).
Meta-analysis showed that the DD+ID genotype was associated with susceptibility to vitiligo (OR 1.277, 95% CI 1.019–1.600, p = 0.034) (Table 2). However, when one study not in H-W equilibrium was excluded from the meta- analysis, the association did not remain significant (OR 1.149, 95% CI 0.867–1.521, p = 0.334) (Table 2). Meta- analysis showed no association between vitiligo and the I/D polymorphism using the allele contrast, recessive model or homozygote contrast model (Table 2; Figure 1).
Meta-analysis showed that the D allele was associated with susceptibility to RA (OR 1.610, 95% CI 1.059–2.450, p = 0.026) (Table 2). However, when one study not in H-W equilibrium was excluded from the meta-analysis, the asso- ciation did not remain significant (OR 1.558, 95% CI 0.925–2.627, p = 0.096) (Table 2). Meta-analysis of the DD+ID genotype showed an association with RA (OR 2.199, 95% CI 1.379–3.506, p = 0.001) (Table 2). In addi- tion, excluding the study that deviated from the H-W equi- librium among controls did not affect the result (OR 2.169,
95% CI 1.174–4.007, p = 0.003) (Table 2; Figure 1).
However, meta-analysis showed no association between the RA and I/D polymorphism using the dominant model or homozygote contrast model (Table 2).
Meta-analysis of the association between the ACE I/D polymorphism and psoriasis, vitiligo and RA in each ethnic group
Subgroup analysis by ethnicity revealed a non-significant association between the D allele and psoriasis in Europeans (OR 0.912, 95% CI 0.644–1.291, p = 0.602) (Table 3).
Ethnicity-specific meta-analysis showed that the D allele was not associated with susceptibility to vitiligo in South Asians (OR 1.086, 95% CI 0.642–1.837, p = 0.759) (Table 3). However, subgroup analysis by ethnicity revealed a sig- nificant association between the D allele and RA in Arab populations (OR 2.697, 95% CI 1.803–4.034, p = 1.3 × 10−5) (Table 3).
Heterogeneity and publication bias
The distribution of genotypes of the ACE I/D polymor- phism in control groups was consistent with H-W equilib- rium in 13 of the 15 studies. Deviation from H-W equilibrium among controls suggests the possibility of bias during control selection or genotyping errors. When we excluded these studies,14,19 the overall results of the DD+ID genotype in RA were not substantially affected (Table 2).
Between-study heterogeneity was found during meta- analyses of all diseases, vitiligo and RA, but no evidence of Table 2. Meta-analysis of the association between the ACE I/D polymorphism and psoriasis, vitiligo and RA in overall group.
Diseases Comparison No. of studies Test of association Test of heterogeneity
OR 95% CI p-value Model p-value I2
Psoriasis D vs. I 5 0.923 0.813–1.048 0.215 F 0.132 43.4
DD+ID vs. II 5 0.753 0.616–0.921 0.006 F 0.318 15.1
DD vs. ID+II 5 1.090 0.888–1.339 0.409 F 0.621 0
DD vs. II 5 0.880 0.672–1.153 0.353 F 0.381 4.53
Vitiligo D vs. I 5 1.086 0.836–1.411 0.535 R 0.018 66.5
DD+ID vs. II 5 1.277 1.019–1.600 0.034 F 0.181 36.1
DD+ID vs. II* 4 1.149 0.867–1.521 0.334 F 0.193 36.4
DD vs. ID+II 5 1.019 0.682–1.522 0.928 R 0.048 58.2
DD vs. II 5 1.167 0.698–1.952 0.556 R 0.026 63.8
RA
D vs. I 5 1.610 1.059–2.450 0.026 R 0.000 80.5
D vs. Ia 4 1.558 0.925–2.627 0.096 R 0.001 82.7
DD+ID vs. II 5 1.182 0.728–1.918 0.500 R 0.030 62.6
DD vs. ID+II 5 2.199 1.379–3.506 0.001 R 0.023 64.7
DD vs. ID+II* 4 2.169 1.174–4.007 0.013 R 0.014 71.8
DD vs. II 5 1.810 1.001–3.272 0.050 R 0.016 67.2
ACE I/D: angiotensin-converting enzyme insertion and deletion; RA: rheumatoid arthritis; OR: odds ratio; CI: confidence interval; F: fixed effects model;
I: insertion; D: deletion; R: random effects model.
aStudies in Hardy–Weinberg equilibrium.
heterogeneity was found for meta-analyses in psoriasis (Tables 2 and 3). Publication bias causes a disproportionate number of positive studies, and poses a problem for meta- analyses. Egger’s regression test showed no evidence of publication bias in this meta-analysis of the ACE I/D poly- morphism in any of the diseases studied (Egger’s regres- sion test p-values > 0.1).
Discussion
ACE is expressed in a wide range of tissues including those of the kidneys, heart, lungs, vascular endothelium, skin,
joints and testes. ACE plays an important role in RAS, and angiotensin II conversion, directly increases vascular smooth muscle cell contraction and affects smooth muscle proliferation, monocyte adhesion, platelet adhesion, and aggregation. Angiotensin II also acts as a potent pro- inflammatory modulator.7,31 The ACE I/D polymorphism is located on an intron of the ACE gene, and is in strong link- age disequilibrium with genetic factors that influence serum ACE levels.8 In fact, the ACE I/D polymorphism accounts for approximately one-half of the variance in ACE plasma levels in humans. Furthermore, the polymorphism has been studied in several diseases, including Alzheimer’s Figure 1. Odds ratios and 95% confidence intervals (CIs) of individual studies and pooled data for the association between the DD + ID genotype and psoriasis (a), between the D allele and vitiligo (b), and between the DD genotype and rheumatoid arthritis (RA) (c).
disease, myocardial infarction, cerebral infarction, hyper- tension and diabetic nephropathy. These studies also reported associations between susceptibilities to these dis- eases and the DD genotype and D allele.9–22
In this meta-analysis, we combined evidence on the associations between the ACE I/D polymorphism and sus- ceptibility to psoriasis, vitiligo and RA. Meta-analysis of the DD+ID genotype showed significant associations with psoriasis (OR 0.753, 95% CI 0.601–0.921, p = 0.006), whereas no such relation was found for vitiligo. In addition, meta-analysis of the DD+ID genotype showed an associa- tion with RA (OR 2.199, 95% CI 1.379–3.506, p = 0.001).
Subgroup analysis by ethnicity revealed a significant asso- ciation between the D allele and RA in Arab populations (OR 2.697, 95% CI 1.803–4.034, p = 1.3 × 10−5).
ACE is expressed by skin components such as vascular endothelial cells, fibroblasts, and keratinocytes.32,33 It has been known that administration of ACE inhibitors can induce or exacerbate psoriasis in clinical practice.34 Tissue ACE can control the cutaneous inflammatory response by degrading bradykinin and substance P, which are strong mediators of inflammation.35 Activation of the kallikrein–kininogen sys- tem in plasma and tissue has been associated with psoriasis.36 Moreover, in view of the fact that the ACE I/D polymor- phism accounts for approximately one-half of the variance in ACE plasma levels, it is likely that the ACE I/D polymor- phism plays a role in susceptibility to psoriasis.8 This finding suggests that the ACE II genotype reduces ACE activity in skin and may augment the activation of the kallikrein–
kininogen system and increase the risk of psoriasis.12 Although the etiology of vitiligo has not been deter- mined, autoimmune destruction of melanocytes has been suggested. Genetic studies have established that vitiligo susceptibility has a genetic component.37,38 In the present
study, we found no association between vitiligo and the ACE I/D polymorphism. The lack of association between vitiligo and psoriasis is unclear. The difference may be due to small sample sizes or differences in the type of skin dis- ease. These two disorders may follow different pathways at the cellular and molecular levels. Relatively few studies reported the association between vitiligo and the ACE I/D polymorphism and their results were heterogeneous.
Further studies are required on this topic.
ACE, as a key regulator in inflammatory signal trans- duction pathway, has been considered to be involved in the pathogenesis of RA.39 ACE levels are increased in RA syn- ovial fluid suggesting that locally produced ACE may con- tribute to the joint destruction of RA.40 ACE converts angiotensin I to angiotensin II, which has a role as a growth factor and as a proinflammatory modulator. Angiotensin II modulates the expression of many cytokines, chemokines, adhesion molecules, endothelin-1, prostaglandins, platelet- activating factor, nitric oxide and cyclooxygenase-2.39
Our results should be interpreted with caution due to the limited number of studies included in this meta-analysis, which restricted further sub-group analyses. The relative importance of the ACE I/D polymorphism during the development of autoimmune diseases may be dependent on ethnicity. However, we were unable to perform ethnicity- specific meta-analysis due to limited data. Thus, further studies are required to allow meta-analysis by ethnic group to clarify the role of the ACE I/D polymorphism in various ethnic populations.
Our study has several limitations including potential publication bias, heterogeneity and confounding factors that may have distorted the meta-analysis. Secondly, there are varying levels of severity for each disease and the activ- ity level in each disease was unclear. Further research is Table 3. Meta-analysis of the association between the ACE I/D polymorphism and psoriasis, vitiligo and RA in each ethnic group.
Diseases (comparison) Population No. of studies Test of association Test of heterogeneity
OR 95% CI p-value Model p-value I2
Psoriasis (D vs. I) European 2 0.912 0.644–1.291 0.602 R 0.063 75.0
East Asian 1 0.817 0.660–1.010 0.062 NA NA NA
Turkish 1 1.153 0.785–1.692 0.468 NA NA NA
Arab 1 1.202 0.725–1.991 0.475 NA NA NA
Vitiligo (D vs. I) European 1 0.855 0.607–1.203 0.368 NA NA NA
South Asian 2 1.086 0.642–1.837 0.759 R 0.014 83.5
East Asian 1 1.446 1.084–1.929 0.012 NA NA NA
Turkish 1 0.930 0.529–1.635 0.801 NA NA NA
RA (D vs. I) European 1 1.023 0.731–1.473 0.893 NA NA NA
East Asian 1 0.973 0.693–1.366 0.874 NA NA NA
Turkish 1 1.881 1.317–2.686 0.001 NA NA NA
Arab 2 2.697 1.803–4.034 1.3 × 10−5 F 0.831 0
ACE I/D: angiotensin-converting enzyme insertion and deletion; RA: rheumatoid arthritis; OR: odds ratio; CI: confidence interval; F: fixed effects model;
D: deletion; I: insertion; R: random effects model.
required to examine whether an association exists between the ACE I/D polymorphism and the activity or clinical fea- tures of the diseases. This was not possible in the present study due to limited data.
In conclusion, this meta-analysis of the ACE I/D poly- morphism based on a total sample of 2094 patients and 2871 controls demonstrates that the ACE I/D polymor- phism is associated with susceptibility to RA, especially in Arab populations. Accordingly, our findings support the notion that the ACE I/D polymorphism plays a role in the pathogenesis of RA. Larger scale studies in populations with different ethnicities are required to explore relation- ships between polymorphisms of the ACE gene and the pathogenesis of psoriasis and RA.
Conflict of interest None declared.
Funding
This work was supported by the Korean Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (grant no. A102065).
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