Gene 558 (2015) 181–186
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Review
Association between VEGF − 634G/C polymorphism and susceptibility to autoimmune diseases: A meta-analysis Haikui Chen a,1, Tianyun Zhang b,1, Bolin Gong c, Xiaohong Cao a,⁎ a b c
Department of Life Science, Beifang University of Nationalities, Yinchuan 750021, China The First Hospital of Chinese People's Liberation Army (PLA), Lanzhou 730050, China Key Laboratory of Energy & Chemical Engineering, Ningxia University, Yinchuan 750021, China
a r t i c l e
i n f o
Article history: Received 15 October 2014 Received in revised form 22 December 2014 Accepted 12 January 2015 Available online 14 January 2015 Keywords: VEGF −634G/C Polymorphism Autoimmune diseases Meta-analysis
a b s t r a c t The role of VEGF −634G/C polymorphism has been involved in the investigations of susceptibility to autoimmune diseases, but the conclusion remains controversial. Here, we have performed a meta-analysis to clarify the relationship between them. All relevant articles updating to August 2013 were searched in PubMed and EMBASE. Crude odds ratios (ORs) with 95% confidence intervals (CIs) based on the available articles were calculated. A total of 24 independent studies associated with autoimmune disease were analyzed in our research. The results show that VEGF −634G/C polymorphism was associated with susceptibility to autoimmune disease in Asian population (C vs. G: OR = 0.88, 95% CI: 0.80–0.96, P = 0.543; CC vs. GG: OR = 0.77, 95% CI: 0.63–0.93, P = 0.787; CC + GC vs. GG: OR = 0.80, 95% CI: 0.67–0.96, P = 0.080 by random effects model). Nevertheless, no significant associations were found in total population or in other stratified groups. In the current metaanalysis, we reveal a significant association between VEGF −634G/C polymorphism and susceptibility to autoimmune diseases in Asian population. © 2015 Published by Elsevier B.V.
1. Introduction Many people have been suffered from autoimmune diseases which are considered as the result of the damaging immune response (Lleo et al., 2010). Autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type I diabetes mellitus, and psoriasis, are thought to have similar immune pathogenesis (Shapira et al., 2010; Deane et al., 2010; Arbuckle et al., 2003). According to some studies, autoimmune diseases result from immune system disorders which are thought to be under the control of genetic factors (Cho and Gregersen, 2011; Manolio et al., 2009; Costenbader et al., 2012; Leung et al., 2010). Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors and a product of endothelial cells, fibroblasts, smooth muscle cells, and macrophages (Jain, 2003; Senger et al., 1983; Ferrara, 2009). Some studies suggest that VEGF can regulate endothelial cells growth resulting in the initiation of vessel formation (Leung et al., 1989; Houck et al., 1992). Subsequent analyses confirm that VEGF is also indispensable for the establishment of mature vascular network Abbreviations: OR, odds ratio; CI, confidence interval; KD, Kawasaki disease; GCA, giant cell arteritis; BD, behcet disease; IBD, inflammatory bowel disease; SSc, systemic sclerosis; SLE, systemic lupus erythematosus; GD, graves' disease; T1DM, type I diabetes mellitus. ⁎ Corresponding author at: Department of Life Science, Beifang University of Nationalities, Yinchuan 730000, China. E-mail addresses: [email protected] (H. Chen), [email protected] (T. Zhang), [email protected] (B. Gong), [email protected] (X. Cao). 1 These two authors contributed equally to this work.
http://dx.doi.org/10.1016/j.gene.2015.01.023 0378-1119/© 2015 Published by Elsevier B.V.
(Carmeliet, 2000; Yancopoulos et al., 2000). More than the significant impacts of VEGF in angiogenesis, it is reported that VEGF also has an important role in autoimmune diseases (Carvalho et al., 2007). Additionally, some studies suggest that the level of VEGF is higher in individuals with autoimmune diseases than that in healthy people (Robak et al., 2003; Taylor, 2005; Mackiewicz et al., 2002). Overall, these researches may present evidences that VEGF is closely linked with susceptibility to autoimmune diseases. Previous study indicates that VEGF − 634G/C (rs2010963) polymorphism is linked with the regulation of VEGF expression levels (Lambrechts et al., 2003). Regarding to this, a number of studies are investigated to find the association between VEGF −634G/C (rs2010963) polymorphism and autoimmune diseases. Nevertheless, no consistent results were yielded. Considering the influences of the sample size, ethnical context and other limited factors, we performed a meta-analysis to elucidate whether VEGF −634G/C (rs2010963) polymorphism is susceptible to autoimmune diseases. Hence, in our study, we hope to find a new mechanism of autoimmune diseases and try to provide a potent therapeutic target for autoimmune diseases. 2. Materials and methods 2.1. Search strategy Articles dated to August 2013 were searched in PUBMED and EMBASE databases using the key words “VEGF”, “polymorphism”, “autoimmune
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diseases” and “autoimmunity” in various combinations. In this current study, articles we searched were limited to be published in English.
Egger's linear regression asymmetry test, P b 0.05 suggested statistically significant publication bias. All statistical analyses were tested with STATA version 10.1 (Stata Corporation, College Station, TX).
2.2. Selection criteria 3. Results Identification of eligible studies was as follows: (1) studies about VEGF − 634G/C polymorphism and the susceptibility of autoimmune diseases; (2) studies defined as case–control studies; and (3) studies containing available and sufficient data. 2.3. Data extraction Data extraction was carried out by two authors. The following information was extracted from eligible studies: first author, published year, country or area of study population, clinical features, ethnicity, sample size, and the number of genotypes in cases and controls. 2.4. Statistical analysis The assessment of effect estimate was primarily determined by the odds ratio with its 95% confidence interval. We calculated the pooled ORs by performing the genetic models for the allelic effect (C versus G), homozygote comparison (CC versus GG), dominant model (CC versus GG + GC) and recessive model (CC + GC versus GG) respectively. Analyses of stratified groups were performed according to clinical features and ethnicity. Heterogeneity was assessed by a chi-square-based Q-statistic test (Higgins and Thompson, 2002) and was thought to be significant if the result was P b 0.10. If so, ORs were calculated depending on random-effects model (the DerSimonian and Laird model) (DerSimonian and Laird, 1986), otherwise the fixed-effects model (the Mantel and Haenszel model) was used (Mantel and Haenszel, 2004). Sensitive analyses were carried out to evaluate the stability of the results. Analysis of publication bias was shown with the funnel plot and
A total of one hundred and ninety eight relevant articles were indentified through literature search and twenty four eligible studies were included in further analysis (Fig. 1). Generally, the meta-analysis includes seven studies of psoriasis, four studies referred to rheumatoid arthritis (RA), four studies focusing on Kawasaki disease (KD), three studies associated with giant cell arteritis (GCA), and each one study with behcet's disease (BD), inflammatory bowel disease (IBD), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), graves' disease (GD) and type I diabetes mellitus (T1DM), respectively. Among them, there were eleven studies of Asian descent, eleven studies of Caucasians and two remaining studies of unknown ethnicity. In total, the analyses involved 11,087 subjects (4884 patients and 6203 healthy controls). Characteristics of all studies are summarized and the distribution of the VEGF − 634G/C genotype among total population is shown in Table 1. After the data of twenty four studies were pooled into meta-analysis, the result was presented in allelic comparison (OR = 0.99, 95% CI: 0.93– 1.05, P = 0.691 for heterogeneity), in homozygote comparison (OR = 0.96, 95% CI: 0.85–1.09, P = 0.553 for heterogeneity), in dominant model (OR = 0.98, 95% CI: 0.88–1.10, P = 0.762 for heterogeneity) and recessive model (OR = 0.98, 95% CI: 0.91–1.07, P = 0.701 for heterogeneity). Additionally, stratified analyses were further carried out in order to avoid the side effect of heterogeneity and illustrate an exact relationship between VEGF −634G/C polymorphism and susceptibility to autoimmune diseases. Considering the clinical features, we divided the studies into five subgroups. No evidence of significant association between
Fig. 1. Flow chart of article selection.
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Table 1 Characteristic of included studies. Author (reference)
Year
Nam (24) Ferrante (25) McKnight (26) Allanore (27) Wongpiyabovorn (28) Vural (29) Boiardi (30) Rueda (31) Enjuanes (32) Han (33) Rueda (34) Lv (35) Zhang (36) Kariyazono (37) Breunis (38) Hsueh (39) Huang (40) Young (41) Barile (42) Butt (43) Wang (44) Wongpiyabovorn (45) Wu (46) Zablotna (47)
2005 2006 2006 2007 2010 2012 2003 2005 2012 2004 2005 2011 2013 2004 2006 2007 2008 2004 2006 2007 2008 2008 2010 2011
Country/area
Korea Belgium Ireland France Thailand Turkey Italy Spain Spain China Spain China China Japan Netherland Taiwan Taiwan UK Italy Canada China Thailand China Poland
Ethnicity
Asian Caucasian Caucasian Caucasian Asian Unknown Caucasian Caucasian Caucasian Asian Caucasian Asian Asian Asian Caucasian Asian Asian Unknown Caucasian Caucasian Asian Asian Asian Caucasian
Clinical feature
BD IBD T1DM SSc SLE GD GCA GCA GCA RA RA RA RA KD KD KD KD Psoriasis Psoriasis Psoriasis Psoriasis Psoriasis Psoriasis Psoriasis
VEGF − 634G/C polymorphism and susceptibility to autoimmune diseases was found in any genetic model among these subgroups (Table 2). By sample size, the studies were stratified into two subgroups. One was composed of studies with more than 400 subjects. The other was composed of studies with fewer than 400 subjects. Similarly, no obvious evidence of significant association between variant VEGF −634G/C genotypes and autoimmune diseases was found (Table 2). Considering the impact of ethnicity, we divided the studies into two subgroups. A significant association between VEGF −634G/C polymorphism and susceptibility to autoimmune diseases was found among Asian population (C vs. G: OR = 0.88, 95% CI: 0.80–0.96, P = 0.543; CC vs. GG: OR = 0.77, 95% CI: 0.63–0.93, P = 0.787; CC + GC vs. GG: OR = 0.80, 95% CI: 0.67–0.96, P = 0.080 by random effects model), but negative association was found in non-Asian populations (Fig. 2). Sensitivity analysis was performed under various comparisons in total population and all subgroups. When a single study was excluded, none of the results were significantly altered each time (data not shown).
Sample size (case/control)
101/138 452/271 242/301 416/249 193/234 167/203 92/200 103/226 81/166 140/149 753/801 98/100 318/695 103/144 166/297 93/96 154/672 137/102 117/215 255/127 103/103 154/234 257/258 189/214
Case
Control
GG
GC
CC
GG
GC
CC
38 166 60 168 70 106 20 52 36 36 339 40 104 39 73 35 45 50 53 118 51 69 100 94
49 232 135 181 97 48 53 36 33 63 312 48 167 46 71 40 87 67 50 118 39 74 111 81
14 54 47 67 26 13 19 15 12 41 102 10 47 18 22 18 22 20 14 19 13 11 46 14
39 96 85 97 87 152 72 101 86 28 357 35 238 50 132 22 225 47 88 64 37 87 73 121
74 139 165 115 118 47 100 86 71 72 330 49 340 63 130 62 333 48 99 45 52 118 133 86
25 36 51 37 29 4 28 39 9 49 114 16 117 31 35 12 114 7 28 18 14 29 52 7
Publication bias was assessed by Begg's funnel plot and Egger's test (figure not shown) in total population and all subgroups. Egger's linear regression test suggested moderate publication bias in allelic model (C vs. G) for Asian population (t = − 2.4, P = 0.04) and for non-Asian population (t = 2.30, P = 0.042), but no evidence of publication bias in any other genetic model for total population and subgroups (data not shown). 4. Discussion A complex of immune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, and psoriasis are described as autoimmune diseases. Recently, a number of studies have been investigated the association between autoimmune diseases and VEGF polymorphism (Nam et al., 2005; Ferrante et al., 2006; McKnight et al., 2007; Allanore et al., 2007; Wongpiyabovorn et al., 2008, 2011; Vural et al., 2012; Boiardi et al., 2003; Rueda et al., 2005a,b; Enjuanes et al., 2012; Han et al., 2004; Lv et al., 2011; Zhang
Table 2 Results of meta-analysis for VEGF −634G/C polymorphism and susceptibility to autoimmune diseases. Study groups
Total
na
Sample size (case/control)
C vs. G
CC vs. GG
CC vs. GG + GC
CC + GC vs. GG
OR (95% CI)
Pb
OR (95% CI)
Pb
OR (95% CI)
Pb
OR (95% CI)
Pb
24
4884/6203
0.99 (0.93–1.05)
0.691
0.96 (0.85–1.09)
0.553
0.98 (0.88–1.10)
0.762
0.98 (0.91–1.07)
0.701
Clinical features Psoriasis RA KD GCA Other diseases
7 4 4 3 6
1212/1253 1309/1745 516/1207 276/602 1571/1396
0.92 (0.82–1.04) 0.95 (0.85–1.05) 0.97 (0.83–1.13) 1.23 (1.00–1.52) 1.04 (0.93–1.16)
0.192 0.306 0.703 0.050 0.467
0.82 (0.63–1.07) 0.87 (0.69–1.08) 0.95 (0.69–1.33) 1.51 (0.98–2.34) 1.09 (0.86–1.38)
0.151 0.205 0.784 0.061 0.498
0.91 (0.70–1.16) 0.88 (0.72–1.07) 0.98 (0.73–1.31) 1.37 (0.92–2.04) 1.09 (0.88–1.35)
0.436 0.201 0.882 0.121 0.444
0.90 (0.76–1.06) 0.96 (0.83–1.12) 0.96 (0.77–1.20) 1.22 (0.91–1.64) 1.04 (0.89–1.21)
0.207 0.630 0.733 0.184 0.627
Sample size ≥400 subjects b400 subjects
10 14
3140/3992 1744/2211
1.00 (0.93–1.07) 0.97 (0.88–1.07)
0.948 0.561
0.99 (0.85–1.15) 0.93 (0.75–1.14)
0.849 0.459
0.98 (0.86–1.13) 0.98 (0.82–1.19)
0.802 0.865
1.00 (0.91–1.11) 0.95 (0.83–1.09)
0.928 0.448
Ethnicity Asian Non-Asian
11 13
1714/2821 3170/3382
0.88 (0.80–0.96) 1.07 (1.00–1.16)
0.543 0.060
0.77 (0.63–0.93) 1.13 (0.97–1.33)
0.787 0.123
0.85 (0.72–1.01) 1.10 (0.95–1.28)
0.808 0.201
0.80 (0.67–0.96) 1.09 (0.98–1.20)
0.080c 0.107
Bold value represents statistically significant results. a Number of comparisons. b P value of Q-test for heterogeneity test. c Random effects model was used when P value for heterogeneity test b0.1; otherwise, fixed-effects model was used.
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et al., 2013; Kariyazono et al., 2004; Breunis et al., 2006; Hsueh et al., 2008; Huang et al., 2008; Young et al., 2004; Barile et al., 2006; Butt et al., 2007; Wang et al., 2008; Blobe et al., 2000; Zablotna et al., 2011). Moreover, some studies indicate that VEGF variants are located within a chromosomal linkage to rheumatoid arthritis (Carvalho et al., 2007; Jawaheer et al., 2003). Although these researches present the evidences that VEGF polymorphism influences on the susceptibility to autoimmune diseases, inconsistent results have been yielded. Hence, a meta-analysis is performed to detect the association between VEGF polymorphism and autoimmune diseases. In the present research, a total of twenty four independent studies including 11,087 individuals were analyzed after literature search. After pooling the data, we found a negative association between VEGF −634G/C polymorphism and autoimmune diseases in total population. Considering the effect of clinical features, sample size and ethnicity, stratified analyses were performed. After calculating the data, we observed that no significant association between VEGF − 634G/C polymorphism and autoimmune diseases in these subgroups except in the stratified analysis of Asian population (Table 2). In the subgroup of Asian population, a total of eleven relevant studies were involved. After assessment, it was shown that a significant association was revealed between VEGF − 634G/C polymorphism and susceptibility to autoimmune diseases (Table 2). The specific significance we found in Asian population suggests that the ethnicity has an important role in the association between VEGF − 634G/C polymorphism and autoimmune diseases. Although our meta-analysis points out the significance in Asian population, there are still some limitations. In the present study, Egger's test showed that publication bias existed in allelic model among Asian population. Therefore, more studies with larger sample sizes are demanded. Additionally, the articles involved in our study are limited to be published in English. Some other studies published in non-English languages are excluded and our result may be distorted. Certainly, in addition to the influence of genetics, other factors such as environmental factors, life style and age may have a deep influence on autoimmune diseases. In conclusion, our results suggest that VEGF − 634G/C polymorphism has a significant effect on the susceptibility to autoimmune diseases in Asian population. In addition, considering the relatively small sample, more studies with lager sample size are further required to the confirmation of our meta-analysis. Conflicts of interest The authors declare that no conflicts of interest exist. Authors' contributions HK C and XH C design the research. HK C and TY Z collect and analyze the data. HK C, TY Z, BL Z and XH C write the manuscript. All authors read and approved the final manuscript. Acknowledgments This work was supported by the National technology support project (No.2012BAK17B07), the National Natural Science Foundation of China (No.31060217). References Allanore, Y., Borderie, D., Airo, P., 2007. Lack of association between three vascular endothelial growth factor gene polymorphisms and systemic sclerosis: results from a multicenter EUSTAR study of European Caucasian patients. Ann. Rheum. Dis. 66, 257–259.
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Fig. 2. Meta-analysis of the relationship between VEGF − 634G/C polymorphism and autoimmune diseases in Asian population using the model of (A) C vs. G; (B) CC vs. GG; (C) CC + GC vs. GG.
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Gene journal homepage: www.elsevier.com/locate/gene
Review
Association between VEGF − 634G/C polymorphism and susceptibility to autoimmune diseases: A meta-analysis Haikui Chen a,1, Tianyun Zhang b,1, Bolin Gong c, Xiaohong Cao a,⁎ a b c
Department of Life Science, Beifang University of Nationalities, Yinchuan 750021, China The First Hospital of Chinese People's Liberation Army (PLA), Lanzhou 730050, China Key Laboratory of Energy & Chemical Engineering, Ningxia University, Yinchuan 750021, China
a r t i c l e
i n f o
Article history: Received 15 October 2014 Received in revised form 22 December 2014 Accepted 12 January 2015 Available online 14 January 2015 Keywords: VEGF −634G/C Polymorphism Autoimmune diseases Meta-analysis
a b s t r a c t The role of VEGF −634G/C polymorphism has been involved in the investigations of susceptibility to autoimmune diseases, but the conclusion remains controversial. Here, we have performed a meta-analysis to clarify the relationship between them. All relevant articles updating to August 2013 were searched in PubMed and EMBASE. Crude odds ratios (ORs) with 95% confidence intervals (CIs) based on the available articles were calculated. A total of 24 independent studies associated with autoimmune disease were analyzed in our research. The results show that VEGF −634G/C polymorphism was associated with susceptibility to autoimmune disease in Asian population (C vs. G: OR = 0.88, 95% CI: 0.80–0.96, P = 0.543; CC vs. GG: OR = 0.77, 95% CI: 0.63–0.93, P = 0.787; CC + GC vs. GG: OR = 0.80, 95% CI: 0.67–0.96, P = 0.080 by random effects model). Nevertheless, no significant associations were found in total population or in other stratified groups. In the current metaanalysis, we reveal a significant association between VEGF −634G/C polymorphism and susceptibility to autoimmune diseases in Asian population. © 2015 Published by Elsevier B.V.
1. Introduction Many people have been suffered from autoimmune diseases which are considered as the result of the damaging immune response (Lleo et al., 2010). Autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type I diabetes mellitus, and psoriasis, are thought to have similar immune pathogenesis (Shapira et al., 2010; Deane et al., 2010; Arbuckle et al., 2003). According to some studies, autoimmune diseases result from immune system disorders which are thought to be under the control of genetic factors (Cho and Gregersen, 2011; Manolio et al., 2009; Costenbader et al., 2012; Leung et al., 2010). Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors and a product of endothelial cells, fibroblasts, smooth muscle cells, and macrophages (Jain, 2003; Senger et al., 1983; Ferrara, 2009). Some studies suggest that VEGF can regulate endothelial cells growth resulting in the initiation of vessel formation (Leung et al., 1989; Houck et al., 1992). Subsequent analyses confirm that VEGF is also indispensable for the establishment of mature vascular network Abbreviations: OR, odds ratio; CI, confidence interval; KD, Kawasaki disease; GCA, giant cell arteritis; BD, behcet disease; IBD, inflammatory bowel disease; SSc, systemic sclerosis; SLE, systemic lupus erythematosus; GD, graves' disease; T1DM, type I diabetes mellitus. ⁎ Corresponding author at: Department of Life Science, Beifang University of Nationalities, Yinchuan 730000, China. E-mail addresses: [email protected] (H. Chen), [email protected] (T. Zhang), [email protected] (B. Gong), [email protected] (X. Cao). 1 These two authors contributed equally to this work.
http://dx.doi.org/10.1016/j.gene.2015.01.023 0378-1119/© 2015 Published by Elsevier B.V.
(Carmeliet, 2000; Yancopoulos et al., 2000). More than the significant impacts of VEGF in angiogenesis, it is reported that VEGF also has an important role in autoimmune diseases (Carvalho et al., 2007). Additionally, some studies suggest that the level of VEGF is higher in individuals with autoimmune diseases than that in healthy people (Robak et al., 2003; Taylor, 2005; Mackiewicz et al., 2002). Overall, these researches may present evidences that VEGF is closely linked with susceptibility to autoimmune diseases. Previous study indicates that VEGF − 634G/C (rs2010963) polymorphism is linked with the regulation of VEGF expression levels (Lambrechts et al., 2003). Regarding to this, a number of studies are investigated to find the association between VEGF −634G/C (rs2010963) polymorphism and autoimmune diseases. Nevertheless, no consistent results were yielded. Considering the influences of the sample size, ethnical context and other limited factors, we performed a meta-analysis to elucidate whether VEGF −634G/C (rs2010963) polymorphism is susceptible to autoimmune diseases. Hence, in our study, we hope to find a new mechanism of autoimmune diseases and try to provide a potent therapeutic target for autoimmune diseases. 2. Materials and methods 2.1. Search strategy Articles dated to August 2013 were searched in PUBMED and EMBASE databases using the key words “VEGF”, “polymorphism”, “autoimmune
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diseases” and “autoimmunity” in various combinations. In this current study, articles we searched were limited to be published in English.
Egger's linear regression asymmetry test, P b 0.05 suggested statistically significant publication bias. All statistical analyses were tested with STATA version 10.1 (Stata Corporation, College Station, TX).
2.2. Selection criteria 3. Results Identification of eligible studies was as follows: (1) studies about VEGF − 634G/C polymorphism and the susceptibility of autoimmune diseases; (2) studies defined as case–control studies; and (3) studies containing available and sufficient data. 2.3. Data extraction Data extraction was carried out by two authors. The following information was extracted from eligible studies: first author, published year, country or area of study population, clinical features, ethnicity, sample size, and the number of genotypes in cases and controls. 2.4. Statistical analysis The assessment of effect estimate was primarily determined by the odds ratio with its 95% confidence interval. We calculated the pooled ORs by performing the genetic models for the allelic effect (C versus G), homozygote comparison (CC versus GG), dominant model (CC versus GG + GC) and recessive model (CC + GC versus GG) respectively. Analyses of stratified groups were performed according to clinical features and ethnicity. Heterogeneity was assessed by a chi-square-based Q-statistic test (Higgins and Thompson, 2002) and was thought to be significant if the result was P b 0.10. If so, ORs were calculated depending on random-effects model (the DerSimonian and Laird model) (DerSimonian and Laird, 1986), otherwise the fixed-effects model (the Mantel and Haenszel model) was used (Mantel and Haenszel, 2004). Sensitive analyses were carried out to evaluate the stability of the results. Analysis of publication bias was shown with the funnel plot and
A total of one hundred and ninety eight relevant articles were indentified through literature search and twenty four eligible studies were included in further analysis (Fig. 1). Generally, the meta-analysis includes seven studies of psoriasis, four studies referred to rheumatoid arthritis (RA), four studies focusing on Kawasaki disease (KD), three studies associated with giant cell arteritis (GCA), and each one study with behcet's disease (BD), inflammatory bowel disease (IBD), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), graves' disease (GD) and type I diabetes mellitus (T1DM), respectively. Among them, there were eleven studies of Asian descent, eleven studies of Caucasians and two remaining studies of unknown ethnicity. In total, the analyses involved 11,087 subjects (4884 patients and 6203 healthy controls). Characteristics of all studies are summarized and the distribution of the VEGF − 634G/C genotype among total population is shown in Table 1. After the data of twenty four studies were pooled into meta-analysis, the result was presented in allelic comparison (OR = 0.99, 95% CI: 0.93– 1.05, P = 0.691 for heterogeneity), in homozygote comparison (OR = 0.96, 95% CI: 0.85–1.09, P = 0.553 for heterogeneity), in dominant model (OR = 0.98, 95% CI: 0.88–1.10, P = 0.762 for heterogeneity) and recessive model (OR = 0.98, 95% CI: 0.91–1.07, P = 0.701 for heterogeneity). Additionally, stratified analyses were further carried out in order to avoid the side effect of heterogeneity and illustrate an exact relationship between VEGF −634G/C polymorphism and susceptibility to autoimmune diseases. Considering the clinical features, we divided the studies into five subgroups. No evidence of significant association between
Fig. 1. Flow chart of article selection.
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Table 1 Characteristic of included studies. Author (reference)
Year
Nam (24) Ferrante (25) McKnight (26) Allanore (27) Wongpiyabovorn (28) Vural (29) Boiardi (30) Rueda (31) Enjuanes (32) Han (33) Rueda (34) Lv (35) Zhang (36) Kariyazono (37) Breunis (38) Hsueh (39) Huang (40) Young (41) Barile (42) Butt (43) Wang (44) Wongpiyabovorn (45) Wu (46) Zablotna (47)
2005 2006 2006 2007 2010 2012 2003 2005 2012 2004 2005 2011 2013 2004 2006 2007 2008 2004 2006 2007 2008 2008 2010 2011
Country/area
Korea Belgium Ireland France Thailand Turkey Italy Spain Spain China Spain China China Japan Netherland Taiwan Taiwan UK Italy Canada China Thailand China Poland
Ethnicity
Asian Caucasian Caucasian Caucasian Asian Unknown Caucasian Caucasian Caucasian Asian Caucasian Asian Asian Asian Caucasian Asian Asian Unknown Caucasian Caucasian Asian Asian Asian Caucasian
Clinical feature
BD IBD T1DM SSc SLE GD GCA GCA GCA RA RA RA RA KD KD KD KD Psoriasis Psoriasis Psoriasis Psoriasis Psoriasis Psoriasis Psoriasis
VEGF − 634G/C polymorphism and susceptibility to autoimmune diseases was found in any genetic model among these subgroups (Table 2). By sample size, the studies were stratified into two subgroups. One was composed of studies with more than 400 subjects. The other was composed of studies with fewer than 400 subjects. Similarly, no obvious evidence of significant association between variant VEGF −634G/C genotypes and autoimmune diseases was found (Table 2). Considering the impact of ethnicity, we divided the studies into two subgroups. A significant association between VEGF −634G/C polymorphism and susceptibility to autoimmune diseases was found among Asian population (C vs. G: OR = 0.88, 95% CI: 0.80–0.96, P = 0.543; CC vs. GG: OR = 0.77, 95% CI: 0.63–0.93, P = 0.787; CC + GC vs. GG: OR = 0.80, 95% CI: 0.67–0.96, P = 0.080 by random effects model), but negative association was found in non-Asian populations (Fig. 2). Sensitivity analysis was performed under various comparisons in total population and all subgroups. When a single study was excluded, none of the results were significantly altered each time (data not shown).
Sample size (case/control)
101/138 452/271 242/301 416/249 193/234 167/203 92/200 103/226 81/166 140/149 753/801 98/100 318/695 103/144 166/297 93/96 154/672 137/102 117/215 255/127 103/103 154/234 257/258 189/214
Case
Control
GG
GC
CC
GG
GC
CC
38 166 60 168 70 106 20 52 36 36 339 40 104 39 73 35 45 50 53 118 51 69 100 94
49 232 135 181 97 48 53 36 33 63 312 48 167 46 71 40 87 67 50 118 39 74 111 81
14 54 47 67 26 13 19 15 12 41 102 10 47 18 22 18 22 20 14 19 13 11 46 14
39 96 85 97 87 152 72 101 86 28 357 35 238 50 132 22 225 47 88 64 37 87 73 121
74 139 165 115 118 47 100 86 71 72 330 49 340 63 130 62 333 48 99 45 52 118 133 86
25 36 51 37 29 4 28 39 9 49 114 16 117 31 35 12 114 7 28 18 14 29 52 7
Publication bias was assessed by Begg's funnel plot and Egger's test (figure not shown) in total population and all subgroups. Egger's linear regression test suggested moderate publication bias in allelic model (C vs. G) for Asian population (t = − 2.4, P = 0.04) and for non-Asian population (t = 2.30, P = 0.042), but no evidence of publication bias in any other genetic model for total population and subgroups (data not shown). 4. Discussion A complex of immune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, and psoriasis are described as autoimmune diseases. Recently, a number of studies have been investigated the association between autoimmune diseases and VEGF polymorphism (Nam et al., 2005; Ferrante et al., 2006; McKnight et al., 2007; Allanore et al., 2007; Wongpiyabovorn et al., 2008, 2011; Vural et al., 2012; Boiardi et al., 2003; Rueda et al., 2005a,b; Enjuanes et al., 2012; Han et al., 2004; Lv et al., 2011; Zhang
Table 2 Results of meta-analysis for VEGF −634G/C polymorphism and susceptibility to autoimmune diseases. Study groups
Total
na
Sample size (case/control)
C vs. G
CC vs. GG
CC vs. GG + GC
CC + GC vs. GG
OR (95% CI)
Pb
OR (95% CI)
Pb
OR (95% CI)
Pb
OR (95% CI)
Pb
24
4884/6203
0.99 (0.93–1.05)
0.691
0.96 (0.85–1.09)
0.553
0.98 (0.88–1.10)
0.762
0.98 (0.91–1.07)
0.701
Clinical features Psoriasis RA KD GCA Other diseases
7 4 4 3 6
1212/1253 1309/1745 516/1207 276/602 1571/1396
0.92 (0.82–1.04) 0.95 (0.85–1.05) 0.97 (0.83–1.13) 1.23 (1.00–1.52) 1.04 (0.93–1.16)
0.192 0.306 0.703 0.050 0.467
0.82 (0.63–1.07) 0.87 (0.69–1.08) 0.95 (0.69–1.33) 1.51 (0.98–2.34) 1.09 (0.86–1.38)
0.151 0.205 0.784 0.061 0.498
0.91 (0.70–1.16) 0.88 (0.72–1.07) 0.98 (0.73–1.31) 1.37 (0.92–2.04) 1.09 (0.88–1.35)
0.436 0.201 0.882 0.121 0.444
0.90 (0.76–1.06) 0.96 (0.83–1.12) 0.96 (0.77–1.20) 1.22 (0.91–1.64) 1.04 (0.89–1.21)
0.207 0.630 0.733 0.184 0.627
Sample size ≥400 subjects b400 subjects
10 14
3140/3992 1744/2211
1.00 (0.93–1.07) 0.97 (0.88–1.07)
0.948 0.561
0.99 (0.85–1.15) 0.93 (0.75–1.14)
0.849 0.459
0.98 (0.86–1.13) 0.98 (0.82–1.19)
0.802 0.865
1.00 (0.91–1.11) 0.95 (0.83–1.09)
0.928 0.448
Ethnicity Asian Non-Asian
11 13
1714/2821 3170/3382
0.88 (0.80–0.96) 1.07 (1.00–1.16)
0.543 0.060
0.77 (0.63–0.93) 1.13 (0.97–1.33)
0.787 0.123
0.85 (0.72–1.01) 1.10 (0.95–1.28)
0.808 0.201
0.80 (0.67–0.96) 1.09 (0.98–1.20)
0.080c 0.107
Bold value represents statistically significant results. a Number of comparisons. b P value of Q-test for heterogeneity test. c Random effects model was used when P value for heterogeneity test b0.1; otherwise, fixed-effects model was used.
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et al., 2013; Kariyazono et al., 2004; Breunis et al., 2006; Hsueh et al., 2008; Huang et al., 2008; Young et al., 2004; Barile et al., 2006; Butt et al., 2007; Wang et al., 2008; Blobe et al., 2000; Zablotna et al., 2011). Moreover, some studies indicate that VEGF variants are located within a chromosomal linkage to rheumatoid arthritis (Carvalho et al., 2007; Jawaheer et al., 2003). Although these researches present the evidences that VEGF polymorphism influences on the susceptibility to autoimmune diseases, inconsistent results have been yielded. Hence, a meta-analysis is performed to detect the association between VEGF polymorphism and autoimmune diseases. In the present research, a total of twenty four independent studies including 11,087 individuals were analyzed after literature search. After pooling the data, we found a negative association between VEGF −634G/C polymorphism and autoimmune diseases in total population. Considering the effect of clinical features, sample size and ethnicity, stratified analyses were performed. After calculating the data, we observed that no significant association between VEGF − 634G/C polymorphism and autoimmune diseases in these subgroups except in the stratified analysis of Asian population (Table 2). In the subgroup of Asian population, a total of eleven relevant studies were involved. After assessment, it was shown that a significant association was revealed between VEGF − 634G/C polymorphism and susceptibility to autoimmune diseases (Table 2). The specific significance we found in Asian population suggests that the ethnicity has an important role in the association between VEGF − 634G/C polymorphism and autoimmune diseases. Although our meta-analysis points out the significance in Asian population, there are still some limitations. In the present study, Egger's test showed that publication bias existed in allelic model among Asian population. Therefore, more studies with larger sample sizes are demanded. Additionally, the articles involved in our study are limited to be published in English. Some other studies published in non-English languages are excluded and our result may be distorted. Certainly, in addition to the influence of genetics, other factors such as environmental factors, life style and age may have a deep influence on autoimmune diseases. In conclusion, our results suggest that VEGF − 634G/C polymorphism has a significant effect on the susceptibility to autoimmune diseases in Asian population. In addition, considering the relatively small sample, more studies with lager sample size are further required to the confirmation of our meta-analysis. Conflicts of interest The authors declare that no conflicts of interest exist. Authors' contributions HK C and XH C design the research. HK C and TY Z collect and analyze the data. HK C, TY Z, BL Z and XH C write the manuscript. All authors read and approved the final manuscript. Acknowledgments This work was supported by the National technology support project (No.2012BAK17B07), the National Natural Science Foundation of China (No.31060217). References Allanore, Y., Borderie, D., Airo, P., 2007. Lack of association between three vascular endothelial growth factor gene polymorphisms and systemic sclerosis: results from a multicenter EUSTAR study of European Caucasian patients. Ann. Rheum. Dis. 66, 257–259.
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Fig. 2. Meta-analysis of the relationship between VEGF − 634G/C polymorphism and autoimmune diseases in Asian population using the model of (A) C vs. G; (B) CC vs. GG; (C) CC + GC vs. GG.
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