552311
research-article2014
JRA0010.1177/1470320314552311Journal of the Renin-Angiotensin-Aldosterone SystemSHEN et al.
Original Article
Adiponectin gene polymorphisms contributes to ischemic stroke risk: A meta-analysis
Journal of the Renin-AngiotensinAldosterone System 1–7 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320314552311 jra.sagepub.com
Dingzhu Shen, Sanli Xing and Chuan Chen
Abstract Background: Previous studies have reported the relation between the adiponectin polymorphisms and the risk of ischemic stroke. However, the findings is inclusive. In the present study, we performed a meta-analysis to clarify the relation between the adiponectin polymorphisms and the stroke. Methods: Relevant studies were identified by searching PubMed, EMBASE, ISI Web of Science, ScienceDirect, Wiley Online Library, Wanfang database in China, and Chinese National Knowledge Infrastructure databases (CNKI) through July 2013 and other method such as reviewing the reference of retrieved literatures. We selected literatures that reported Odds ratio (OR) and 95% confidence interval (CI) for the relation between the ischemic stroke and the adiponectin genetic polymorphisms. With 1720 stroke cases and 5549 controls, were included. Our results showed that rs2241766 was associated with the risk of ischemic stroke in a recessive model (GG vs (TT+TG), OR = 1.29, 95% CI: 1.01–1.64, p = 0.04). However, rs1501299 and rs266729 were not found to be associated with ischemic stroke in our analysis. Conclusion: The present study suggested that rs2241766 polymorphism of adiponectin gene was associated with the risk for ischemic stroke. Keywords Meta-analysis, ischemic stroke, adiponectin Date received: 19 June 2014; accepted: 22 August 2014
Introduction Stroke is the leading cause of disability in the world and post-stroke disability places a heavy burden on our society.1 Strong evidence from genetic association studies indicates that genetic predisposition, in addition to recognized risk factors such as hypertension, smoking, diabetes, obesity, and advanced age, contributes to the development of stroke.2 In addition, individuals with a family history of stroke are more likely to suffer a stroke. Understanding these genetic influences may lead to better prevention of and intervention in stroke. Adiponectin, an adipose tissue-specific plasma protein, is structurally homologous to collagens VIII and X and complement factor C1q3 and plays an important role in regulating energy homeostasis, glucose and lipid metabolism, and anti-inflammatory responses in the vascular system.4–6 Low plasma concentrations of adiponectin have been associated with myocardial
infarction7 and ischemic stroke.8 Recent evidence has implicated the genetic polymorphism of the adiponectin gene (ADIPOQ) in association with risk of coronary heart disease and ischemic stroke.9–20 Three singlenucleotide polymorphisms (SNPs) including rs266766 (T is converted to G), rs1501299 (G is converted to T) Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital Affiliated Shanghai University of Traditional Chinese Medicine, P.R. China. D.S. and S.X. are co-first authors and contributed equally to this work. Corresponding author: Dingzhu Shen and Chuan Chen, Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital Affiliated Shanghai University of Traditional Chinese Medicine, Building C, No 365 Xiangyang South Road, Xuhui district, Shanghai 200031, P.R. China. Email: [email protected] and [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm). Downloaded from jra.sagepub.com at Umea University Library on April 1, 2015
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and rs266729 (C is converted to G) were focused on in these studies. However, the conclusions of these studies were inconsistent. Leu et al.18 did not find any association between ADIPOQ polymorphisms and ischemic stroke. But Liu et al.19 found a positive association of ADIPOQ polymorphisms with ischemic stroke. In their studies, compared with CC genotype, GG genotype of rs266729 increased the risk of ischemic stroke in a Chinese Han population (odds ratio (OR) = 2.062, 95% confidence interval (CI) = 1.145–3.715, p = 0.016). After adjustment for potential risk factors by multivariate logistic analysis, rs266729 remained in positive correlation with ischemic stroke (OR = 2.165; 95% CI = 1.116–4.197, p = 0.022). Also, Arregui et al.’s findings11 suggest that rs2943634 of ADIPOQ is associated with ischemic stroke risk and with plasma levels of highdensity lipoprotein (HDL)-cholesterol and adiponectin in this German population. Since the relatively small sample size of a single study may not have enough power to detect slight effects of ADIPOQ on stroke, meta-analysis may provide more credible evidence by systematically summarizing existing data. In this study, we have extensively reviewed the literature and performed a meta-analysis based on all eligible case-control published data to evaluate the association between ADIPOQ genetic polymorphisms and stroke susceptibility.
Materials and methods Literature search and selection We carried out a publication search in PubMed, EMBASE, ISI Web of Science, ScienceDirect, Wiley Online Library, Wanfang database in China, and Chinese National Knowledge Infrastructure (CNKI) databases with the following search terms: (“ADIPOQ” or “adiponectin”) and (“stroke” or “brain infarction” or “cerebrovascular disease”) and (“SNP” or “polymorphism” or “mutation”) by two independent investigators. Publication language was not restricted in our search. Abstracts, reviews or editorials were not included. The references of all identified publications were searched for any additional studies, and the related articles option was used to search for further potentially relevant articles. The following criteria have to be meet by the included studies. 1)the study must be case-control study; 2) the ischemic stroke diagnosis must confirmed by computed tomography (CT) or magnetic resonance imaging (MRI); 3) reported the relation between ADIPOQ polymorphism and ischemic stroke and 4) sufficient data for examining an OR and 95%CI. If a study in line with 1) patients were under 18 years of age, or 2) original genotype data were not provided must be excluded from the meta-analysis.
Data extraction The data extraction was performed by two independent investigators (DZS and SLX). The first author’s last name, the publication year, country, the genotype data of cases and controls, and the methods for genotyping for each study were collected.
Statistical analysis We recalculated the Hardy-Weinberg equilibrium (HWE) by χ2 test. The OR value of each polymorphism and its 95%CI were calculated to measure the strength of the genetic association. Meta-analysis was performed by using RevMan 5.0 software provided by the Cochrane Collaboration. We directly used Q-test and I2 test to examine the heterogeneity between each study. By heterogeneity test, if p > 0.05, we select the fixed-effects model, and if p < 0.05, we selected the random-effects model to merge OR. Analysis of sensitivity includes the difference of point estimation and CIs of the combined effects value at a different model, to observe whether it changes the result. To test the publication bias, we used the RevMan 5.0 statistical software to make the funnel plot. Each SNP was tested for associations with stroke susceptibility based on different genetic models. To contrast the wild-type homozygote, we first estimated the risk of the rare allele homozygote and heterozygous genotypes on stroke, then evaluated the risk of stroke under a dominant model and a recessive model. The statistical significance of the pooled OR was determined with the Z test, and a p value of 0.05, I2 = 0%). For the sensitivity analysis, we deleted one single study from the overall pooled analysis each time to check the influence of the removed data set to the overall ORs. The pooled ORs and 95% CIs were not significantly altered when any part of the study was omitted, which indicated that any single study had little impact on the overall ORs.
Publication bias Funnel plot and Egger’s test were performed to assess the publication bias of the literature. Symmetrical funnel plots were obtained in the SNPs tested in all of the models. Egger’s test further confirmed the absence of publication bias in this meta-analysis (p > 0.05) (Figure 5).
Discussion In this meta-analysis, an association between the three common SNPs in ADIPOQ (rs2241766, rs1501299 and rs266729) and ischemic stroke risk was evaluated by the pooled results from eight published studies. The results demonstrated that rs2241766 was associated with an increased risk for developing ischemic stroke, and that rs1501299 and rs266729 were not observed to be associated with stroke.
Downloaded from jra.sagepub.com at Umea University Library on April 1, 2015
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Table 1. The characteristics of included studies. Author
Year
Country
Genotyping methods
Groups
No.
Genotypes (n)
rs2241766
TT
Hegener21 Yamada22 Xin23 Chen16 Liu19 Leu18 Li24 Li24
2006
US
TaqMan
2008
Japan
2009
China
2010
China
PCRsequence PCRsequence TaqMan
2011
China
PCR-RFLP
2011
China
PCR-RFLP
2009
China
PCR-RFLP
2009
China
PCR-RFLP
Case Control Case Control Case Control Case Control Case Control Case Control Case Control Case Control
259 259 313 971 64 51 357 345 302 338 80 3250 206 204 139 131
203 188
TG 52 64
rs1501299 GG 4 7
192 221 157 187
117 95 123 136
36 18 22 15
115 135 77 86
70 56 47 39
21 13 15 6
GG
rs266729
GT
TT
137 136
98 104
24 19
23 39
27 9
14 3
139 164 39 1750
128 142 35 1261
35 32 6 239
CC
CG
GG
123 134 163 575
128 98 120 346
174 176 144 189
108 104 125 128
101 103 73 73
70 65 38 39
8 27 28 50 35 24 33 21 22 20 13 4
US: United States; PCR: polymerase chain reaction; RFLP: restriction fragment length polymorphism.
Figure 2. Forest plot of stroke and rs2241766. The horizontal lines correspond to the study-specific odds ratio (OR) and 95% confidence interval (CI), respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of OR and 95% CI. In this analysis, a fixed-effects model was used. (a) TT vs (TG+GG); (b) GG vs (TG+TT); (c) GG vs TT; (d) TG vs TT.
This is the first meta-analysis to evaluate the association of ADIPOQ genetic polymorphisms with ischemic stroke. Although several previous studies focusing on the relation between ADIPOQ polymorphism and ischemic
stroke did not come to same conclusion, the present study clarified this association. Adiponectin is also called GBP-28, apM1, ADIPOQ and Acrp30.25 It was identified as an adipocytokine, a
Downloaded from jra.sagepub.com at Umea University Library on April 1, 2015
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Shen et al.
Figure 3. Forest plot of stroke and rs1501299. The horizontal lines correspond to the study-specific odds ratio (OR) and 95% confidence interval (CI), respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of OR and 95% CI. In this analysis, a fixed-effects model was used. (a) GG vs (GT+TT); (b) TT vs (TG+GG); (c) TT vs GG; (d) TG vs GG.
Figure 4. Forest plot of stroke and rs266729. The horizontal lines correspond to the study-specific odds ratio (OR) and 95% confidence interval (CI), respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of OR and 95% CI. In this analysis, a fixed-effects model was used. (a) CC vs (CG+GG); (b) GG vs (CG+CC); (c) GG vs CC; (d) GC vs CC.
244-amino-acid protein, the product of the ADIPOQ gene, which is highly expressed in adipose cells.3 ADIPOQ, a novel adipose tissue-specific protein, is a structural homolog of collagen VIII and X, complement factor C1q, and tumor necrosis factor-α (TNFα).26,27 ADIPOQ
regulates the homeostasis of glucose, energy storage, and fatty acid metabolism6,28 and acts as an anti-inflammatory29 and anti-atherogenic plasma protein.30,31 ADIPOQ is associated with obesity, metabolic syndrome, type 2 diabetes mellitus, hypertension and coronary artery
Downloaded from jra.sagepub.com at Umea University Library on April 1, 2015
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Figure 5. Begg’s funnel plot for publication bias tests. Each point represents a separate study for the indicated association. Log(OR) represents natural logarithm of the odds ratio. The vertical line represents the mean effects size. (a) rs2241766; (b) rs1501299; (c) rs2667.
diseases. Furthermore, low levels of plasma adiponectin have been linked to ischemic cerebrovascular disease (CVD).7,8 And a recently published paper suggested the genetic polymorphisms of ADIPOQ were associated with ischemic stroke.9–24 In this meta-analysis, a total of eight case-control studies were analyzed to provide a comprehensive assessment of the association between ADIPOQ polymorphisms and ischemic stroke. Genotypes in all studies were detected with genetic DNA from blood samples using a total of three genotyping methods. All of the studies checked genotypes for quality control. Genotype distribution of controls in all studies was consistent with HWE. By the metaanalysis, our results did support a genetic association between rs2241766 and susceptibility to ischemic stroke. Exploring heterogeneity is one of the important goals of meta-analysis. In the present study no significant heterogeneity was found among the included studies. Sensitivity analysis also showed that omission of any single study did
not have a significant impact on the combined ORs. Furthermore, funnel plot did not reflect obvious asymmetry, and Egger’s test further indicated no considerable publication bias in this meta-analysis. This made the results of this meta-study more reliable to some extent. Be that as it may, there remained some limitations in this meta-analysis. In the studies included, the genotyping methods used were not the same. In addition, other clinical factors such as age, sex and different chemotherapies in each study might lead to bias. Determining whether these factors influence the results of this meta-analysis would need further investigation.
Conclusion Our study suggested that SNP rs2241766 in the ADIPOQ gene was associated with a significantly increased risk of ischemic stroke. Larger well-designed
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Shen et al. epidemiological studies with ethnically diverse populations and functional evaluations are warranted to confirm our findings. Conflict of interest None declared.
Funding This work was financially supported by the National Natural Science Foundation of China (No.81202731), the China Postdoctoral Science Foundation (No.2014M550999) and the Shanghai Municipal Health Bureau Found (No.20114047).
References 1. Bonita R, Mendis S, Truelsen T, et al. The global stroke initiative. Lancet Neurol 2004; 3: 391–393. 2. Sharma P. Genes for ischemic stroke: Strategies for their detection. J Hypertens 1996; 14: 277–285. 3. Maeda K, Okubo K, Shimomura I, et al. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 1996; 221: 286–289. 4. Hu E, Liang P and Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 1996; 271: 10697–10703. 5. Goldstein BJ and Scalia R. Adiponectin: A novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab 2004; 89: 2563–2568. 6. Ouchi N, Kihara S, Funahashi T, et al. Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol 2003; 14: 561–566. 7. Pischon T, Girman CJ, Hotamisligil GS, et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004; 291: 1730–1737. 8. Chen MP, Tsai JC, Chung FM, et al. Hypoadiponectinemia is associated with ischemic cerebrovascular disease. Arterioscler Thromb Vasc Biol 2005; 25: 821–826. 9. Kawai T, Ohishi M, Takeya Y, et al. Adiponectin single nucleotide polymorphism is a genetic risk factor for stroke through high pulse wave pressure: A cohort study. J Atheroscler Thromb 2013; 20: 152–160. 10. Rizk NM, El-Menyar A, Marei I, et al. Association of adiponectin gene polymorphism (+T45G) with acute coronary syndrome and circulating adiponectin levels. Angiology 2013; 64: 257–265. 11. Arregui M, Fisher E, Knüppel S, et al. Significant associations of the rs2943634 (2q36.3) genetic polymorphism with adiponectin, high density lipoprotein cholesterol and ischemic stroke. Gene 2012; 494: 190–195. 12. Katakami N, Kaneto H, Matsuoka TA, et al. Adiponectin G276T gene polymorphism is associated with cardiovascular disease in Japanese patients with type 2 diabetes. Atherosclerosis 2012; 220: 437–442. 13. Chung CM, Lin TH, Chen JW, et al. A genome-wide association study reveals a quantitative trait locus of adiponectin on CDH13 that predicts cardiometabolic outcomes. Diabetes 2011; 60: 2417–2423. 14. Kolovou G, Kolovou V, Vasiliadis I, et al. Ideal lipid profile and genes for an extended life span. Curr Opin Cardiol 2011; 26: 348–355.
15. Bevan S, Meidtner K, Lorenz M, et al. Adiponectin level as a consequence of genetic variation, but not leptin level or leptin: Adiponectin ratio, is a risk factor for carotid intimamedia thickness. Stroke 2011; 42: 1510–1514. 16. Chen XL, Cheng JQ, Zhang RL, et al. Study on the relationship between polymorphism of adiponectin gene and risk of ischemic stroke among Han population in the Northern parts of China [article in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi 2010; 31: 129–132. 17. Cheong MY, Bang OS, Cha MH, et al. Association of the adiponectin gene variations with risk of ischemic stroke in a Korean population. Yonsei Med J 2011; 52: 20–25. 18. Leu HB, Chung CM, Chuang SY, et al. Genetic variants of connexin37 are associated with carotid intima-medial thickness and future onset of ischemic stroke. Atherosclerosis 2011; 214: 101–106. 19. Liu F, He Z, Deng S, et al. Association of adiponectin gene polymorphisms with the risk of ischemic stroke in a Chinese Han population. Mol Biol Rep 2011; 38: 1983–1988. 20. Qi L, Li T, Rimm E, et al. The +276 polymorphism of the APM1 gene, plasma adiponectin concentration, and cardiovascular risk in diabetic men. Diabetes 2005; 54: 1607– 1610. 21. Hegener HH, Lee IM, Cook NR, et al. Association of adiponectin gene variations with risk of incident myocardial infarction and ischemic stroke: A nested case-control study. Clin Chem 2006; 52: 2021–2027. 22. Yamada Y, Kato K, Oguri M, et al. Association of genetic variants with atherothrombotic cerebral infarction in Japanese individuals with metabolic syndrome. Int J Mol Med 2008; 21: 801–808. 23. Xin YP, Zhang SH, Li QJ, et al. Correlation between adiponectin SNP45 and cerebral infarction with type 2 diabetes. Chinese Journal of Practical Nervous Diseases 2009; 12: 29–31. 24. Li XX, Guan HJ, Guo YP, et al. The relation between adiponectin gene polymorphism and ischemic stroke. China Public Health 2009; 25: 1341–1343. 25. Díez JJ and Iglesias P. The role of the novel adipocytederived hormone adiponectin in human disease. Eur J Endocrinol 2003; 148: 293–300. 26. Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995; 270: 26746–26749. 27. Nakano Y, Tobe T, Choi-Miura NH, et al. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem 1996; 120: 803–812. 28. Goldstein BJ and Scalia R. Adiponectin: A novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab 2004; 89: 2563–2568. 29. Yokota T, Oritani K, Takahashi I, et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 2000; 96: 1723–1732. 30. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial adhesion molecules: Adipocyte-derived plasma protein adiponectin. Circulation 1999; 100: 2473–2476. 31. Ouchi N, Kihara S, Arita Y, et al. Adiponectin, an adipocytederived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 2000; 102: 1296–1301.
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research-article2014
JRA0010.1177/1470320314552311Journal of the Renin-Angiotensin-Aldosterone SystemSHEN et al.
Original Article
Adiponectin gene polymorphisms contributes to ischemic stroke risk: A meta-analysis
Journal of the Renin-AngiotensinAldosterone System 1–7 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1470320314552311 jra.sagepub.com
Dingzhu Shen, Sanli Xing and Chuan Chen
Abstract Background: Previous studies have reported the relation between the adiponectin polymorphisms and the risk of ischemic stroke. However, the findings is inclusive. In the present study, we performed a meta-analysis to clarify the relation between the adiponectin polymorphisms and the stroke. Methods: Relevant studies were identified by searching PubMed, EMBASE, ISI Web of Science, ScienceDirect, Wiley Online Library, Wanfang database in China, and Chinese National Knowledge Infrastructure databases (CNKI) through July 2013 and other method such as reviewing the reference of retrieved literatures. We selected literatures that reported Odds ratio (OR) and 95% confidence interval (CI) for the relation between the ischemic stroke and the adiponectin genetic polymorphisms. With 1720 stroke cases and 5549 controls, were included. Our results showed that rs2241766 was associated with the risk of ischemic stroke in a recessive model (GG vs (TT+TG), OR = 1.29, 95% CI: 1.01–1.64, p = 0.04). However, rs1501299 and rs266729 were not found to be associated with ischemic stroke in our analysis. Conclusion: The present study suggested that rs2241766 polymorphism of adiponectin gene was associated with the risk for ischemic stroke. Keywords Meta-analysis, ischemic stroke, adiponectin Date received: 19 June 2014; accepted: 22 August 2014
Introduction Stroke is the leading cause of disability in the world and post-stroke disability places a heavy burden on our society.1 Strong evidence from genetic association studies indicates that genetic predisposition, in addition to recognized risk factors such as hypertension, smoking, diabetes, obesity, and advanced age, contributes to the development of stroke.2 In addition, individuals with a family history of stroke are more likely to suffer a stroke. Understanding these genetic influences may lead to better prevention of and intervention in stroke. Adiponectin, an adipose tissue-specific plasma protein, is structurally homologous to collagens VIII and X and complement factor C1q3 and plays an important role in regulating energy homeostasis, glucose and lipid metabolism, and anti-inflammatory responses in the vascular system.4–6 Low plasma concentrations of adiponectin have been associated with myocardial
infarction7 and ischemic stroke.8 Recent evidence has implicated the genetic polymorphism of the adiponectin gene (ADIPOQ) in association with risk of coronary heart disease and ischemic stroke.9–20 Three singlenucleotide polymorphisms (SNPs) including rs266766 (T is converted to G), rs1501299 (G is converted to T) Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital Affiliated Shanghai University of Traditional Chinese Medicine, P.R. China. D.S. and S.X. are co-first authors and contributed equally to this work. Corresponding author: Dingzhu Shen and Chuan Chen, Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital Affiliated Shanghai University of Traditional Chinese Medicine, Building C, No 365 Xiangyang South Road, Xuhui district, Shanghai 200031, P.R. China. Email: [email protected] and [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm). Downloaded from jra.sagepub.com at Umea University Library on April 1, 2015
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and rs266729 (C is converted to G) were focused on in these studies. However, the conclusions of these studies were inconsistent. Leu et al.18 did not find any association between ADIPOQ polymorphisms and ischemic stroke. But Liu et al.19 found a positive association of ADIPOQ polymorphisms with ischemic stroke. In their studies, compared with CC genotype, GG genotype of rs266729 increased the risk of ischemic stroke in a Chinese Han population (odds ratio (OR) = 2.062, 95% confidence interval (CI) = 1.145–3.715, p = 0.016). After adjustment for potential risk factors by multivariate logistic analysis, rs266729 remained in positive correlation with ischemic stroke (OR = 2.165; 95% CI = 1.116–4.197, p = 0.022). Also, Arregui et al.’s findings11 suggest that rs2943634 of ADIPOQ is associated with ischemic stroke risk and with plasma levels of highdensity lipoprotein (HDL)-cholesterol and adiponectin in this German population. Since the relatively small sample size of a single study may not have enough power to detect slight effects of ADIPOQ on stroke, meta-analysis may provide more credible evidence by systematically summarizing existing data. In this study, we have extensively reviewed the literature and performed a meta-analysis based on all eligible case-control published data to evaluate the association between ADIPOQ genetic polymorphisms and stroke susceptibility.
Materials and methods Literature search and selection We carried out a publication search in PubMed, EMBASE, ISI Web of Science, ScienceDirect, Wiley Online Library, Wanfang database in China, and Chinese National Knowledge Infrastructure (CNKI) databases with the following search terms: (“ADIPOQ” or “adiponectin”) and (“stroke” or “brain infarction” or “cerebrovascular disease”) and (“SNP” or “polymorphism” or “mutation”) by two independent investigators. Publication language was not restricted in our search. Abstracts, reviews or editorials were not included. The references of all identified publications were searched for any additional studies, and the related articles option was used to search for further potentially relevant articles. The following criteria have to be meet by the included studies. 1)the study must be case-control study; 2) the ischemic stroke diagnosis must confirmed by computed tomography (CT) or magnetic resonance imaging (MRI); 3) reported the relation between ADIPOQ polymorphism and ischemic stroke and 4) sufficient data for examining an OR and 95%CI. If a study in line with 1) patients were under 18 years of age, or 2) original genotype data were not provided must be excluded from the meta-analysis.
Data extraction The data extraction was performed by two independent investigators (DZS and SLX). The first author’s last name, the publication year, country, the genotype data of cases and controls, and the methods for genotyping for each study were collected.
Statistical analysis We recalculated the Hardy-Weinberg equilibrium (HWE) by χ2 test. The OR value of each polymorphism and its 95%CI were calculated to measure the strength of the genetic association. Meta-analysis was performed by using RevMan 5.0 software provided by the Cochrane Collaboration. We directly used Q-test and I2 test to examine the heterogeneity between each study. By heterogeneity test, if p > 0.05, we select the fixed-effects model, and if p < 0.05, we selected the random-effects model to merge OR. Analysis of sensitivity includes the difference of point estimation and CIs of the combined effects value at a different model, to observe whether it changes the result. To test the publication bias, we used the RevMan 5.0 statistical software to make the funnel plot. Each SNP was tested for associations with stroke susceptibility based on different genetic models. To contrast the wild-type homozygote, we first estimated the risk of the rare allele homozygote and heterozygous genotypes on stroke, then evaluated the risk of stroke under a dominant model and a recessive model. The statistical significance of the pooled OR was determined with the Z test, and a p value of 0.05, I2 = 0%). For the sensitivity analysis, we deleted one single study from the overall pooled analysis each time to check the influence of the removed data set to the overall ORs. The pooled ORs and 95% CIs were not significantly altered when any part of the study was omitted, which indicated that any single study had little impact on the overall ORs.
Publication bias Funnel plot and Egger’s test were performed to assess the publication bias of the literature. Symmetrical funnel plots were obtained in the SNPs tested in all of the models. Egger’s test further confirmed the absence of publication bias in this meta-analysis (p > 0.05) (Figure 5).
Discussion In this meta-analysis, an association between the three common SNPs in ADIPOQ (rs2241766, rs1501299 and rs266729) and ischemic stroke risk was evaluated by the pooled results from eight published studies. The results demonstrated that rs2241766 was associated with an increased risk for developing ischemic stroke, and that rs1501299 and rs266729 were not observed to be associated with stroke.
Downloaded from jra.sagepub.com at Umea University Library on April 1, 2015
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Table 1. The characteristics of included studies. Author
Year
Country
Genotyping methods
Groups
No.
Genotypes (n)
rs2241766
TT
Hegener21 Yamada22 Xin23 Chen16 Liu19 Leu18 Li24 Li24
2006
US
TaqMan
2008
Japan
2009
China
2010
China
PCRsequence PCRsequence TaqMan
2011
China
PCR-RFLP
2011
China
PCR-RFLP
2009
China
PCR-RFLP
2009
China
PCR-RFLP
Case Control Case Control Case Control Case Control Case Control Case Control Case Control Case Control
259 259 313 971 64 51 357 345 302 338 80 3250 206 204 139 131
203 188
TG 52 64
rs1501299 GG 4 7
192 221 157 187
117 95 123 136
36 18 22 15
115 135 77 86
70 56 47 39
21 13 15 6
GG
rs266729
GT
TT
137 136
98 104
24 19
23 39
27 9
14 3
139 164 39 1750
128 142 35 1261
35 32 6 239
CC
CG
GG
123 134 163 575
128 98 120 346
174 176 144 189
108 104 125 128
101 103 73 73
70 65 38 39
8 27 28 50 35 24 33 21 22 20 13 4
US: United States; PCR: polymerase chain reaction; RFLP: restriction fragment length polymorphism.
Figure 2. Forest plot of stroke and rs2241766. The horizontal lines correspond to the study-specific odds ratio (OR) and 95% confidence interval (CI), respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of OR and 95% CI. In this analysis, a fixed-effects model was used. (a) TT vs (TG+GG); (b) GG vs (TG+TT); (c) GG vs TT; (d) TG vs TT.
This is the first meta-analysis to evaluate the association of ADIPOQ genetic polymorphisms with ischemic stroke. Although several previous studies focusing on the relation between ADIPOQ polymorphism and ischemic
stroke did not come to same conclusion, the present study clarified this association. Adiponectin is also called GBP-28, apM1, ADIPOQ and Acrp30.25 It was identified as an adipocytokine, a
Downloaded from jra.sagepub.com at Umea University Library on April 1, 2015
5
Shen et al.
Figure 3. Forest plot of stroke and rs1501299. The horizontal lines correspond to the study-specific odds ratio (OR) and 95% confidence interval (CI), respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of OR and 95% CI. In this analysis, a fixed-effects model was used. (a) GG vs (GT+TT); (b) TT vs (TG+GG); (c) TT vs GG; (d) TG vs GG.
Figure 4. Forest plot of stroke and rs266729. The horizontal lines correspond to the study-specific odds ratio (OR) and 95% confidence interval (CI), respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of OR and 95% CI. In this analysis, a fixed-effects model was used. (a) CC vs (CG+GG); (b) GG vs (CG+CC); (c) GG vs CC; (d) GC vs CC.
244-amino-acid protein, the product of the ADIPOQ gene, which is highly expressed in adipose cells.3 ADIPOQ, a novel adipose tissue-specific protein, is a structural homolog of collagen VIII and X, complement factor C1q, and tumor necrosis factor-α (TNFα).26,27 ADIPOQ
regulates the homeostasis of glucose, energy storage, and fatty acid metabolism6,28 and acts as an anti-inflammatory29 and anti-atherogenic plasma protein.30,31 ADIPOQ is associated with obesity, metabolic syndrome, type 2 diabetes mellitus, hypertension and coronary artery
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Journal of the Renin-Angiotensin-Aldosterone System
Figure 5. Begg’s funnel plot for publication bias tests. Each point represents a separate study for the indicated association. Log(OR) represents natural logarithm of the odds ratio. The vertical line represents the mean effects size. (a) rs2241766; (b) rs1501299; (c) rs2667.
diseases. Furthermore, low levels of plasma adiponectin have been linked to ischemic cerebrovascular disease (CVD).7,8 And a recently published paper suggested the genetic polymorphisms of ADIPOQ were associated with ischemic stroke.9–24 In this meta-analysis, a total of eight case-control studies were analyzed to provide a comprehensive assessment of the association between ADIPOQ polymorphisms and ischemic stroke. Genotypes in all studies were detected with genetic DNA from blood samples using a total of three genotyping methods. All of the studies checked genotypes for quality control. Genotype distribution of controls in all studies was consistent with HWE. By the metaanalysis, our results did support a genetic association between rs2241766 and susceptibility to ischemic stroke. Exploring heterogeneity is one of the important goals of meta-analysis. In the present study no significant heterogeneity was found among the included studies. Sensitivity analysis also showed that omission of any single study did
not have a significant impact on the combined ORs. Furthermore, funnel plot did not reflect obvious asymmetry, and Egger’s test further indicated no considerable publication bias in this meta-analysis. This made the results of this meta-study more reliable to some extent. Be that as it may, there remained some limitations in this meta-analysis. In the studies included, the genotyping methods used were not the same. In addition, other clinical factors such as age, sex and different chemotherapies in each study might lead to bias. Determining whether these factors influence the results of this meta-analysis would need further investigation.
Conclusion Our study suggested that SNP rs2241766 in the ADIPOQ gene was associated with a significantly increased risk of ischemic stroke. Larger well-designed
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Shen et al. epidemiological studies with ethnically diverse populations and functional evaluations are warranted to confirm our findings. Conflict of interest None declared.
Funding This work was financially supported by the National Natural Science Foundation of China (No.81202731), the China Postdoctoral Science Foundation (No.2014M550999) and the Shanghai Municipal Health Bureau Found (No.20114047).
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