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Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemicstroke


GENE-37338; No. of pages: 9; 4C:
Gene xxx (2012) xxx–xxx

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Gene
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Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemic stroke in a meta-analysis
Fei Ye a, c, Xiao-Qing Jin b, Guang-Hui Chen a, Xiao-Ling Den a, Yong-Qiang Zheng a, Cheng-Yan Li c,?
a b c

Department of Neurology of Ren Min Hospital, Hubei University of Medicine, PR China Department of Emergency, Zhong Nan Hospital of Wuhan University, PR China Department of Neurology, Ren Min Hospital of Wuhan University, PR China

a r t i c l e

i n f o

a b s t r a c t
Many epidemiological studies have investigated the associations between polymorphisms of interleukin-1 (IL1) and interleukin-6 (IL6) genes and risk of ischemic stroke (IS), but no conclusions are available because of con?icting results. The aim of this study was to assess the relationships by meta-analysis. The databases of Pubmed, Embase and Wangfang, updated to August 1st, 2011, were retrieved. Odds ratio (OR) and corresponding 95% con?dence interval (95% CI) as effect size were calculated by a ?xed- or random-effect model. In total, three case–control studies for IL1α-889C/T, eight studies for IL1β-511C/T, eight studies for IL1-Ra and seven studies for IL6-147G/C were included in this meta-analysis. Combined analysis indicated that IL1β-511C/T polymorphism was not overall associated with risk of IS [OR (95% CI) = 1.22 (0.85–1.87) for TT vs. CC]. However, when subgroup analyses for countries were conducted, the results indicated that T allele was associated with increased risk of IS for Polish and associated with a trend of increased risk of IS for Chinese although it did not reach statistical signi?cance [TT vs. CC: OR (95% CI) = 1.97 (1.22–3.17) for Polish and 1.40 (0.99–1.99) for Chinese]. In addition, overall and subgroup analyses indicated that IL1α889C/T, IL1-Ra and IL6-147G/C polymorphisms were also not associated with risk of IS [OR (95% CI) = 1.21 (0.86–1.70) for TT vs. CC of IL1α-889C/T, 1.22 (0.85–1.75) for RN2/RN2 vs. RN1/RN1 for IL1-Ra and 1.09 (0.84–1.40) for G carriers vs. C carriers for IL6-147G/C]. This study inferred that IL1β-511C/T polymorphism might be moderately associated with increased risk of IS, but no suf?cient evidence was available to support any associations between IL1-Ra and IL6-147G/C polymorphisms and IS. We could not draw a conclusion between IL1α-889C/T polymorphism and risk of IS based on the limited data, and further large sample-sized studies were required. ? 2012 Elsevier B.V. All rights reserved.

Article history: Accepted 16 February 2012 Available online xxxx Keywords: In?ammation Interleukin-1 Interleukin-6 Ischemic stroke Risk Meta-analysis

1. Introduction As the major causes of morbidity and mortality, stroke remains a serious health problem in the world (Langhorne et al., 2011). According to the WHO report in 2005, there were about 5.7 million deaths caused by stroke, and over 50% of cases occurred in Asians, such as Chinese, Koreans and Japanese (Gunarathne et al., 2009; Li et al., 2010). Similarly, there were about 150 per 100,000 incidence of stroke in Americans (Bhatnagar et al., 2010). Ischemic stroke (IS) is the major subtype of stroke, which accounts for over 50% of the stroke cases. IS is caused by extra- or intra-cranial embolism or decreased cerebral blood ?ow. Hemorrhagic stroke (HS) is another important

Abbreviations: IS, ischemic stroke; HS, hemorrhagic stroke; OR, odds ratio; 95% CI, 95% con?dence interval; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; IL-1, interleukin-1; IL1-Ra, IL-1 receptor antagonist; IL1-Ra, IL-1 receptor antagonist; HWE, Hardy–Weinberg Equilibrium. ? Corresponding author at: Department of Neurology, Ren Min Hospilal of Wuhan University; Zi Yang Road No. 99, 442000 Wu Han City, Hubei Province, PR China. E-mail address: lcy_doctor@126.com (C.-Y. Li). 0378-1119/$ – see front matter ? 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.gene.2012.02.026

subtype of stroke. Although HS causes high rates of mortality and morbidity, it only represents approximately 5% of all the stroke cases (Martin and Rymer, 2011). The development of IS is an extremely complex process, which is attributed to the interactions of multi-factors, including host susceptibility, risk behaviors and in?ammation (Drake et al., 2011; Larsson et al., 2011; Li et al., 2010). In?ammation and in?ammation-related atherosclerosis play a crucial role in IS progress and prognosis. Chronic in?ammation of atherosclerotic plaques is related to plaque ?ssuring and disruption, and subsequent thrombosis leading to narrowing and occlusion of the cranial vessel lumen (Jander et al., 1998). A study by Lee et al. (2011) con?rmed that cerebral atherosclerosis was an independent risk factor for stroke development, with odds ratio (OR) and 95% con?dence interval (95% CI) were 1.35 (1.16–1.56). In addition, Welsh et al. (2008) claimed that interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were associated with 1.33- and 1.46-fold risks of IS recurrence. IL-1, a key mediator of in?ammatory response, plays a crucial role in atherosclerotic in?ammation and IS incidence (Dinarello, 2011). IL-1 can induce high expression of adhesional molecules from

Please cite this article as: Ye, F., et al., Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemic stroke in a metaanalysis, Gene (2012), doi:10.1016/j.gene.2012.02.026

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F. Ye et al. / Gene xxx (2012) xxx–xxx

endothelial cells, attract circulating leukocytes, promote synthesis of some types of pro-in?ammatory factors such as IL-6, ?brinogen and C-reactive protein and eventually participate in the pathogenesis of atherosclerosis (Jander et al., 1998). Similar as IL-1, IL-6 is also an important type of pro-in?ammatory cytokine, which is abundantly expressed in atherosclerotic plaques, and involved in IS progress. Lu et al. (2011) found that ?brinogen and ?brin degradation produced a pro-in?ammatory effect on the pathogenesis of atherosclerosis mainly by a high level of IL6 and TNF-α. Tuttolomondo et al. (2010) found that circular IL1β, IL6 and TNF-α signi?cantly in?uenced the stiffness of vessels distant to those involved in the process of acute IS. The functional polymorphisms of IL-1 genes, including IL1α-889C/ T, IL1β-511C/T, IL-1 receptor antagonist (IL1-Ra), and IL6-147G/C have been commonly studied and indicated to be associated with plasma levels of these pro-in?ammatory cytokines (Al-Tahhan et al., 2011; Fishman et al., 1998; Reiner et al., 2008), and they were hypothesized to be subsequently associated with risk of IS. Although the relationships between these polymorphisms and IS risk have been extensively studied in the past decade, the total number of participants in a single study was always small, and the results were controversial (Dziedzic et al., 2005; Iacoviello et al., 2005; Li et al., 2010). Till now, whether these genetic polymorphisms were associated with IS risk remained unresolved issues. The aim of this study was to further explore the associations between these genetic polymorphisms and IS risk by the method of a meta-analysis, which could enhance the statistical power and draw a more reliable conclusion compared to a single study (Stroup et al., 2000). 2. Materials and methods 2.1. Search strategy In this meta-analysis, computer-based search strategy was comprehensively used to ?nd eligible studies. The following databases were retrieved: Pubmed (1950–August 1st, 2011), Embase (1966–August 1st, 2011) and Wanfang (Chinese database, 1986–August 1st, 2011). The following key words were used: (“Interleukin 1*” OR “IL-1*” OR “Interleukin 6” OR “IL-6”) AND (stroke) AND (“polymorphism” OR “allele” OR “genotype”). Meanwhile, the reference lists of eligible studies and relevant review papers in 5 years were manually retrieved and screened to identify the eligible studies. The search was done without language limitation. 2.2. Inclusion and exclusion criteria The primary studies included in this analysis had to meet the following inclusion criteria: (1) the study must explore the associations between IL1 (including IL1α-889C/T, IL1β-511C/T, IL1-Ra) and IL6147G/C genetic polymorphisms and IS risk; (2) the study must be a case–control study; and (3) the study must provide total number of cases and controls, and also the number of cases and controls for each genotype. The major reasons for exclusion were: (1) being a review, editorial, or comment; (2) duplicated studies; (3) laboratory molecular or animal studies; and (4) in addition, we did not consider the relationships of these genetic polymorphisms on the stroke risk for infants. If more than one study was published using the same data series, the latest study or the study with a larger sample size was selected prior to the others. 2.3. Eligible study selection

2008; Li et al., 2010; Um et al., 2003a), eight studies with 1434 cases and 1594 controls for IL1β-511C/T (Dziedzic et al., 2005; Iacoviello et al., 2005; Lai et al., 2006; Li et al., 2010; Rubattu et al., 2005; Seripa et al., 2003; Zee et al., 2008), eight studies with 1423 cases and 1729 controls for IL1-Ra (Balding et al., 2004; Lai et al., 2006; Lee et al., 2010; Rezaii et al., 2009; Seripa et al., 2003; Um et al., 2003a; Worrall et al., 2007) and seven studies with 1879 cases and 2092 controls for IL6-147G/C (Balding et al., 2004; Banerjee et al., 2008; Chamorro et al., 2005; Flex et al., 2004; Lalouschek et al., 2006; Tong et al., 2010) were included in this meta-analysis. 2.4. Data extraction Two authors (Ye F and Jin XQ) extracted data independently using a standard form, and disagreements were solved by discussion with co-authors. The following data were extracted: the ?rst author's name, ethnicities and countries of participants, year of publication, goodness-in-?tness of Hardy–Weinberg Equilibrium (HWE) in control group, number of cases and controls, source of controls (population- or hospital-based controls), genotypes and matching factors. A population-based case–control study was de?ned as one where the controls are selected from healthy people or the community; the controls of a hospital-based case–control study were selected from hospitalized people. In addition, we de?ned a large sample-sized study as one where the total number of subjects was more than 400; otherwise, the study was categorized as small sized. 2.5. Statistical methods OR and 95% CI were used to present the strength of the associations between IL1α-889C/T, IL1β-511C/T, IL1-Ra and IL6-147G/C polymorphisms and IS risk. The pooled OR and 95% CI were calculated for several comparisons such as co-dominant model, dominant model and recessive model (Attia et al., 2003). Taking consideration of a possible between-study heterogeneity, a statistical test for heterogeneity was performed by the χ 2 test or Fisher exact test if appropriate. P b 0.10 indicated the obviously between-study heterogeneity (Attia et al., 2003), and OR (95% CI) was calculated by the random-effects model using the DerSimonian and Laird method (DerSimonian and Laird, 1986); otherwise, a ?xed-effects model using the Mantel– Haenszel method (Mantel and Haenszel, 1959) was applied. Strati?ed analyses were performed by ethnicities, countries, HWE, sources of controls and sample sizes. In addition to these, the Galbraith plot (Liu et al., 2011) was also used to detect the possible source of heterogeneity if necessary. HWE in control group was extracted from the primary studies if reported. χ 2 test or Fisher exact test was conducted for the studies without reporting HWE testing, and P b 0.05 indicated statistical signi?cance. Sensitivity analyses were performed to assess the stability of the results, namely, one case–control study was omitted each time to re?ect the in?uence of the individual data set to the pooled OR. Several methods were used to diagnose the possible publication bias. Asymmetry of funnel plot indicated the possible publication bias. Begger and Egger's linear regression tests (Begg and Mazumdar, 1994; Egger et al., 1997) were also used, and P b 0.05 indicated statistical signi?cance. In this meta-analysis, all statistical tests were done by STATA software (version 11.0; Stata Corporation, College Station, TX) with twosided P-value. 3. Results

Fig. 1 showed detailed information for selecting eligible studies. Through four steps, i.e., reviewing titles, abstracts, full texts and browsing reference lists of eligible studies and relevant review papers, eligible studies were identi?ed. In total, three case–control studies with 864 cases and 1223 controls for IL1α-889C/T (Banerjee et al.,

Table 1 showed the basic information of all eligible studies included in our meta-analysis. In total, twenty case–control studies in seventeen articles (Balding et al., 2004; Banerjee et al., 2008; Chamorro et al., 2005; Dziedzic et al., 2005; Flex et al., 2004; Iacoviello et al.,

Please cite this article as: Ye, F., et al., Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemic stroke in a metaanalysis, Gene (2012), doi:10.1016/j.gene.2012.02.026

F. Ye et al. / Gene xxx (2012) xxx–xxx

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Fig. 1. Flow chart showing the detailed steps for eligible study selection.

2005; Lai et al., 2006; Lalouschek et al., 2006; Lee et al., 2010; Li et al., 2010; Rezaii et al., 2009; Rubattu et al., 2005; Seripa et al., 2003; Tong et al., 2010; Um et al., 2003a; Worrall et al., 2007; Zee et al., 2008) were included in this meta-analysis. Of these studies, ?ve studies (Lai et al., 2006; Lee et al., 2004; Li et al., 2010; Tong et al., 2010; Um et al., 2003a) were for Asians, one study (Worrall et al., 2007) was for American Africans, and the other studies were for Caucasians. The participants of one study were Indians, whose ancestors were Whites; thus they were categorized as Caucasians (Banerjee et al., 2008; Fan et al., 2011). Nevertheless, re-analyses for Caucasians were performed by excluding this study to verify the reliability of results. Four studies were hospital-based case–controls studies

(Chamorro et al., 2005; Dziedzic et al., 2005; Flex et al., 2004; Um et al., 2003a), thirteen studies were population-based case–control studies, and one study (Worrall et al., 2007) did not report the source of controls. All of the studies were in goodness-in-?tness of HWE except for three studies (Lee et al., 2010; Li et al., 2010; Rezaii et al., 2009). Three case–control studies with 864 cases and 1223 controls for IL1α-889C/T (Banerjee et al., 2008; Li et al., 2010; Um et al., 2003a), eight studies with 1434 cases and 1594 controls for IL1β-511C/T (Dziedzic et al., 2005; Iacoviello et al., 2005; Lai et al., 2006; Li et al., 2010; Rubattu et al., 2005; Seripa et al., 2003; Zee et al., 2008), eight studies with 1423 cases and 1729 controls for IL1-Ra (Balding

Please cite this article as: Ye, F., et al., Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemic stroke in a metaanalysis, Gene (2012), doi:10.1016/j.gene.2012.02.026

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F. Ye et al. / Gene xxx (2012) xxx–xxx

Table 1 The basic characteristics of primary studies included in this meta-analysis. Author Year Ethnicity Country Source of controlsc No. of case– control 363/640 112/212 371/371 1–1 (case– control) TT Korea India China Hospital-based Hospital-based Population-based 3/5 12/19 84/70 CC 41/39 52/111 99/103 47/79 66/52 25/30 113/111 93/101 RN1/RN1 78/50 299/546 49/183 105/78 178/107 84/42 73/107 146/128 GG 100/56 33/123 104/46 143/156 77/156 648/645 99/98 1–2 (case– control) CT 68/81 62/89 117/141 CT 47/58 48/94 94/100 51/83 59/61 55/46 123/120 170/178 RN1/RN2 13/40 50/63 41/159 5/16 137/78 14/7 58/41 13/2 CG 115/99 60/198 134/50 187/192 35/52 0/3 1/2 2–2 (case– control) CC 292/554 38/104 170/160 TT 13/13 22/22 28/16 17/18 9/21 32/19 22/27 108/92 RN2/RN2 7/13 4/3 9/31 1/1 39/12 3/1 14/13 0/1 CC 22/68 12/68 35/9 74/67 0/4 0/0 0/0 MAFa HWEb Matched factors

IL1α-889C/T polymorphism Um et al. 2003a Asian Banerjee et al.c 2008 Caucasian Li et al. 2010 Asian IL1β-511C/T polymorphism Seripa et al. 2003 Dziedzic et al. (a) 2005 Dziedzic et al. (b) 2005 Rubattu et al. 2005 Iacoviello et al. 2005 Lai et al. 2006 Zee et al. 2008 Li et al. 2010 IL1-Ra Polymorphism Seripa et al. 2003 Um et al. 2003a Balding et al. 2004 Lai et al. 2006 Worrall et al. (a) 2007 Worrall et al. (b) 2007 Rezaii et al. 2009 Lee et al. 2010 IL6-147G/C polymorphism Flex et al. 2004 Balding et al. 2004 Chamorro et al. 2005 Lalouschek et al. 2006 Banerjee et al.c 2008 Tong et al.(a) 2010 Tong et al.(b) 2010

0.10/0.07 0.38/0.30 0.38/0.39

Yes Yes No

Age and gender Age, sex and geography N/A

Caucasian Caucasian Caucasian Caucasian Caucasian Asian Caucasian Asian

Italy Poland Poland Italy Italy China U.S. China

Population-based Hospital-based Hospital-based Population-based Population-based Population-based Population-based Population-based

101/110 122/227 221/219 115/180 134/134 112/95 258/258 371/371

0.36/0.38 0.38/0.30 0.34/0.30 0.37/0.33 0.29/0.38 0.53/0.44 0.32/0.34 0.52/0.49

Yes Yes Yes Yes Yes Yes Yes Yes

Age Age and gender Age and gender Age Age and gender Geography Geography N/A

Caucasian Asian Caucasian Asian Caucasian Africa Caucasian Asian

Italy Korea Ireland China U.S. U.S. Iran Korea

Population-based Hospital-based Population-based Population-based N/A N/A Population-based Population-based

101/110 353/612 99/373 111/95 354/197 101/50 145/161 159/131

0.14/0.32 0.08/0.06 0.30/0.30 0.03/0.09 0.30/0.26 0.10/0.09 0.30/0.21 0.04/0.02

Yes Yes Yes Yes Yes Yes No No

Age Age and gender N/A Geography N/A N/A Age and gender N/A

Caucasian Caucasian Caucasian Caucasian Caucasian Asian Asian

Italy Ireland Spain Austria India China China

Hospital-based Population-based Hospital-based Population-based Hospital-based Population-based Population-based

237/223 105/389 273/105 404/415 112/212 648/648 100/100

0.33/0.53 0.40/0.43 0.37/0.32 0.41/0.39 0.16/0.14 0/0.002 0.005/0.01

Yes Yes Yes Yes Yes Yes Yes

Age and sex N/A Age and sex Age and sex Age, sex and geography Age, sex, ethnicity Age, sex, ethnicity

Abbreviation: N/A, not available. a MAF, minor allele frequency. b HWE, Hardy–Weinberg Equilibrium. c The participants of one study were Indians, whose ancestors were Whites; thus they were categorized as Caucasians.

et al., 2004; Lai et al., 2006; Lee et al., 2010; Rezaii et al., 2009; Seripa et al., 2003; Um et al., 2003a; Worrall et al., 2007) and seven studies with 1879 cases and 2092 controls for IL6-147G/C (Balding et al., 2004; Banerjee et al., 2008; Chamorro et al., 2005; Flex et al., 2004; Lalouschek et al., 2006; Tong et al., 2010) were included eventually. The minor allele frequencies of IL1α-889C/T, IL1β-511C/T, IL1-Ra and IL6-147G/C ranged from 0.10 to 0.41, from 0.29 to 0.53, from 0.04 to 0.40 and from 0.005 to 0.41 respectively. 3.1. Association between IL1α-889C/T polymorphism and IS risk Table 2 showed the results of combined analyses for IL1α-889C/T polymorphism. The results indicated that IL1α-889C/T polymorphism was not associated with risk of IS [OR (95% CI): 1.21 (0.86– 1.70) for TT vs. CC and 1.18 (0.98–1.41) for T carriers vs. C carriers]. Due to limited data of IL1α-889C/T polymorphism, subgroup analysis was impossible. 3.2. Association between IL1β-511C/T polymorphism and IS risk Table 2 showed the results of combined analyses for IL1β-511C/T polymorphism. The overall analyses indicated that there was no association between IL1β-511C/T polymorphism and IS risk [OR (95% CI): 1.22 (0.85–1.87) for TT vs. CC and 1.05 (0.93–1.19) for T carriers vs. C carriers]. Interestingly, when subgroup analyses for countries were performed, the results indicated that T allele was associated with increased risk of IS for Polish and associated with a trend of increased risk of IS for Chinese (Fig. 2).

3.3. Association between IL1-Ra polymorphism and IS risk Table 2 showed the results of combined analyses for IL1-Ra polymorphism. The overall analyses indicated that IL1-Ra polymorphism was not associated with IS risk [OR (95% CI): 1.22 (0.85–1.75) for RN2/RN2 vs. RN1/RN1 and 0.98 (0.68–1.41) for RN2 carriers vs. RN1 carriers] (Fig. 3). All subgroup analyses also indicated no association between IL1-Ra polymorphism and IS risk except for studies out of HWE law. 3.4. Association between IL6-147G/C polymorphism and IS risk Table 3 showed the results of combined analyses for IL6-147G/C polymorphism. Overall analyses indicated that there was no association between IL6-147G/C polymorphism and IS risk [OR (95% CI): 1.56 (0.61–3.99) for GG vs. CC and 1.09 (0.84–1.40) for G carriers vs. C carriers] (Fig. 4). The results of subgroup analyses for sources of controls and Caucasians were persistent. Because the C allele frequency (around 0.14) in Indians, who were categorized as Caucasians, was obviously lower in the study by Banerjee et al. (2008) than other Caucasian studies (about 0.35), hence re-analyses for Caucasians were performed by excluding this study, and the results were persistent. 3.5. Sensitive analyses, heterogeneity test and publication bias Sensitive analyses for IL1-Ra and IL6-147G/C polymorphisms showed that no single study could change the pooled results (data were not shown), which were proved to be robust and reliable.

Please cite this article as: Ye, F., et al., Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemic stroke in a metaanalysis, Gene (2012), doi:10.1016/j.gene.2012.02.026

F. Ye et al. / Gene xxx (2012) xxx–xxx Table 2 Pooled analyses for the effects of IL-1 genetic polymorphisms on stroke risk. Groups 1–1: vs. 2–2 OR (95% CI) IL1α-889C/T Total IL1β-511C/T Asian Caucasian Italy China Poland Population-baseda Hospital-baseda Small-sample sizeb Large-sample sizeb Total IL1-Ra Asian Caucasian Population-baseda Studies in HWE Studies out of HWE Small-sample sizeb Large-sample sizeb Total TT vs.CC 1.21 (0.86–1.70) TT vs. CC 1.40 (0.99–1.99) 1.11 (0.60–1.87) 0.81 (0.33–2.01) 1.40 (0.99–1.99) 1.97 (1.22–3.17) 1.04 (0.67–1.61) 1.97 (1.22–3.18) 1.21 (0.63–2.30) 1.23 (0.91–1.65) 1.23 (0.85–1.87) Phet. 0.64 1–2 vs. 2–2 OR (95% CI) CT vs.CC 1.31 (0.75–2.28) CT vs. CC 1.11 (0.82–1.52) 0.94 (0.79–1.12) 0.86 (0.63–1.16) 1.11 (0.82–1.52) 1.02 (0.75–1.39) 0.98 (0.82–1.18) 1.02 (0.75–1.39) 0.97 (0.77–1.24) 1.01 (0.82–1.25) 0.99 (0.85–1.16) Phet 0.002 1 carrier vs. 2–2 OR (95% CI) T carriers vs. CC 1.35 (0.85–2.13) T carriers vs. CC 1.21 (0.91–1.62) 0.99 (0.83–1.18) 0.85 (0.64–1.13) 1.21 (0.91–1.62) 1.17 (0.88–1.56) 1.00 (0.84–1.19) 1.17 (0.88–1.56) 1.03 (0.82–1.29) 1.06 (0.87–1.30) 1.05 (0.90–1.21) Phet. 0.01 1–1 vs. 2 carriers OR (95% CI) TT vs. C carriers 1.24 (0.91–1.70) TT vs C carriers 1.31 (0.98–1.75) 1.15 (0.72–1.86) 0.89 (0.39–2.02) 1.31 (0.98–1.75) 1.94 (1.23–3.06) 1.06 (0.74–1.15) 1.94 (1.24–3.06) 1.21 (0.71–2.08) 1.22 (0.94–1.58) 1.23 (0.89–1.68) Phet. 0.97 1 carrier vs. 2 carriers OR (95% CI) Phet.

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T carriers vs. C carriers 1.18 (0.98–1.41) 0.18 T carriers vs. C carriers 1.13 (0.92–1.39) 0.56 1.01 (0.87–1.18) 0.57 0.92 (0.73–1.17) 0.40 1.13 (0.92–1.39) 0.56 1.16 (0.91–1.48) 0.66 1.02 (0.89–1.17) 0.57 1.16 (0.91–1.48) 0.66 1.04 (0.87–1.26) 0.36 1.06 (0.90–1.24) 0.77 1.05 (0.93–1.19) 0.67 RN2 carriers vs. RN1 carriers 1.08 (0.35–3.40) b 0.01 0.93 (0.59–1.47) b 0.01 0.85 (0.44–1.65) b 0.01 0.86 (0.50–1.48) b 0.01 1.26 (0.98–1.62) 0.34 0.87 (0.39–1.95) b 0.01 1.15 (0.94–1.40) 0.53 0.98 (0.68–1.41) b 0.01

0.30 0.01 0.03 0.30 0.74 0.04 0.74 0.01 0.20 0.02

0.40 0.88 0.65 0.40 0.73 0.70 0.73 0.54 0.98 0.87

0.31 0.38 0.28 0.31 0.58 0.26 0.58 0.12 0.83 0.36

0.50 0.02 0.04 0.50 0.82 0.07 0.82 0.03 0.19 0.04

RN2/RN2 vs. RN1/RN1 1.33 (0.41–4.29) 0.44 1.10 (0.55–2.18) 0.04 0.89 (0.55–1.42) 0.19 0.81 (0.48–1.38) 0.30 1.80 (1.06–3.03) 0.69 0.83 (0.48–1.46) 0.19 1.62 (1.00–2.62) 0.47 1.22 (0.85–1.75) 0.17

RN1/RN2 vs. RN1/RN1 1.16 (0.27–4.97) b 0.01 0.85 (0.41–1.77) b 0.01 0.83 (0.31–2.25) b 0.01 0.79 (0.37–1.68) b 0.01 1.45 (0.75–2.80) 0.03 0.85 (0.26–2.78) b 0.01 1.15 (0.91–1.45) 0.36 0.94 (0.56–1.59) b 0.01

RN2 carriers vs. RN1/RN1 1.08 (0.31–3.79) b 0.01 0.89 (0.44–1.79) b 0.01 0.83 (0.33–2.05) b 0.01 0.80 (0.40–1.60) b 0.01 1.48 (0.90–2.43) 0.09 0.84 (0.29–2.47) b 0.01 1.19 (0.95–1.49) 0.50 0.96 (0.59–1.56) b 0.01

RN2/RN2 vs. RN1 carriers 1.32 (0.41–4.23) 0.46 1.22 (0.83–1.76) 0.20 0.90 (0.57–1.44) 0.67 0.92 (0.55–1.55) 0.61 1.59 (0.96–2.64) 0.38 0.85 (0.49–1.49) 0.67 1.58 (0.99–2.53) 0.48 1.22 (0.86–1.75) 0.51

Abbreviations: OR, odds ratio; 95% CI, 95% con?dence interval; Phet, P value for heterogeneity; HWE, Hardy–Weinberg Equilibrium. a Controls of the hospital-based case–control study were selected from hospitalized people; controls of population-based case–control studies were selected from healthy people or the community. b The total number of participants for a large sample-sized study was >400 and ≤ 400 for a small-sized study.

However, the study by Iacoviello et al. (2005) for IL1β-511C/T had substantial in?uence on the overall results. When it was excluded, the results of re-analyses were 1.32 (1.06–1.64) for TT vs. CC, 1.02

(0.86–1.21) for CT vs. CC, 1.10 (0.94–1.29) for T carriers vs. CC, 1.34 (1.09–1.65) for TT vs. C carriers and 1.09 (0.96–1.23) for T carriers vs. C carries.

Fig. 2. Forest plot showed that the T allele of IL1α-511C/T was associated with increased risk of IS for Polish (TT vs. CC). The squares and horizontal lines corresponded to the studyspeci?c OR and 95% CI. The area of the squares re?ected the study-speci?c weight. The diamond represented the pooled OR and 95% CI.

Please cite this article as: Ye, F., et al., Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemic stroke in a metaanalysis, Gene (2012), doi:10.1016/j.gene.2012.02.026

6

F. Ye et al. / Gene xxx (2012) xxx–xxx

The detail information of testing heterogeneity and publication bias was shown in Table 4. The Galbraith plot was used to detect the potential source of heterogeneity, and analyses were re-performed when the studies as the major source of heterogeneity were excluded. The results of re-analyses were persistent except for IL1β-511C/T. As was shown above, the results of overall pooled analyses for IL1β511C/T were in?uenced by the study of Iacoviello et al. (2005). Through inspection of the funnel plot, and Begger and Egger's tests, no publication bias was found to exist. 4. Discussion Although a lot of epidemiological studies with respect to genetic polymorphisms on the risks of diseases such as IS (Reiner et al., 2008; Rezaii et al., 2009) and cancer (Liu et al., 2011) have been widely conducted, always no consistent results can be available. This situation makes us feel confused, thus more and more attempts are made to further assess the associations. Although the con?icting results may be a result of various reasons such as demographic features of subjects and different life styles, sample size closely related with statistical power and less bias plays a crucial role (Attia et al., 2003; Stroup et al., 2000). In recent years, meta-analysis as a useful statistical method has been employed to gain more reliable evidence. Based on a large number of primary studies with the homogeneous design for the same topic, meta-analysis can greatly enlarge the sample size, improve statistical power and encounter less bias (Attia et al., 2003; Liu et al., 2011). Similarly, the relationships between IL1α889C/T, IL1β-511C/T, IL1-Ra and IL6-147G/C polymorphisms and IS risk also have been widely studied; however, the sample sizes of these studies were comparatively small, and the results were contradictory. We ?rstly reported the relationships between IL1α-889C/T, IL1β-511C/T, IL1-Ra and IL6-147G/C polymorphisms and IS by the method of a meta-analysis based on twenty case–control studies.

The results of our meta-analysis indicated that the T allele of IL1α511C/T was associated with a 1.97-fold risk of IS for Polish compared with the control group. As to the IL1β-889C/T, IL1-Ra and IL6-147G/C polymorphisms, we could not get any evidence to support the associations between the polymorphisms and IS risk. The ?ndings of our studies provided additional information for understanding the in?ammation on the IS risk. Interleukin1 (IL1) is a potent pro-in?ammatory cytokine with two agonistic isoforms, i.e., IL1α and IL1β. Both IL1α and IL1β play a key role in acute and chronic in?ammation involving atherosclerosis, progress and prognosis of IS (Jander et al., 1998). IL1β is involved in every facet of stroke and presents different plasma levels in every diagnostic subtype of IS, therefore it has been recommended as a plasma marker for diagnosis of IS (Tuttolomondo et al., 2008). IL1α-889C/ T and IL1β-511C/T at IL1 regulatory region are two of the most commonly studied genetic loci, which are assumed to be closely associated with expression of IL1β, and sequentially associated with incidence of IS (Dziedzic et al., 2005; Um et al., 2003a, b). Al-Tahhan et al. (2011) found that cervical cancer patients carrying the TT genotype of IL1β-511C/T had a signi?cantly higher level of circular IL1β than that of the CC genotype (44.2 pg/ml of TT vs. 38.3 pg/ml for CC). In this meta-analysis, we found that IL1β-511C/T was statistically associated with IS risk for Polish. The results should be explained with caution because of the limited number of participants. In addition, the results of pooled analyses for IL1β-511C/T were substantially in?uenced by one study (Iacoviello et al., 2005), which was the major source of between-study heterogeneity. This study reported that TT of IL1β-511C/T was associated with decreased risk of IS. However, other primary studies (Dziedzic et al., 2005; Li et al., 2010; Zee et al., 2008) reported no or positive association between T allele and IS risk. Through close inspection of this study, we found that the patients were young (≤ 45 years old). It was possible that the effect of IL1β511C/T polymorphism on IS risk might be modi?ed by age or other

Fig. 3. Forest plots showed absence of association between IL1-Ra polymorphisms and risk of IS (RN2/RN2 vs. RN1/RN1). The squares and horizontal lines corresponded to the study-speci?c OR and 95% CI. The area of the squares re?ected the study-speci?c weight. The diamond represented the pooled OR and 95% CI.

Please cite this article as: Ye, F., et al., Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemic stroke in a metaanalysis, Gene (2012), doi:10.1016/j.gene.2012.02.026

F. Ye et al. / Gene xxx (2012) xxx–xxx Table 3 Pooled analyses for the effects of IL6-147G/C polymorphism on stroke risk. Variables GG vs. CC OR (95% CI) Caucasian Caucasiana Population-basedb Hospital-basedb Small-sample sizec Large-sample sizec Total 1.56 1.43 1.09 1.82 1.07 1.89 1.56 (0.61–3.99) (0.53–3.86) (0.62–1.92) (0.20–16.60) (0.64–1.78) (0.57–6.27) (0.61–3.99) Phet b 0.01 b 0.01 0.21 b 0.01 0.18 b 0.01 b 0.01 GC vs. CC OR (95% CI) 1.51 1.41 1.17 1.62 0.88 0.73 1.51 (0.73–3.12) (0.67–2.97) (0.87–1.57) (0.32–8.14) (0.43–1.81) (0.71–4.22) (0.73–3.12) Phet b 0.01 b 0.01 0.13 b 0.01 0.16 b 0.01 b 0.01 G carriers vs. CC OR (95% CI) 1.53 1.42 1.12 1.69 0.78 1.80 1.53 (0.67–3.46) (0.60–3.32) (0.84–1.49) (0.29–10.94) (0.39–1.58) (0.65–5.01) (0.67–3.46) Phet b 0.01 b 0.01 0.13 b 0.01 0.18 b 0.01 b 0.01 GG vs. C carriers OR (95% CI) 1.05 1.12 0.95 1.32 0.81 1.32 1.09 (0.72–1.53) (0.72–1.74) (0.79–1.15) (0.49–3.56) (0.58–1.13) (0.76–2.28) (0.76–1.57) Phet 0.002 0.002 0.73 b 0.01 0.20 b 0.01 0.01 G carriers vs. C carriers OR (95% CI) 1.06 1.11 0.99 1.22 0.88 1.22 1.09 (0.82–1.38) (0.82–1.48) (0.85–1.16) (0.63–2.35) (0.65–1.18) (0.83–2.35) (0.84–1.40) Phet 0.02 0.01 0.74 0.01 0.80 0.01 0.04

7

Abbreviations: OR, odds ratio; 95% CI, 95% con?dence interval; Phet, P value for heterogeneity. a Excluding the study by Banerjee et al., whose participants were Indians. b Controls of the hospital-based case–control study were selected from hospitalized people; controls of population-based case–control studies were selected from healthy people or the community. c The total number of participants of large sample-sized study was >400 and ≤ 400 for a small-sized study.

unknown factors. The ?nding in our study for the association between IL1α-889C/T and IS risk was weak because of few studies, and the relationship needed to be studied further. IL-1 receptor antagonist (IL1-Ra) is an anti-in?ammatory protein and has been encoded. It has the variable number of an 86 base pair (bp) tandem repeat polymorphism in intron 2 (Tarlow et al., 1993). Allele 2 (RN2) of IL1-Ra is the shortest among the ?ve alleles, and it has been reported to be involved in atherosclerosis (Dewberry et al., 2000; Worrall et al., 2007). Animal and cell culture data have suggested that the homozygote of IL1-Ra*RN2 had 2- to 3-fold lower production of IL1-Ra than the homozygote of IL1Ra*RN1 (Dewberry et al., 2000). Similar as IL1β-511C/T, IL1-Ra polymorphism has also been widely studied, and inferred to be potentially associated with stroke risk. The results of our pooled analyses, however, suggested that no association between IL1-Ra*RN2 and IS risk was observed. Although statistical signi?cance was observed for combining analysis of studies out of HWE law, bias could not be excluded because that deviation

from HWE indicated the possible presence of genotyping errors, population strati?cation or selection bias (Attia et al., 2003). Our ?ndings were in part consistent with previous studies (Balding et al., 2004; Um et al., 2003a). A study by Um et al. (2003a) with 363 cases and 640 controls con?rmed that there was no statistical signi?cance of RN2 distributions between case and control group (14.9% vs. 11.3%, P = 0.096). A similar result was also reported by Balding et al. (2004), who conducted a case–control study including 105 cases and 398 controls. However, con?icting result has also been reported. The studies by Seripa et al. (2003), Worrall et al. (2007) and Lai et al. (2006) con?rmed that the frequency of IL1-Ra*RN2 was signi?cantly higher in IS group than in control group. Due to the limited number of the subjects in this meta-analysis, the association between IL1-RN polymorphism and IS risk should be warranted in the future. IL-6 is also a type of pro-in?ammatory cytokines, and has both bene?cial and destructive potentials. Although IL-6 is involved in the pathogenesis of IS, its biological function seems to be less important than IL-1

Fig. 4. Forest plots showed absence of association between IL1-147G/C polymorphism and risk of stroke (G carriers vs. C carriers). The squares and horizontal lines corresponded to the study-speci?c OR and 95% CI. The area of the squares re?ected the study-speci?c weight. The diamond represented the pooled OR and 95% CI.

Please cite this article as: Ye, F., et al., Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemic stroke in a metaanalysis, Gene (2012), doi:10.1016/j.gene.2012.02.026

8 Table 4 Analyses for sources of heterogeneity and test for publication bias. Variables

F. Ye et al. / Gene xxx (2012) xxx–xxx

Sources of heterogeneitya

Re-analysesb OR (95% CI) Phet. 0.51 – – 0.37 – – 0.01 0.02 – 0.04 0.22 0.16 0.16 0.70 0.71

Publication bias PEgger 0.52 1.00 0.99 0.59 0.82 0.54 0.55 0.50 0.52 0.55 0.73 0.63 0.70 0.56 0.55 PBegger 0.76 0.90 1.00 1.00 0.90 0.17 0.90 0.90 0.39 1.00 0.86 0.81 0.81 0.37 0.37

IL1β-511C/T TT vs. CC CT vs. CC T carriers vs. CC TT vs. C carriers T carriers vs. C carriers IL1-Ra RN2/RN2 vs. RN1/RN1 RN1/RN2 vs. RN1/RN1 RN2 carriers vs. RN1/RN1 RN2/RN2 vs. RN1 carriers RN2 carriers vs. RN1 carriers IL6-147G/C GG vs. CC GC vs. CC G carriers vs. CC GG vs. C carriers G carriers vs. C carriers

Iacoviello et al. – – Iacoviello et al. – – Rezaii et al. and Seripa et al. Rezaii et al. and Seripa et al. – Seripa et al. Flex Flex Flex Flex Flex et al. et al. et al. et al. et al.

1.32 (1.06–1.64) – – 1.34 (1.09–1.65) – – 1.05 (0.67–1.64) 1.08 (0.73–1.60) – 1.15 (0.86–1.53) 0.91 1.02 0.97 0.90 0.96 (0.67–1.25) (0.76–1.38) (0.73–1.29) (0.74–1.10) (0.82–1.12)

Abbreviations: OR, odds ratio; 95% CI, 95% con?dence interval; Phet, P value for heterogeneity. a Through a Galbraith plot, the primary studies that were potential sources of heterogeneity were detected. b Analyses were re-performed when the studies as the major source of heterogeneity were excluded

(Karahan et al., 2005). An animal study (Clark et al., 2000) indicated that lack of IL-6 production has little in?uence in the acute phase of IS, which indicated that IL-6 might be involve in modulating other pro-in?ammatory cytokines. The C allele of IL6-174G/C was found to be associated with lower plasma IL-6 level, and hypothesized to be associated with decreased risk of IS (Chamorro et al., 2005; Unal et al., 2008). The result of our study indicated no association of IL6-174G/C polymorphism on IS risk with obvious between-study heterogeneity. After excluding the studies as the potential source of heterogeneity, the null association was persistent. Our result was partly consistent with previous studies by Lalouschek et al. (2006), Banerjee et al. (2008) and Tong et al. (2010). Chamorro et al. (2005) reported that CC genotype was independently associated with a 3.22-fold risk of lacunar stroke (95% CI: 1.12–9.09) but not for other subtypes of stroke. Similar as most other gene-related meta-analysis (Attia et al., 2003; Liu et al., 2011), this study had its limitations and encountered some potential bias. Although a perfect search strategy was used to identify eligible studies, it was possible that some eligible studies were not included. Of course, this situation also existed in other meta-analyses. The number of subjects in our meta-analysis was comparatively small, especially for IL1α-889C/T polymorphism. However, according to previous experience, it was feasible to perform this study based on the current literatures. Most gene-related metaanalyses were performed without adjustment, so did our study. If the potential confounders were required to be adjusted, it was necessary to gain all raw data used in primary studies, which was seemed to be beyond possibility. At last, similar to a case–control study, metaanalysis belonged to a retrospective study, and recall bias might exist. Given the limitations above, our ?ndings should be explained with caution, and be warranted by future studies. In summary, this study suggested that IL1β-511C/T was probably associated with IS risk for Polish. However, no associations of IL1-Ra and IL6-147G/C polymorphisms on IS risk were identi?ed. With respect to IL1α-889C/T polymorphism, it was dif?cult to draw a solid conclusion in our study because of limited data, and large sample-sized studies with a good design were required to further assess the association. Acknowledgement This study was supported by Hubei Province Education Of?ce of Scienti?c Research (Q20082405) and Hubei Province Health Of?ce of Scienti?c Research (QJX2010-50).

Con?ict of interest statement There is no con?ict of interest for all authors. References
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Please cite this article as: Ye, F., et al., Polymorphisms of interleukin-1 and interleukin-6 genes on the risk of ischemic stroke in a metaanalysis, Gene (2012), doi:10.1016/j.gene.2012.02.026


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