Skip to main content
NCBI home page
Disease Markers logoLink to Disease Markers
. 2014 Aug 26;2014:913678. doi: 10.1155/2014/913678

Two Polymorphisms in the Fractalkine Receptor CX3CR1 Gene Influence the Development of Atherosclerosis: A Meta-Analysis

Jian Wu 1, Rui-Xing Yin 1,*, Quan-Zhen Lin 1, Tao Guo 1, Guang-Yuan Shi 1, Jia-Qi Sun 1, Shao-Wen Shen 1, Qing Li 2
PMCID: PMC4158466  PMID: 25221380

Abstract

Background. The associations between the Fractalkine receptor (CX3CR1) gene T280M (rs3732378) and V249I (rs3732379) polymorphisms and atherosclerosis (AS) risk are conflicting. The aim of this meta-analysis was undertaken to assess their associations. Methods. PubMed, Embase, Web of Science, Medline, Cochrane database, and CNKI were searched to get the genetic association studies. All statistical analyses were done with Stata 11.0. Results. Twenty-five articles involving 49 studies were included in the final meta-analysis. The analysis showed that the 280M allele carriers of the CX3CR1 T280M polymorphism decreased the risk of AS and coronary artery disease (CAD) in the heterozygous state but increased the risk of ischemic cerebrovascular disease (ICVD) in the homozygote state. The 249I allele carriers of the CX3CR1 V249I polymorphism decreased the risk of AS and CAD in the heterozygous state. The V249I-T280M combined genotype VITM and IITM also decreased the risk of AS. Conclusions. The present meta-analysis suggests that the CX3CR1 T280M and V249I polymorphisms are associated with the susceptibility to AS. However, the results should be interpreted with caution because of the high heterogeneity in the meta-analysis.

1. Introduction

Atherosclerosis (AS) is a multifactorial, progressive disease and a major global cause of morbidity and mortality. Atherosclerosis-related cardiovascular diseases, such as coronary artery disease (CAD), acute myocardial infarction (AMI), and ischemic cerebrovascular disease (ICVD), are the causes of death in almost 50% of cases in developed countries [1]. The exact mechanisms of AS are indistinct. Many studies indicate that the genetic factors play a significant role in the development of AS [2–5]. Until recently, much attention has been focused on this field, and the association of the Fractalkine (FKN) receptor (CX3CR1) gene polymorphisms and AS has been extensively studied [6–31].

It has recently been accepted that AS is predominantly an inflammatory process [32, 33] and begins with a fatty streak, which is made up almost entirely of monocyte-derived macrophages [33, 34]. During the process of vascular inflammation, chemokines and adhesive molecules exert a vital role via mediating the activation of inflammatory cells and their aggregation or adhesion to vascular walls [35, 36]. FKN is a special chemotactic factor existing in both membrane-bound and soluble forms [37]; the expression of FKN and its receptor CX3CR1 is upregulated in AS lesions [38–40], and the severity of AS is greatly improved by inhibiting their expression [40–42], suggesting that the FKN/CX3CR1 is closely correlated to AS. Given the crucial role of CX3CR1 in the inflammatory process, the mutations in the CX3CR1 may also play a significant role in the development of atherosclerotic diseases. Recently, a number of molecular epidemiological studies have been done to evaluate the associations between the CX3CR1 gene polymorphisms (T280M and V249I) and the risk of atherosclerotic diseases [6–31]. However, the results of different studies are inconsistent, possibly due to small sample sizes in the individual studies. In 2009, Apostolakis et al. [43] performed a meta-analysis to evaluate the association between the CX3CR1 T280M and V249I polymorphisms and CAD and demonstrated that the CX3CR1 280M allele was associated with a reduced risk of CAD in the heterozygous state and 249I-280M haplotype had a atheroprotective effect on CAD. However, they just studied the 280M allele and 249I-280M haplotype of CX3CR1 in Caucasians. Considering the meta-analysis only focused on the association of the CX3CR1 polymorphism with the single atherosclerotic disease, we, therefore, performed this meta-analysis of all the studies available now to get a more precise estimation of the associations between the CX3CR1 T280 M (rs3732378) and V249I (rs3732379) polymorphisms and overall AS risk.

2. Materials and Methods

2.1. Literature Search and Selection

This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria [45]. Eligible literatures published before the end of March 1, 2014, were identified by the search of PubMed, Embase, Web of Science, Medline, Cochrane database, and CNKI. Library uses combinations of the following keywords: “chemokine receptor 1” or “FKN” or “CX3CR1” or “fractalkine” and “polymorphism” or “mutation” or “variant” or “variation” or “genotype” and “coronary artery disease” or “CAD” or “coronary heart disease” or “CHD” or “myocardial infarction” or “MI” or “ischemic cardiovascular disease” or “ischemic cardiovascular events” or “ischemic stroke” or “IS” or “cerebrovascular disease” or “ischemic cerebrovascular events” or “cerebral infarction” or “cerebral ischemia” or “brain infarction” or “carotid artery stenosis” or “CAAD” or “transient ischemic attack” or “TIA” or “peripheral arterial disease” or “PAD” or “peripheral artery occlusive disease” or “PAOD” or “renal artery stenosis” or “RAS” or “retinal artery occlusion” or “RAO” or “aortic aneurysm” or “atherosclerosis”. In addition, all references cited were reviewed to identify additional studies. If two or more studies sharing the same studied populations, the one with the small size was abandoned. Two reviewers (JW and QZL) searched the above databases independently. Decisions were compared and disagreements about study selection were resolved by involving a third reviewer (RXY). The search was limited to English and Chinese language papers. There was no restriction on time period, sample size, or population.

2.2. Inclusion and Exclusion Criteria

To be included in the present meta-analysis, the studies had to comply with the following major criteria: (1) case-control or cohort studies evaluating the associations between the CX3CR1 T280M and V249I polymorphisms and AS risk; (2) published studies with full text articles; (3) sufficient published data for calculating odds ratios (ORs) with their 95% confidence intervals (CIs); (4) study population being adults; (5) the diagnosis of ischemic heart disease (CAD and AMI) being accorded with the result of coronary angiography, criteria of World Health Organization (WHO), criteria of European Society of Cardiology (ESC), or criteria of American College of Cardiology/American Heart Association (ACC/AHA); the diagnosis of ICVD is accorded with result of computed tomography (CT) or magnetic resonance imaging (MRI); the diagnosis of carotid atherosclerosis (CAA) was assessed by ultrasound color Doppler (USCD), and peripheral arterial disease (PAD) was diagnosed by the following criteria: clinical symptoms of PAD (intermittent claudication, rest pain, or gangrene) accompanied by an ankle-brachial-index and significant stenosis of leg arteries confirmed by FCDS and/or angiography.

Studies were excluded if they were (1) review or meta-analysis; (2) not conducted in humans; (3) duplicate studies.

2.3. Data Extraction

Data, including name of the first author, year of publication, study population (country, ethnicity), study type (case-control and cohort study), type of atherosclerotic disease, source of controls (population-based studies and hospital-based studies), sample size (total numbers of cases and controls), and number of genotypes in cases and controls, were extracted from each study by two reviewers independently (JW and QZL) according to the prespecified inclusion criteria. Studies that reported a comparison of two case samples, such as different age groups, were included in the meta-analysis as independent studies. Decisions were compared and disagreements about study selection were resolved by consensus or by involving a third reviewer (RXY).

2.4. Quality Assessment for Individual Studies

The quality of the individual studies was evaluated and scored by two reviewers independently based on the Newcastle-Ottawa Scale (NOS) [46]. Each study was assessed based on three broad perspectives: selection, comparability, and exposure, and each satisfactory answer received one point. The NOS ranges between zero (none of the quality criterion was met) up to nine stars (all the quality criteria were met), and the high-quality study was considered as the one with a score higher than six. The reviewer (RXY) examined the results, and a consensus was reached.

2.5. GRADE Quality Assessment

GRADE (grades of recommendation, assessment, development and evaluation) approach was adopted to grade quality of evidence for each association [47]. The GRADE system included level of evidence: (1) high quality, we are very confident that the true effect lies close to that of the estimate of the effect; (2) moderate quality, we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; (3) low quality, our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect; and (4) very low quality, we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. Two reviewers (JW and QZL) assessed quality independently and solved disagreement by discussion.

2.6. Statistical Analysis

For the controls of each study, Hardy-Weinberg equilibrium (HWE) was assessed using the chi-square test (P < 0.05 was considered significant deviation from HWE). We performed a haplotype analysis based on the genotype data, the haplotype frequencies were calculated by CubeX analysis software for each study separately and for the whole sample [48]. The strength of associations between the CX3CR1 T280M and V249I polymorphisms and AS risk was assessed by ORs with 95% CIs. The pooled ORs were performed for dominant model (T/M + M/M versus T/T for T280M; V/I + I/I versus V/V for V249I), recessive model (M/M versus T/T + T/M for T280M; I/I versus V/V + V/I for V249I), codominant model (T/M versus T/T + M/M for T280M; V/I versus V/V + I/I for V249I), additive model (M/M versus T/T for T280M; I/I versus V/V for V249I), and allelic model (M allele versus T allele for T280M; I allele versus V allele for V249I). Bonferroni correction was used to control for the multiple testing in view of five genetic models under investigation (significance was set at 0.05/5 = 0.01), then another statistical significance was set as P < 0.05.

Heterogeneity across individual studies was calculated using Cochran's Q statistic (P Q) and the I 2 statistic. Values for P Q < 0.10 and I 2 > 50% indicate a presence of heterogeneity among studies [49, 50], and the random-effects model was used for the meta-analysis. Otherwise, the fixed-effects model was used. Subgroup analysis was used to alleviate the heterogeneity based on ethnicity (Asian and Caucasians), the type of disease (CAD, ICVD, CAA, and PAD), and source of controls (population-based and hospital-based).

Sensitivity analyses were performed based on HWE (studies without HWE were excluded) and NOS score (studies with score ≤ 6 were excluded). Begg's funnel plot and Egger's regression test were conducted to identify possible publication bias in the current meta-analysis (P < 0.05 was considered representative of statistically significant publication bias). The analyses were performed using Stata software11.0 (StataCorp LP, College Station, USA).

3. Results

3.1. Study Characteristics

The present study met the PRISMA statements and PRISMA flow chart (Checklist S1 available online at http://dx.doi.org/10.1155/2014/913678 and Figure 1). A total of 667 articles were identified after searching. After careful review, 26 articles involving 49 studies (24 studies for T280M and 25 studies for V249I polymorphisms) met the inclusion criteria and were selected in this meta-analysis [6–31]; one duplicate study was cut [18]. For the CX3CR1 T280M polymorphism, 7732 AS cases and 5905 controls were included to assess the association between the variant and AS risk [6–12, 15–19, 21–28, 30, 31]. For the CX3CR1 V249I polymorphism, 7952 AS cases and 6035 controls were included to assess the association between the variant and AS risk [6–12, 15–24, 26–31]. Main characteristics of the included studies were listed in Tables 1 and 2. The most commonly atherosclerotic disease included in the present meta-analysis was CAD in 21 studies. In addition, there were 8 studies involving carotid atherosclerosis, 8 studies involving cerebral infarction, 6 studies involving AMI, 2 studies involving ICVD, 2 studies involving ischemic stroke (IS), and 2 studies involving PAD. There were 24 studies of Asians and 25 studies of Caucasians. Three studies did not follow the HWE [8, 23, 26]. The results of GRADE were shown in Table S1.

Figure 1.

Figure 1

Open in a new tab

Flow chart showing study selection process.

Table 1.

Characteristics of studies included in this meta-analysis.

Position First author Year Country Study type Disease Source of control SS (Case/Control) Genotypes distribution (case/control) HWE
Y/N (P)		 Score
T/T T/M M/M T M
T280M Moatti [15] 2001 France CCS CAD HB 151/249 123/179 25/65 3/5 271/423 31/75 Y (0.748) 8
Gugl [8] 2003 Austria CCS PAD HB 492/503 333/326 143/165 16/12 809/817 175/189 Y (0.093) 8
Ghilardi [7] 2004 Italia CCS CAA HB 108/204 87/142 18/58 3/4 192/342 24/66 Y (0.490) 8
Lavergne [10] 2005 France CCS CI HB 460/469 314/338 125/123 21/8 753/799 167/139 Y (0.400) 7
Niessner [17, 18] 2005 Austria CCS CAD HB 720/432 514/319 189/100 17/13 1217/738 223/126 Y (0.141) 7
Apostolakis [43] 2007 Greece CCS CAD HB 210/165 159/109 48/53 3/3 366/271 54/59 Y (0.228) 7
An [24] 2008 China CCS CAD HB 108/80 88/59 18/20 2/1 194/138 22/22 Y (0.629) 6
Nassar-a [16] 2008 Canada CCS CAD PB 149/149 97/94 49/48 3/7 243/236 55/62 Y (0.784) 8
Nassar-b [16] 2008 Canada CCS CAD PB 150/149 92/94 49/48 9/7 233/236 67/62 Y (0.784) 8
Peng [25] 2008 China CCS ICVD PB 165/150 138/143 25/7 2/0 301/293 29/7 Y (0.770) 8
Zheng [31] 2008 China CCS CAA HB 117/93 77/73 32/17 8/3 186/163 48/23 Y (0.131) 6
Kimouli [9] 2009 Greece CCS CAA PB 150/151 112/87 31/58 7/6 255/232 45/70 Y (0.334) 8
Matzhold [12] 2009 Austria CCS CAD PB 2565/728 1797/483 706/217 59/26 4300/1183 824/269 Y (0.790) 7
Xiao [28] 2010 China CCS CAD PB 139/90 129/81 10/9 0/0 268/171 10/9 Y (0.618) 7
Zhang [30] 2010 China CCS CI PB 120/102 98/71 20/30 2/1 216/172 24/32 Y (0.258) 7
Zhao [23] 2010 China CCS CAA HB 318/292 246/201 56/70 16/21 548/472 88/112 N (0.000) 7
Li [11] 2012 China CCS CI PB 308/294 284/280 24/14 0/0 592/574 24/14 Y (0.676) 8
Shi [26] 2012 China CCS CI HB 563/563 493/518 50/38 20/7 1036/1074 90/52 N (0.000) 7
Singh-a [21, 22] 2012 India CCS CAD PB 152/300 126/191 24/99 2/10 276/481 28/119 Y (0.513) 8
Singh-b [21, 22] 2012 India CCS CAD PB 156/300 124/191 28/99 4/10 276/481 36/119 Y (0.513) 8
Singh-c [21, 22] 2012 India CCS AMI PB 230/300 190/191 36/99 4/10 416/481 44/119 Y (0.513) 7
Wu [27] 2012 China CCS IS PB 163/100 135/95 26/5 2/0 296/195 30/5 Y (0.798) 7
Pucci-a [19] 2013 Italy CCS AMI HB 25/22 21/14 4/7 0/1 46/35 4/9 Y (0.917) 7
Pucci-b [19] 2013 Italy CCS AMI HB 16/22 9/14 7/7 0/1 25/35 7/9 Y (0.917) 7
Position First
author		 Year Country Study type Disease Source of control SS (case/control) Genotypes distribution (case/control) HWE
Y/N (P)		 Score
V/V V/I I/I V I
V249I Moatti [15] 2001 France CCS CAD HB 151/249 97/126 47/104 7/19 241/356 61/142 Y (0.699) 8
Gugl [8] 2003 Austria CCS PAD HB 492/503 261/268 198/210 33/25 720/746 264/260 N (0.045) 8
Ghilardi [7] 2004 Italia CCS CAA HB 108/204 63/108 34/84 11/12 160/300 56/108 Y (0.409) 8
Lavergne [10] 2005 France CCS CI HB 458/468 234/236 178/203 46/29 646/675 270/261 Y (0.089) 7
Niessner [17, 18] 2005 Austria CCS CAD HB 720/432 395/246 271/161 54/25 1061/653 379/211 Y (0.842) 7
Rios [20] 2005 Brazil CS CAD HB 219/129 120/72 80/51 19/6 320/195 118/63 Y (0.420) 7
Apostolakis [43] 2007 Greece CCS CAD HB 210/165 111/86 81/59 18/20 303/231 117/99 Y (0.056) 7
An [24] 2008 China CCS CAD HB 108/80 70/41 33/34 5/5 173/116 43/44 Y (0.556) 6
Nassar-a [16] 2008 Canada CCS CAD PB 149/149 73/63 63/69 13/17 209/195 89/103 Y (0.772) 7
Nassar-b [16] 2008 Canada CCS CAD PB 150/149 58/63 77/69 15/17 193/195 107/103 Y (0.772) 8
Zhang [29] 2008 China CCS ICVD PB 165/150 122/132 40/18 3/0 284/282 46/18 Y (0.434) 8
Zheng [31] 2008 China CCS CAA HB 117/93 69/53 33/32 15/8 171/138 63/48 Y (0.328) 6
Kimouli [9] 2009 Greece CCS CAA PB 150/151 82/73 59/64 9/14 223/210 77/92 Y (0.996) 8
Matzhold [12] 2009 Austria CCS CAD PB 2565/728 1374/372 1012/283 179/73 3760/1027 1370/429 Y (0.081) 7
Xiao [28] 2010 China CCS CAD PB 139/90 126/68 13/19 0/3 265/155 13/25 Y (0.265) 7
Zhang [30] 2010 China CCS CI PB 120/102 81/51 35/43 4/8 197/145 43/59 Y (0.798) 7
Zhao [23] 2010 China CCS CAA HB 318/292 194/164 66/65 58/63 454/393 182/191 N (0.000) 7
Li [11] 2012 China CCS CI PB 308/294 289/280 19/14 0/0 597/574 19/14 Y (0.676) 8
Shi [26] 2012 China CCS CI HB 563/563 497/512 52/44 14/7 1046/1068 80/58 N (0.000) 7
Singh-a [21, 22] 2012 India CCS CAD PB 152/300 111/150 37/118 4/32 259/418 45/182 Y (0.230) 8
Singh-b [21, 22] 2012 India CCS CAD PB 156/300 96/150 48/118 12/32 240/418 72/182 Y (0.230) 8
Singh-c [21, 22] 2012 India CCS AMI PB 230/300 157/150 61/118 12/32 375/419 85/182 Y (0.230) 7
Wu [27] 2012 China CCS IS PB 163/100 119/88 41/12 3/0 279/188 47/12 Y (0.523) 7
Pucci-a [19] 2013 Italy CCS AMI HB 25/22 13/2 10/12 2/8 36/16 14/28 Y (0.402) 7
Pucci-b [19] 2013 Italy CCS AMI HB 16/22 1/2 10/12 5/8 12/16 20/28 Y (0.402) 7
Open in a new tab

CCS: case-control study, CS: cohort study, SS: sample size, PB: population-based, HB: hospital-based, HWE: Hardy-Weinberg equilibrium, Y: yes, N: no, AMI: acute myocardial infarction, CAA: carotid artery atherosclerosis, CAD: coronary artery disease, CI: cerebral infarction, ICVD: ischemic cerebrovascular disease, IS: ischemic stroke, PAD: peripheral arterial disease.

Table 2.

Meta-analyses of CX3CR1 T280M and V249I polymorphisms and risk of AS in each subgroup.

Position SS (case/control) Dominant model Recessive model Codominant model Additive model Allelic model
OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P
Overall analysis
T280M 7732/5905 0.83 [0.68, 1.02] 0.08 1.01 [0.82, 1.26] 0.91 0.81 [0.67, 0.99] 0.04 0.96 [0.77, 1.19] 0.72 0.88 [0.73, 1.05] 0.16
V249I 7952/6035 0.84 [0.71, 0.98] 0.03 0.88 [0.69, 1.11] 0.27 0.87 [0.76, 0.99] 0.04 0.81 [0.62, 1.05] 0.12 0.86 [0.75, 0.99] 0.04
Subgroup analysis based on ethnicity
T280M (C) 5193/3241 0.83 [0.69, 0.99] 0.04 0.97 [0.74, 1.28] 0.85 0.82 [0.68, 0.98] 0.03 0.94 [0.71, 1.23] 0.64 0.87 [0.75, 1.01] 0.06
T280M (A) 2539/2664 0.92 [0.60, 1.43] 0.72 1.09 [0.76, 1.56] 0.66 0.88 [0.58, 1.32] 0.54 1.00 [0.70, 1.44] 0.99 0.98 [0.66, 1.47] 0.93
V249I (C) 5413/3371 0.91 [0.81, 1.03] 0.15 0.96 [0.72, 1.28] 0.79 0.94 [0.86, 1.03] 0.18 0.92 [0.67, 1.27] 0.62 0.92 [0.82, 1.04] 0.19
V249I (A) 2539/2664 0.80 [0.57, 1.14] 0.22 0.75 [0.48, 1.16] 0.19 0.84 [0.63, 1.13] 0.25 0.66 [0.40, 1.09] 0.10 0.84 [0.62, 1.15] 0.28
Subgroup analysis based on type of diseases
T280M (CAD) 4768/2984 0.67 [0.52, 0.85] <0.01 0.69 [0.51, 0.93] 0.01 0.68 [0.53, 0.88] <0.01 0.64 [0.48, 0.87] <0.01 0.70 [0.58, 0.86] <0.01
T280M (PAD) 492/503 0.88 [0.68, 1.14] 0.34 1.38 [0.64, 2.94] 0.41 0.84 [0.64, 1.10] 0.20 1.31 [0.61, 2.80] 0.49 0.94 [0.75, 1.17] 0.56
T280M (CAA) 693/740 0.73 [0.43, 1.23] 0.23 0.98 [0.60, 1.60] 0.94 0.68 [0.41, 1.14] 0.15 0.89 [0.55, 1.46] 0.65 0.81 [0.52, 1.25] 0.33
T280M (ICVD) 1779/1678 1.58 [0.98, 2.53] 0.06 2.83 [1.62, 4.95] <0.01 1.43 [0.88, 2.31] 0.15 2.90 [1.65, 5.07] <0.01 1.65 [1.06, 2.55] 0.03
V249I (CAD) 4990/3115 0.69 [0.55, 0.86] <0.01 0.70 [0.53, 0.92] 0.01 0.79 [0.66, 0.94] <0.01 0.62 [0.43, 0.87] <0.01 0.72 [0.59, 0.87] <0.01
V249I (PAD) 492/503 1.01 [0.79, 1.30] 0.94 1.38 [0.81, 2.35] 0.24 0.94 [0.73, 1.21] 0.63 1.36 [0.78, 2.34] 0.28 1.05 [0.86, 1.28] 0.62
V249I (CAA) 693/740 0.82 [0.66, 1.01] 0.07 1.02 [0.65, 1.60] 0.94 0.82 [0.65, 1.03] 0.09 0.93 [0.61, 1.40] 0.71 0.87 [0.74, 1.03] 0.11
V249I (ICVD) 1777/1677 1.29 [0.83, 2.01] 0.25 1.50 [0.78, 2.90] 0.23 1.22 [0.80, 1.85] 0.35 1.44 [0.65, 3.17] 0.37 1.33 [0.89, 1.99] 0.16
Subgroup analysis based on source of controls
T280M (HB) 3288/3094 0.89 [0.71, 1.13] 0.34 1.30 [0.97, 1.74] 0.08 0.86 [0.70, 1.06] 0.16 1.27 [0.95, 1.70] 0.11 0.94 [0.75, 1.17] 0.56
T280M (PB) 4444/2811 0.81 [0.57, 1.14] 0.22 0.74 [0.54, 1.03] 0.07 0.80 [0.57, 1.13] 0.21 0.68 [0.49, 0.94] 0.02 0.84 [0.63, 1.13] 0.25
V249I (HB) 3505/3222 0.91 [0.78, 1.06] 0.22 1.13 [0.86, 1.49] 0.37 0.89 [0.80, 1.00] 0.04 1.08 [0.79, 1.48] 0.64 0.94 [0.82, 1.09] 0.42
V249I (PB) 4447/2813 0.80 [0.59, 1.09] 0.15 0.62 [0.48, 0.81] <0.01 0.88 [0.68, 1.15] 0.35 0.55 [0.38, 0.78] <0.01 0.81 [0.63, 1.04] 0.10
Sensitivity analysis
T280M (BS) 7507/5732 0.81 [0.66, 1.00] 0.05 0.99 [0.79, 1.23] 0.90 0.80 [0.65, 0.98] 0.03 0.93 [0.75, 1.16] 0.52 0.86 [0.71, 1.03] 0.10
T280M (BH) 6851/5050 0.82 [0.66, 1.00] 0.06 0.97 [0.74, 1.23] 0.79 0.80 [0.65, 0.99] 0.04 0.91 [0.72, 1.16] 0.47 0.85 [0.71, 1.03] 0.09
V249I (BS) 7727/5862 0.84 [0.71, 1.00] 0.05 0.86 [0.67, 1.10] 0.23 0.89 [0.77, 1.02] 0.09 0.79 [0.60, 1.05] 0.11 0.86 [0.74, 1.00] 0.06
V249I (BH) 6579/4677 0.80 [0.67, 0.97] 0.02 0.82 [0.62, 1.07] 0.14 0.85 [0.73, 0.99] 0.04 0.74 [0.54, 1.00] 0.05 0.83 [0.71, 0.98] 0.03
Open in a new tab

A: Asians; C: Caucasians; CAD: coronary artery disease; CAA: carotid artery atherosclerosis; ICVD: ischemic cerebrovascular disease; PAD: peripheral arterial disease; PB: population-based, HB: hospital-based; BS: based on score (studies with score ≤ 6 were excluded); BH: based on HWE (studies without HWE were excluded). Bonferroni correction was used to control for the multiple testing in view of five genetic models under investigation (significance was set at 0.05/5 = 0.01).

3.2. Genotype-Phenotype Association

As shown in Table 2, the overall results showed no significant association between the CX3CR1 T280M polymorphism and the susceptibility to AS in five genetic models (P > 0.01 for all). When we performed a subgroup analysis, there was significant association between T280M polymorphism and the susceptibility to AS in the CAD group in dominant model (P < 0.01), codominant model (P < 0.01), additive model (P < 0.01), and allelic model (P < 0.01), but not in recessive model (P > 0.01), suggesting that the 280M allele carriers decreased the risk of CAD in the heterozygous state. The significant association between T280M polymorphism and the susceptibility to AS was also found in the ICVD group in recessive model (P < 0.01) and additive model (P < 0.01), but not in dominant model (P > 0.01), codominant model (P > 0.01), or allelic model (P > 0.01), suggesting that the 280M allele carriers increased the risk of ICVD in homozygote state. Then, we considered the TT genotype as the baseline risk, we found TM genotype was a protective role for AS (OR = 0.81, 95% CI = 0.66–0.99, P = 0.04; Table 3 and Figure 2), subgroup analysis showed that the TM genotype was a protective role for CAD (OR = 0.67, 95% CI = 0.52–0.87, P < 0.01; Table 3 and Figure S1), and MM genotype was a risk factor for ICVD (OR = 2.88, 95% CI = 1.64–5.04, P < 0.001; Table 3 and Figure S2). There was no association between the T280M polymorphism and the susceptibility to AS in the other groups (Tables 2 and 3).

Table 3.

The independent effect of each genotype/haplotype on susceptibility to atherosclerosis.

Genotype Cases (n) Controls (n) Baseline risk OR 95% CI P I 2 (%) P Q
VVTT 1923 2601   1        
VVTM 49 3 VVTT 11.95 5.00–28.58 <0.001 0 0.44
VITT 516 700 VVTT 1.11 0.96–1.27 0.16 31.4 0.13
VITM 605 1211 VVTT 0.64 0.50–0.82 <0.001 69.2 <0.1
IITT 64 76 VVTT 1.20 0.83–1.74 0.33 0 0.46
IITM 100 182 VVTT 0.69 0.52–0.90 <0.01 41.7 <0.1
IIMM 87 151 VVTT 0.76 0.57–1.02 0.06 0 0.79
VV 4813 3556   1        
VI 2598 2016 VV 0.84 0.72–0.98 0.02 65.9 <0.1
VI (CAD) 1843 1227 VV (CAD) 0.72 0.59–0.90 <0.01 68.1 <0.1
II 541 463 VV 0.81 0.62–1.05 0.12 61.6 <0.1
TT 5786 4293   1        
TM 1743 1456 TT 0.81 0.66–0.99 0.04 76.2 <0.1
TM (CAD) 1193 871 TT (CAD) 0.67 0.52–0.87 <0.01 72.2 <0.1
MM 203 156 TT 0.96 0.77–1.19 0.72 31.9 0.08
MM (ICVD) 47 16 TT (ICVD) 2.88 1.64–5.04 <0.001 0 0.92
VT 5377 6975   1        
VM 77 5 VT 11.47 5.34–24.64 <0.001 43.0 0.12
IT 814 1007 VT 1.09 0.97–1.21 0.14 0 0.55
IM 892 1665 VT 0.63 0.50–0.81 <0.001 82.2 <0.1
Open in a new tab

P Q, P value for Cochran's Q statistic.

Figure 2.

Figure 2

Open in a new tab

Forest plot for CX3CR1 T280M polymorphism and AS risk (TM versus TT).

The overall results showed no significant association between the CX3CR1 V249I polymorphism and the susceptibility to AS in five genetic models (P > 0.01 for all, Table 2). Subgroup analysis showed significant association between V249I polymorphism and the susceptibility to AS in CAD group in dominant model (P < 0.01), codominant model (P < 0.01), additive model (P < 0.01), and allelic model (P < 0.01), but not in recessive model (P > 0.01), suggesting that the 249I alleles decreased the risk of CAD in heterozygote state. Significant associations were also found between this variant and the susceptibility to AS in the population-based (PB) group in recessive and additive models (P < 0.01 for each). Then, we considered the VV genotype as the baseline risk; we found VI genotype was a protective role for AS (OR = 0.84, 95% CI = 0.72–0.98, P = 0.02; Table 3 and Figure 3); subgroup analysis showed that the VI genotype was a protective role for CAD (OR = 0.72, 95% CI = 0.59–0.90, P < 0.01; Table 3 and Figure S3). There was no association between V249I polymorphism and the susceptibility to AS in the other groups (Tables 2 and 3).

Figure 3.

Figure 3

Open in a new tab

Forest plot for CX3CR1 V249I polymorphism and AS risk (VI versus VV).

For V249I-T280M combined genotype (Table S2), when we took VVTT genotype as a baseline risk, significant discrepancies were found in VVTM genotype (OR = 11.95, 95% CI = 5.00–28.58, P < 0.001; Table 3), suggesting that the VVTM genotype was a risk factor for AS, but VVTM was a very rare genotype and may not have potential clinical significance. Significant association was also found in the VITM (OR = 0.64, 95% CI = 0.50–0.82, P < 0.001) and IITM genotypes (OR = 0.69, 95% CI = 0.52–0.90, P < 0.01), suggesting that the VITM and IITM genotypes were protective roles for AS (Table 3).

3.3. Linkage Disequilibrium Analysis

There were nine combined genotypes in Table S2; six studies identified the extremely rare VVTM genotype. Linkage disequilibrium (LD) analysis showed a strong association between the T280M and V249I polymorphisms (Table 4). Thirteen of the fourteen studies conclusively found complete LD; an association analysis of the whole sample (cases and controls) indicated strong (but not complete) LD between the two loci (D′ = 0.9950,  r 2 = 0.5394).

Table 4.

Estimated haplotype frequencies and linkage disequilibrium analysis of the included studies.

First author Estimated haplotype frequencies (cases) Estimated haplotype frequencies (controls) D′a r 2 a
V249 T280 V249 M280 I249 T280 I249 M280 V249 T280 V249 M280 I249 T280 I249 M280
McDermott [13, 14] 0.7817 0 0.0838 0.1345 0.7042 0 0.0986 0.1972 1 0.5848
Moatti [15] 0.7980 0 0.0993 0.1026 0.7149 0 0.1345 0.1506 1 0.4445
Gugl [8] 0.7317 0 0.0904 0.1778 0.7416 0 0.0706 0.1879 1 0.6638
McDermott [13, 14] 0.7304 0 0.1324 0.1373 0.7018 0 0.1157 0.1825 1 0.5253
Ghilardi [7] 0.7407 0 0.1481 0.1111 0.7255 0 0.1225 0.1520 1 0.4736
Hattori [44] 0.9318 0.0256 0.0065 0.0361 0.9444 0.0082 0.0033 0.0441 0.9270 0.7743
Niessner [17, 18] 0.7332 0.0016 0.1113 0.1540 0.7564 0 0.0998 0.1439 1 0.5217
Apostolakis [6, 43] 0.7214 0 0.1500 0.1286 0.7000 0 0.1212 0.1788 1 0.508
An [24] 0.8241 0 0.0833 0.0926 0.7187 0 0.1250 0.1562 1 0.4733
Nassar-a [16] 0.7067 0.0171 0.1440 0.1321 0.6544 0 0.1376 0.2081 1 0.4974
Nassar-b [16] 0.6250 0.0203 0.1622 0.1925 0.6544 0 0.1376 0.2081 1 0.4974
Zhao [23] 0.7138 0 0.1478 0.1384 0.6729 0 0.1353 0.1918 1 0.4882
Singh-a, b [21, 22] 0.7559 0.0542 0.1402 0.0497 0.6967 0 0.1050 0.1983 1 0.5682
Singh-c [21, 22] 0.7739 0.0413 0.1304 0.0543 0.6967 0 0.1050 0.1983 1 0.5682
Total 0.7477 0.0091 0.1120 0.1312 0.7224 0.0006 0.1050 0.1720 0.9950 0.5394
Open in a new tab

a D′ and r 2 statistics refer to control groups.

3.4. Haplotype-Phenotype Association

Haplotype frequencies of each study and the total sample are reported in Table 4, the strong LD between the V249I and T280M polymorphisms resulted in three predominant haplotypes and the extremely rare 249V-280M; the latter haplotype accounts for less than 0.5% of the entire population's gene pool. We assessed the effect of the 249V-280M, 249I-280T, and 249I-280M haplotypes on the risk for AS independently taking the 249V-280T haplotype as a baseline risk. A significant predominance of the 249I-280M haplotype was observed in the control population compared to case subjects (OR = 0.63, 95% CI: 0.50–0.81, P < 0.001; Table 3). No association was observed between the 249I-280T haplotype and susceptibility to AS (OR = 1.09, 95% CI: 0.97–1.21, P = 0.14; Table 3).

3.5. Sensitivity Analysis

Sensitivity analyses were conducted to determine whether modification of the inclusion criteria of the meta-analysis affected the final results. The included studies were limited to those conforming to HWE or the high quality studies (NOS score ≥ 7); the corresponding pooled ORs were not materially altered, either for the CX3CR1 T280M polymorphism or for the V249I polymorphism. This suggested that the overall results of this meta-analysis were statistically robust. The main results of sensitivity analyses are shown in Table 2.

3.6. Heterogeneity Analysis

For both CX3CR1 T280M and V249I polymorphisms, significant heterogeneity existed in the overall comparisons in five genetic models. We performed subgroup analyses based on the ethnic (Caucasians and Asian), atherosclerotic diseases (CAD, PAD, CAA, and ICVD), and source of control (hospital-based or population-based); heterogeneity was distinctly reduced; although it was still significant, we could not point out other possible sources of heterogeneity. The data were shown in Table S3.

For the V249I-T280M combined polymorphism, when the VVTT genotype was taken as the baseline risk, we found significant heterogeneity in the VITM genotype (P Q < 0.1, I 2 = 69.2%). When the 249V-280T haplotype was taken as the baseline risk, we showed obvious heterogeneity in the 249I-280 M haplotype (P Q < 0.1, I 2 = 82.2%; Table 3).

3.7. Publication Bias

Begg's funnel plot and Egger's regression test were performed to assess potential publication bias. For the CX3CR1 T280M polymorphism, visual inspection of the funnel plot (Figure 4(a)) displays symmetrical distribution of OR estimations, suggesting no publication bias. In addition, the results of Egger's regression test also provided evidence for no publication bias (TM versus TT, P > 0.05 for all genetic models). For the CX3CR1 V249I polymorphism, no obvious asymmetry was observed in any genetic model according to the visual assessment of funnel plot (Figure 4(b)). The results of Egger's regression test did not provide any statistical evidence for publication bias (VI versus VV, P > 0.05 for all genetic models).

Figure 4.

Figure 4

Open in a new tab

Begg's funnel plots for CX3CR1 T280M and V249I polymorphisms and AS risk. (a) TM versus TT for T280M polymorphism; (b) VI versus VV for V249I polymorphism.

4. Discussion

In this study, twenty-five articles involving the associations between the CX3CR1 polymorphisms and AS risk were included in the final meta-analysis. According to the GRADE approach, the quality of the evidence of CX3CR1 T280M polymorphism was very low in dominant model and allelic model, moderate in recessive model and additive model, and low in codominant model (Table S1). For the CX3CR1 V249I polymorphism, GRADE suggested that the quality of the evidence was moderate in recessive model, codominant model, and additive model, low in dominant model, and very low in allelic model (Table S1).

The overall findings showed that there was no association between the CX3CR1 polymorphisms and the risk of AS in five genetic models. To make a more comprehensive analysis, subgroup analyses were performed based on ethnicity, atherosclerotic disease, and source of controls. For the CX3CR1 T280M polymorphism, Apostolakis et al. [43] showed that the 280M allele carriers reduced the risk of CAD in heterozygote state. In the present study, we also found atheroprotective effect to AS in the CAD group. In addition, we found that the 280M allele carriers increased the risk of ICVD in homozygote state. For the CX3CR1 V249I polymorphism, significant associations were found between this variant and the atheroprotective effect on AS in CAD and PB groups. These results suggested that the 249I allele carriers reduced the risk of CAD in heterozygote state. The above statistical results were based on Bonferroni correction to control for the multiple testing in view of under investigation.

For the combined genotype, the VITM and IITM genotypes played an atheroprotective effect on AS. The combined VVTM genotype was more common in the cases than in the controls; however, the rarity of the VVTM genotype makes any conclusion rather unsafe. LD analysis indicated a strong association between T280M and V249I, and a protective role of the 249I-280M haplotype was also observed in the control population compared to case subjects. No association was observed between the 249I-280T haplotype and the susceptibility to AS. These results were consistent with those of a previous study [43].

Considering the studies without HWE or with low NOS score may influence the overall results, subsequent sensitivity analyses restricted to the studies with HWE or high NOS score were performed, but no corresponding pooled OR was materially altered in the dominant, recessive, codominant, additive, and allelic models. These results suggested that the studies without HWE or low score should not be considered as a factor influencing the overall results.

Heterogeneity of the included studies is the most important drawback when the genotypic data were analyzed, either for the CX3CR1 T280M or for the CX3CR1 V249I polymorphism. Heterogeneity should not be ignored and should be carefully factored in the interpretation of the final results. For the CX3CR1 T280M and V249I polymorphisms, the heterogeneity can partly be explained by the ethnicity (Caucasians and Asian), subtype of atherosclerotic diseases (CAD, CAA, and ICVD), and source of control (hospital-based and population-based).

However, some limitations of this meta-analysis should be acknowledged. Firstly, there was significant heterogeneity in this meta-analysis. Heterogeneity may affect the precision of overall results, despite the use of appropriate meta-analytic techniques with random-effects model. Secondly, in the subgroup analyses, the sample sizes in some subgroup, such as the PAD and CAA groups of the CX3CR1 T280M and V249I polymorphisms, were relatively small, not having enough statistical power to explore the real association. Thirdly, AS is a complex disease and involves potential interactions of gene-environment. However, many eligible studies included in this meta-analysis did not consider the environmental factors. Therefore, studies with larger sample sizes and better design are needed.

5. Conclusion

The present meta-analysis suggested that the CX3CR1 280M and 249I allele carriers had atheroprotective roles on AS in heterozygote state, and the 280M allele carriers were associated with the susceptibility to AS in homozygote state. The combined genotypes of VITM and IITM also had atheroprotective roles on AS. Consequently, this effect may be attributed to the haplotype of 249I-280M. However, the results should be interpreted with caution because of its limitations. Further studies with large sample size, especially with the consideration of gene-gene and gene-environment interactions, are needed to confirm our findings.

Supplementary Material

Checklist S1: The PRISMA 2009 checklist. Figure S1: Forest plot for CX3CR1 T280M polymorphism and AS risk in CAD group (TM versus TT). Figure S2: Forest plot for CX3CR1 T280M polymorphism and AS risk in ICVD group (MM versus TT). Figure S3: Forest plot for CX3CR1 V249I polymorphism and AS risk in CAD group (VI versus VV). Table S1: GRADE profile evidence of the included studies. Table S2: Genotype distribution in cases and controls. Table S3: Heterogeneity test of CX3CR1 T280M and V249I polymorphisms and risk of AS in each subgroup.

913678.f1.zip (567KB, zip)

Acknowledgment

This study was supported by the National Natural Science Foundation of China (no. 30960130).

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  • 1.Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123:e18–e209. doi: 10.1161/CIR.0b013e3182009701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Zende PD, Bankar MP, Kamble PS, Momin AA. Apolipoprotein e gene polymorphism and its effect on plasma lipids in arteriosclerosis. Journal of Clinical and Diagnostic Research. 2013;7:2149–2152. doi: 10.7860/JCDR/2013/6195.3455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Ekmekçi A, Ozcan KS, Güngör B, et al. The relationship between endothelial nitric oxide synthase 4a/4b gene polymorphism and premature coronary artery disease. Acta Cardiology. 2013;68:464–468. doi: 10.1080/ac.68.5.2994468. [DOI] [PubMed] [Google Scholar]
  • 4.García-Bermúdez M, López-Mejías R, Genre F, et al. SMAD3 rs17228212 gene polymorphism is associated with reduced risk to cerebrovascular accidents and subclinical atherosclerosis in anti-CCP negative Spanish rheumatoid arthritis patients. PLoS ONE. 2013;8 doi: 10.1371/journal.pone.0077695.e77695 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Al-Najai M, Muiya P, Tahir AI, et al. Association of the angiotensinogen gene polymorphism with atherosclerosis and its risk traits in the Saudi population. BMC Cardiovascular Disorders. 2013;13, article 17 doi: 10.1186/1471-2261-13-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Apostolakis S, Baritaki S, Kochiadakis GE, Igoumenidis NE, Panutsopulos D, Spandidos DA. Effects of polymorphisms in chemokine ligands and receptors on susceptibility to coronary artery disease. Thrombosis Research. 2007;119(1):63–71. doi: 10.1016/j.thromres.2005.12.016. [DOI] [PubMed] [Google Scholar]
  • 7.Ghilardi G, Biondi ML, Turri O, Guagnellini E, Scorza R. Internal carotid artery occlusive disease and polymorphisms of fractalkine receptor CX3CR1: a genetic risk factor. Stroke. 2004;35(6):1276–1279. doi: 10.1161/01.STR.0000128528.56009.d4. [DOI] [PubMed] [Google Scholar]
  • 8.Gugl A, Renner W, Seinost G, et al. Two polymorphisms in the fracalkine receptor CX3CR1 are not associated with peripheral arterial disease. Atherosclerosis. 2003;166(2):339–343. doi: 10.1016/s0021-9150(02)00362-3. [DOI] [PubMed] [Google Scholar]
  • 9.Kimouli M, Miyakis S, Georgakopoulos P, Neofytou E, Achimastos AD, Spandidos DA. Polymorphisms of fractalkine receptor CX3CR1 gene in patients with symptomatic and asymptomatic carotid artery stenosis. Journal of Atherosclerosis and Thrombosis. 2009;16(5):604–610. doi: 10.5551/jat.1107. [DOI] [PubMed] [Google Scholar]
  • 10.Lavergne E, Labreuche J, Daoudi M, et al. Adverse associations between CX3CR1 polymorphisms and risk of cardiovascular or cerebrovascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25(4):847–853. doi: 10.1161/01.ATV.0000157150.23641.36. [DOI] [PubMed] [Google Scholar]
  • 11.Li Z, Luo S, Wang F, Zhen J, Sun H, Guo C. An association study between polymorphisms of the Fractalkine receptor gene, CX3CR1, and cerebral infarction in the Han Chinese population. Journal of the Neurological Sciences. 2012;320(1-2):12–15. doi: 10.1016/j.jns.2012.05.044. [DOI] [PubMed] [Google Scholar]
  • 12.Matzhold EM, Trummer O, Grünbacher G, et al. Association of polymorphisms in the chemokine receptor CX3CR1 gene with coronary artery disease. Cytokine. 2009;47(3):224–227. doi: 10.1016/j.cyto.2009.06.010. [DOI] [PubMed] [Google Scholar]
  • 13.McDermott DH, Halcox JPJ, Schenke WH, et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circulation Research. 2001;89(5):401–407. doi: 10.1161/hh1701.095642. [DOI] [PubMed] [Google Scholar]
  • 14.McDermott DH, Fong AM, Yang Q, et al. Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. The Journal of Clinical Investigation. 2003;111(8):1241–1250. doi: 10.1172/JCI16790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Moatti D, Faure S, Fumeron F, et al. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood. 2001;97(7):1925–1928. doi: 10.1182/blood.v97.7.1925. [DOI] [PubMed] [Google Scholar]
  • 16.Nassar BA, Nanji AA, Ransom TP, et al. Role of the fractalkine receptor CX3CR1 polymorphisms V249I and T280M as risk factors for early-onset coronary artery disease in patients with no classic risk factors. Scandinavian Journal of Clinical and Laboratory Investigation. 2008;68(4):286–291. doi: 10.1080/00365510701697390. [DOI] [PubMed] [Google Scholar]
  • 17.Niessner A, Marculescu R, Haschemi A, et al. Opposite effects of CX3CR1 receptor polymorphisms V249I and T280M on the development of acute coronary syndrome. A possible implication of fractalkine in inflammatory activation. Thrombosis and Haemostasis. 2005;93(5):949–954. doi: 10.1160/TH04-11-0735. [DOI] [PubMed] [Google Scholar]
  • 18.Niessner A, Marculescu R, Kvakan H, et al. Fractalkine receptor polymorphisms V2491 and T280M as genetic risk factors for restenosis. Thrombosis and Haemostasis. 2005;94(6):1251–1256. [PubMed] [Google Scholar]
  • 19.Pucci S, Mazzarelli P, Zonetti MJ, et al. CX3CR1 receptor polymorphisms, Th1 cell recruitment, and acute myocardial infarction outcome: looking for a link. BioMed Research International. 2013;2013:9 pages. doi: 10.1155/2013/451349.451349 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Rios DLS, Callegari-Jacques SM, Hutz MH. Endothelial nitric oxide synthase and fractalkine chemokine receptor polymorphisms on angiographically assessed coronary atherosclerosis. Clinica Chimica Acta. 2005;362(1-2):138–146. doi: 10.1016/j.cccn.2005.06.012. [DOI] [PubMed] [Google Scholar]
  • 21.Singh N, Rai H, Sinha N, Kumar S, Pandey CM, Agrawal S. Association of V249I and T280M polymorphisms in the chemokine receptor CX3CR1 gene with early onset of coronary artery disease among North Indians. Genetic Testing and Molecular Biomarkers. 2012;16(7):756–760. doi: 10.1089/gtmb.2011.0256. [DOI] [PubMed] [Google Scholar]
  • 22.Singh N, Sinha N, Kumar S, Pandey CM, Agrawal S. Polymorphism in chemokine receptor genes and risk of acute myocardial infarction in North Indian population. Molecular Biology Reports. 2012;39(3):2753–2759. doi: 10.1007/s11033-011-1031-8. [DOI] [PubMed] [Google Scholar]
  • 23.Zhao R, Wang Y, Shen R, Sun Y. Relationship between CX3CR1 genetic polymorphism and carotid atherosclerosis. Artificial Cells, Blood Substitutes, and Biotechnology. 2010;38(1):19–23. doi: 10.3109/10731190903495728. [DOI] [PubMed] [Google Scholar]
  • 24.An Z, Bi L, Zheng LY, Sun J. Association between polymorphism in chemokine receptor CX3CR1 and coronary atherosclerosis. Journal of Dalian Medical University. 2008;30:314–317. [Google Scholar]
  • 25.Peng X, Zhang ZB, Tang L, Zhou Y. Study on chemokine receptor CX3CR1 gene T280M polymorphism in patients with ischemic cerebrovascular disease. Journal of Clinical Neurology. 2008;21:329–332. [Google Scholar]
  • 26.Shi L, Sun L, Gu P, et al. Relationship between chemokine receptor CX3CR1 gene polymorphism with cerebral infarction of North China population. Journal of Apoplexy and Nervous Diseases. 2012;29:434–438. [Google Scholar]
  • 27.Wu L, Jia L, Guo X, Liu D, Sun H. A study on CX3CR1 gene polymophism of the Han nationality people in Baotou. Journal of Baotou Medical College. 2012;28:9–11. [Google Scholar]
  • 28.Xiao HK, Jin LZ, Xie GT, Chen J, Chen XC, Xu MT. A study on association of Fractalkine receptor CX3CR1 gene polymorphism to coronary heart disease. Chinese Journal of Arteriosclerosis. 2010;18:993–995. [Google Scholar]
  • 29.Zhang ZB, Peng X, Tang L. Research on V249I polymorphisms of chemokine receptor CX3CR1 gene in patients with ischemic cerebrovascular disease. Shandong Medical Journal. 2008;48:15–17. [Google Scholar]
  • 30.Zhang YL, Yu W, Fang B. Association study between the polymorphisms of fractalkine receptor CX3CR1 and cerebral infarction. China Journal of Modern Medicine. 2010;20:4–8. [Google Scholar]
  • 31.Zheng M, Zhang C. The association of CX3CR1 polymorphisms with carotid artery intima-media thickness. Acta Academiae Medicinae Qingdao Universitatis. 2008;44:216–219. [Google Scholar]
  • 32.Jaipersad AS, Lip GY, Silverman S, Shantsila E. The role of monocytes in angiogenesis and atherosclerosis. Journal of the American College of Cardiology. 2014;63:1–11. doi: 10.1016/j.jacc.2013.09.019. [DOI] [PubMed] [Google Scholar]
  • 33.Frostegård J. Immunity, atherosclerosis and cardiovascular disease. BMC Medicine. 2013;11, article 117 doi: 10.1186/1741-7015-11-117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Ghattas A, Griffiths HR, Devitt A, Lip GY, Shantsila E. Monocytes in coronary artery disease and atherosclerosis: where are we now? Journal of the American College of Cardiology. 2013;62(17):1541–1551. doi: 10.1016/j.jacc.2013.07.043. [DOI] [PubMed] [Google Scholar]
  • 35.Weber C, Schober A, Zernecke A. Chemokines: key regulators of mononuclear cell recruitment in atherosclerotic vascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24(11):1997–2008. doi: 10.1161/01.ATV.0000142812.03840.6f. [DOI] [PubMed] [Google Scholar]
  • 36.Liu H, Jiang D. Fractalkine/CX3CR1 and atherosclerosis. Clinica Chimica Acta. 2011;412(13-14):1180–1186. doi: 10.1016/j.cca.2011.03.036. [DOI] [PubMed] [Google Scholar]
  • 37.Bazan JF, Bacon KB, Hardiman G, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature. 1997;385(6617):640–642. doi: 10.1038/385640a0. [DOI] [PubMed] [Google Scholar]
  • 38.Greaves DR, Häkkinen T, Lucas AD, et al. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus- and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21(6):923–929. doi: 10.1161/01.atv.21.6.923. [DOI] [PubMed] [Google Scholar]
  • 39.Wong BWC, Wong D, McManus BM. Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease. Cardiovascular Pathology. 2002;11(6):332–338. doi: 10.1016/s1054-8807(02)00111-4. [DOI] [PubMed] [Google Scholar]
  • 40.Combadière C, Potteaux S, Gao J, et al. Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation. 2003;107(7):1009–1016. doi: 10.1161/01.cir.0000057548.68243.42. [DOI] [PubMed] [Google Scholar]
  • 41.Lesnik P, Haskell CA, Charo IF. Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis. The Journal of Clinical Investigation. 2003;111(3):333–340. doi: 10.1172/JCI15555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Saederup N, Chan L, Lira SA, Charo IF. Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2-/- mice: evidence for independent chemokine functions in atherogenesis. Circulation. 2008;117(13):1642–1648. doi: 10.1161/CIRCULATIONAHA.107.743872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Apostolakis S, Amanatidou V, Papadakis EG, Spandidos DA. Genetic diversity of CX3CR1 gene and coronary artery disease: new insights through a meta-analysis. Atherosclerosis. 2009;207(1):8–15. doi: 10.1016/j.atherosclerosis.2009.03.044. [DOI] [PubMed] [Google Scholar]
  • 44.Hattori H, Ito D, Tanahashi N, et al. T280M and V249I polymorphisms of fractalkine receptor CX3CR1 and ischemic cerebrovascular disease. Neuroscience Letters. 2005;374(2):132–135. doi: 10.1016/j.neulet.2004.10.042. [DOI] [PubMed] [Google Scholar]
  • 45.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. International Journal of Surgery. 2010;8(5):336–341. doi: 10.1016/j.ijsu.2010.02.007. [DOI] [PubMed] [Google Scholar]
  • 46.Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Health Research Institute, http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
  • 47.Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. British Medical Journal. 2008;336(7650):924–926. doi: 10.1136/bmj.39489.470347.AD. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Gaunt TR, Rodríguez S, Day INM. Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool “CubeX”. BMC Bioinformatics. 2007;8, article 428 doi: 10.1186/1471-2105-8-428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. British Medical Journal. 2003;327(7414):557–560. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Berkey CS, Hoaglin DC, Mosteller F, Colditz GA. A random-effects regression model for meta-analysis. Statistics in Medicine. 1995;14(4):395–411. doi: 10.1002/sim.4780140406. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Checklist S1: The PRISMA 2009 checklist. Figure S1: Forest plot for CX3CR1 T280M polymorphism and AS risk in CAD group (TM versus TT). Figure S2: Forest plot for CX3CR1 T280M polymorphism and AS risk in ICVD group (MM versus TT). Figure S3: Forest plot for CX3CR1 V249I polymorphism and AS risk in CAD group (VI versus VV). Table S1: GRADE profile evidence of the included studies. Table S2: Genotype distribution in cases and controls. Table S3: Heterogeneity test of CX3CR1 T280M and V249I polymorphisms and risk of AS in each subgroup.

913678.f1.zip (567KB, zip)

Articles from Disease Markers are provided here courtesy of Wiley

RESOURCES