Interleukin-18 promoter polymorphisms and risk of ischemic stroke

Brain Research Bulletin 81 (2010) 590–594

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Interleukin-18 promoter polymorphisms and risk of ischemic stroke Na Zhang a , Jin-Tai Yu a , Nan-Nan Yu a , Rui-Chun Lu a , Teng Ma b , Nai-Dong Wang c , Dan Miao a , Jing-Hui Song c , Lan Tan a,∗ a

Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province 266071, China Department of Neurology, Qingdao Hiser Hospital, Shandong Province, PR China c Department of Neurology, The Affiliated Hospital of the Medical College of Qingdao University, Shandong Province, PR China b

a r t i c l e

i n f o

Article history: Received 26 October 2009 Received in revised form 10 January 2010 Accepted 14 January 2010 Available online 25 January 2010 Keywords: Ischemic stroke Inflammation Interleukin-18 Polymorphisms

a b s t r a c t Ischemic stroke (IS) is a major cause of morbidity and mortality around the world. Interleukin-18 (IL18) plays an important role in the pathogenesis of IS and IL-18 promoter polymorphisms have been shown to be associated with levels of expression of IL-18. We investigated the association of two functional polymorphisms in IL-18 promoter, −607C/A (rs1946518) and −137G/C (rs187238), with the risk of ischemic stroke in a Han Chinese population of 423 patients and 384 healthy controls matched for sex and age. The results revealed that the −607C allele was associated with an increased risk of IS with an odds ratios (OR) of 1.358 (P = 0.002, power = 100%) and the presence of the −137G allele was correlated with increased the risk of IS in the subtype of patients with large artery atherosclerosis (LAA) (OR = 1.583, P = 0.02, power = 94%). Patients with the −607C/−137G haplotype also had significantly increased risk of IS compared to controls (OR = 1.341, P = 0.005, power = 100%). Our findings suggest that these functional polymorphisms in the IL-18 promoter are involved in development of IS in the Han Chinese population. © 2010 Elsevier Inc. All rights reserved.

1. Introduction Ischemic stroke (IS) is a major cause of morbidity and mortality around the world. There are several subtypes and multiple proven risk factors, such as hypertension, hyperlipidemia, and diabetes [14]. The etiology of IS is complex because of its strong genetic heterogeneity. Convincing evidence indicates that proinflammatory cytokines play an important role in the pathogenesis of atherosclerosis [31,42,47,52,53] and that these inflammatory responses are involved in the pathogenesis of IS [33,48]. There is accumulating evidence that certain polymorphisms in inflammatory genes, including interleukin (IL-6), transforming growth factor (TGF-␤1), interleukin-1 receptor antagonist (IL-1Ra), IL-1␣, phosphodiesterase 4D (PDE4D), IL-1␤, tumor necrosis factor (TNF-␣), and lymphotoxin-␣ (LTA) are associated with increased risk for IS [3–5,25–27,41,49]. IL-18, a member of the IL-1 superfamily, is a pleiotropic proinflammatory cytokine [34] that functions in the inflammatory cascade [18]. Plasma levels of IL-18 are significantly higher in IS patients than in control groups [55,56]. The IL-18 gene is located on the region 11q22.2–22.3, and its promoter region contains multiple transcription initiation sites [34]. Two polymorphisms, −607C/A (rs1946518) and −137G/C (rs187238), are known to influence

∗ Corresponding author. Tel.: +86 532 8890 5659; fax: +86 532 85968434. E-mail address: [email protected] (L. Tan). 0361-9230/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.brainresbull.2010.01.008

expression from the IL-18 gene [15,23,24]. Considerable evidence shows that IL-18 gene polymorphisms are associated with cardiovascular diseases [30,37]. Bis et al. [5] reported that IL-18 gene polymorphisms were associated with cardiovascular outcomes and with myocardial infarction (MI) risk; no IL-18 SNP was associated with IS risk. As cardiovascular diseases and cerebrovascular diseases have the same causal etiologies, including endothelial damage and arteriosclerosis, the lack of association of IL-18 polymorphisms with IS risk was surprising. To clarify the role of IL-18 promoter polymorphisms in IS, we analyzed the −607C/A and the −137G/C polymorphisms of IL-18 promoter samples from Han Chinese population in a case–control study. 2. Materials and methods 2.1. Subjects Our study consecutively recruited 423 ischemic stroke cases (the mean age at onset was 64.3 ± 10.1 years) and 384 healthy controls matched for sex and age from the Department of Neurology at Qingdao Municipal Hospital and several other hospitals in Shandong Province. All subjects were Northern Han Chinese in ethnicity. With the use of clinical, cardiac, ultrasound and brain Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) tests, each IS patient was assessed according to the criteria of the modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) to determine stroke subtype. Among these 423 patients, we observed large artery atherosclerosis (n = 183), small vessel disease (n = 189), cardioembolism (n = 51), and the other strokes with rare or undetermined etiology. The control groups were selected from the Health Examination Center of the Qingdao Municipal Hospital and they were confirmed healthy and neurologically normal by medical history, general examinations, and laboratory examinations. Subjects with significant illness such as type 2 diabetes mellitus (T2DM), myocardial infarction, congestive heart failure,

N. Zhang et al. / Brain Research Bulletin 81 (2010) 590–594 Table 1 The characteristics of the study population.

Age (mean ± SD) Males Smoking BMI (kg/m2 ) (mean ± SD) Hypertension (no.) Hypercholesterolemia (no.)

Ischemic stroke (423)

Control (384)

P

68.3 ± 11.4 256(60.5) 176(41.6) 25.0 ± 3.6 333(78.7) 135(31.9)

67.5 ± 6.6 231(60.2) 47(12.2) 25.0 ± 3.0 161(41.9) 107(27.9)

0.322 0.916 <0.001 1 <0.001 0.21

SD: Standard deviation; no.: number. peripheral vascular diseases, brain tumors, Alzheimer’s disease, rheumatoid arthritis, or asthma were excluded from our study. An informed consent to participate in this study was given by all individuals or their caregivers and the protocol of this study was approved by the Institute Ethical Committee. BMI was defined as weight divided by height squared (kg/m2 ). Hypertension was defined as present if subjects had been previously diagnosed according to World Health Organization/International Society of Hypertension guidelines. Hypercholesterolemia was defined as a total cholesterol blood level >220 mg/dl. 2.2. Genotyping Genomic DNA was isolated from peripheral blood leukocytes using standard procedures. The polymorphisms at positions −607 and −137 in the promoter of the IL-18 gene were genotyped by sequence-specific primers (SSP) using the polymerase chain reaction (PCR) as described by Giedraitis et al. [15] and Yu et al. [54]. All PCR products were visualized on 2% agarose gels stained by ethidium bromide. 2.3. Statistical analysis The Hardy–Weinberg equilibrium between expected and observed genotype distributions were assessed using the Chi-square test. Statistical analysis was per-

591

formed using SPSS statistical software, version 11.5 for Windows. The linkage disequilibrium (LD) between the two tested SNPs was quantified using the Shi’s standardized coefficient D [43]. Haplotypic frequencies were estimated using the EM algorithm implemented in the Arlequin 3.1 software package with number of iterations set at 5000, initial conditions set at 50, and an epsilon value of 10−7 [10,54]. Statistical power was estimated using STPLAN 4.3 software, for the minor allele frequency (MAF) is 0.40 in −607C/A and 0.15 in −137G/C, stroke prevalence is 10% in the dominant genetic model. Differences in the characteristics of the study populations between two groups were examined using the Student t-test or the Chi-square test. Genotype, allele, and haplotype distributions were compared using the Chi-square test. The strength of association between the polymorphisms and IS was estimated with OR with 95% confidence intervals (CI). Logistic regression was used to adjust for confounding variables, including age, gender, current smoking, hypertension, and hypercholesterolemia.

3. Results Patient and control group characteristics are shown in Table 1. Known risk factors for IS (smoking and hypertension) were more commonly seen in patients than controls. The genotype and allele frequencies of IS patients and controls are presented in Table 2. Distributions of genotypes of the two IL18 polymorphisms were in the Hardy–Weinberg equilibrium in the two groups except for −607C/A in SVD (Table 3). A statistically significant different in genotype of the −607C/A (P = 0.006) and a higher frequency of the −607C allele were observed in patients than in controls (odds ratios/OR = 1.358, 95% confidence intervals/CI = 1.116–1.652, P = 0.002, power = 100%). When the subtypes were analyzed separately, both polymorphisms were significant different in genotype distribution between IS and con-

Table 2 Genotype distribution and allele frequencies in patients with ischemic stroke compared with healthy controls. −607C/A

n

Genotype

Allele

CC (%)

CA (%)

AA (%)

P

C (%)

A (%)

P

IS Control

423 384

122(28.8) 81(21.1)

227(53.7) 207(53.9)

74(17.5) 96(25.0)

0.006

471(55.7) 369(48.0)

375(44.3) 399(52.0)

0.002

LAA Control

183 384

77(42.1) 81(21.1)

80(43.7) 207(53.9)

26(14.2) 96(25.0)

<0.001

234(63.9) 369(48.0)

132(36.1) 399(52.0)

<0.001

SVD Control

189 384

35(18.5) 81(21.1)

125(66.1) 207(53.9)

29(15.3) 96(25.0)

0.011

195(51.6) 369(48.0)

183(48.4) 399(52.0)

0.260

CE Control

51 384

10(19.6) 81(21.1)

22(43.1) 207(53.9)

19(37.3) 96(25.0)

0.166

42(41.2) 369(48.0)

60(58.8) 399(52.0)

0.192

≤65 years Patients Control

160 154

52(32.5) 32(20.8)

88(55.0) 82(53.2)

20(12.5) 40(26.0)

0.003

192(60.0) 146(47.4)

128(40.0) 162(52.6)

0.002

Males Patients Control

256 231

78(30.5) 48(20.8)

138(53.9) 106(45.9)

40(15.6) 77(33.3)

<0.001

294(57.4) 212(44.9)

218(42.6) 260(55.1)

<0.001

−137G/C

n

GG (%)

GC (%)

P

G (%)

C (%)

P

IS Control

423 384

313(74.0) 279(72.7)

105(24.8) 91(23.7)

5(1.2) 14(3.6)

0.069

731(86.4) 649(84.5)

115(13.6) 119(15.5)

0.279

LAA Control

183 384

146(79.8) 279(72.7)

36(19.7) 91(23.7)

1(0.5) 14(3.6)

0.044

328(89.6) 649(84.5)

38(10.4) 119(15.5)

0.020

SVD Control

189 384

138(73.0) 279(72.7)

48(25.4) 91(23.7)

3(1.6) 14(3.6)

0.375

324(85.7) 649(84.5)

54(14.3) 119(15.5)

0.591

CE Control

51 384

29(56.9) 279(72.7)

21(41.2) 91(23.7)

1(2.0) 14(3.6)

0.026

79(77.5) 649(84.5)

23(22.5) 119(15.5)

0.070

≤65 years Patients Control

160 154

112(70.0) 115(74.7)

47(29.4) 36(23.4)

1(0.6) 3(1.9)

0.355a

271(84.7) 266(86.4)

49(15.3) 42(13.6)

0.551

Males Patients Control

256 231

194(75.8) 168(72.7)

61(23.8) 54(23.4)

1(0.4) 9(3.9)

0.024

449(87.7) 390(84.4)

63(12.3) 72(15.6)

0.139

a

Genotype

Allele CC (%)

As 2 cells have expected count less than 5, GG versus GC + CC analysis were conducted.

592

N. Zhang et al. / Brain Research Bulletin 81 (2010) 590–594 Table 3 Chi-sqaure values and P values about Hardy–Weinberg equilibrium for IL-18 genotypes. 2

P

−607C/A IS (total) Control LAA SVD CE

3.223 2.444 0.496 19.851 0.612

0.073 0.118 0.481 <0.001 0.434

−137G/C IS (total) Control LAA SVD CE

1.359 3.471 0.597 0.259 1.632

0.244 0.062 0.439 0.210 0.201

P = 0.031; OR = 3.590, 95% CI = 1.436–8.975, P = 0.006, respectively). But we found −137G/C was not statistically significant (P = 0.877). Based on these data, we analyzed four haplotypes from the genotypes of these two IL-18 promoter polymorphisms using the Expectation-Maximization (EM) algorithm (Table 5). The two tested SNPs showed strong linkage disequilibrium (|D | = 0.93). Each haplotypes was compared with all the others and we found that the −607C/−137G haplotype appeared to be a risk factor for IS (OR = 1.341, 95% CI = 1.094–1.643, P = 0.005, power = 100%), whereas −607A/−137C was protective (OR = 0.689, 95% CI = 0.506–0.939, P = 0.018, power = 99%). 4. Discussion

trol (−607C/A: P < 0.001, −137G/C: P = 0.044) in the large artery atherosclerosis (LAA) subtype of patients, the −607C allele and the −137G allele both significantly raised the risk of developing IS (OR = 1.917, 95% CI = 1.484–2.476, P < 0.001, power = 100%, and OR = 1.583, 95% CI = 1.073–2.334, P = 0.02, power = 94%, respectively). In those patients with small vessel disease (SVD), only the prevalence of the −607C/A genotype was significantly different between IS and control groups (P = 0.011). For the cardioembolism (CE) subtype, only the −137G/C genotype frequencies were significantly different (P = 0.026). Furthermore, when the genders were analyzed separately, male patients had a significantly lower genotype of −607AA (P < 0.001) and −137CC (P = 0.016), and −607A allele frequencies than in the controls (OR = 1.654, 95% CI = 1.285–2.128, P < 0.001, power = 100%). Differences in −607C/A genotype frequencies between cases and controls in females were not statistically significant (P = 0.05). We also observed an age bias: patients younger than 66 years of age more frequently had −607C allele than controls (OR = 1.664, 95% CI = 1.213–2.284, P = 0.002, power = 99%). −607C/A and −137G/C were further analyzed by multivariable logistic regression analysis which was performed with adjustment for age, gender, smoking, hypertension, hypercholesterolemia (Table 4). A significant association of −607CC genotype with increased ischemic stroke risk was noted (OR = 1.884, 95% CI = 1.153–3.079, P = 0.011). Similar results were observed in LAA- and SVD-subtype patients, male patients, and patients ≤65 years (OR = 2.693, 95% CI = 1.457–4.977, P = 0.002; OR = 1.960, 95% CI = 1.030–3.729, P = 0.040; OR = 2.063, 95% CI = 1.069–3.978,

The etiology of IS are complex, including hypertension, diabetes mellitus, hyperlipidemia, heave smoking and genetic heterogeneity. Previous studies indicated that the risk of IS was influenced by genetic variation in the inflammatory agents, such as IL-6, TGF-␤1, IL-1Ra, TNF-␣, LTA [3–5,25–27,41,49]. The present study revealed that IL-18 participated in the course of developing IS. Our sample size had a 100% power to detect an OR of 2.0 at a 0.05 significance rate for IL-18 −607 alleles, a power of 99% for IL-18 −137 alleles, and a power of 100% for the −607C/−137 G haplotype. However, −607C/A in SVD was not in Hardy–Weinberg equilibrium (HWE) in our observation. Deviations from HWE can arise from inbreeding, population stratification, problems in genotyping, and a true association [51]. In the present study, we have divided the patients group into three subtypes, the SVD subtype is just one of them. Besides, the sample of SVD subtype is not very large. So, further studies may be necessary. Cloning and gene expression analysis have shown that the presence of these two SNPs can cause the differences in transcription factor binding, and influence IFN-␥, IL-1␤, TNF-␣ production; in addition, −607A and −137C alleles have lower promoter activity upon stimulation [1,15,28]. The −607C allele, −137G allele, and the −607C/−137G haplotype are associated with higher expression of the IL-18 [15,24]. IL-18 is implicated in atherosclerotic plaque propagation and instability [31,32,50]. IL-18 gene polymorphisms have been identified to associate with coronary artery disease [5] and vascular changes in the carotid artery [40]. IL-18 can induce human aortic smooth muscle cell (SMC) proliferation [7], and then involved in the development of atherosclerosis [29,30]. It also participates in neuroinflammation in hypoxic-ischemic brain injuries [12]. Considerable evidence shows that IL-18 can enhance produc-

Table 4 Logistic regression analysis in IS patients and controls. B

Wald

OR

P

95% CI

Total: −607CC versus CA + AA Total: −137GG versus GC + CC

0.634 0.037

6.391 0.024

1.884 0.964

0.011 0.877

1.153–3.079 0.603–1.541

LAA: −607CC versus CA + AA LAA: −137GG versus GC + CC

0.991 0.042

9.997 0.019

2.693 0.959

0.002 0.892

1.457–4.977 0.527–1.746

SVD: −607CC versus CA + AA SVD: −137GG versus GC + CC

0.673 0.003

4.207 0

1.960 1.004

0.040 0.991

1.030–3.729 0.547–1.841

CE: −607CC versus CA + AA CE: −137GG versus GC + CC

0.293 0.341

0.312 0.482

1.340 1.407

0.576 0.488

0.480–3.746 0.537–3.688

Male: −607CC versus CA + AA Male: −137GG versus GC + CC

0.724 0.270

4.667 0.685

2.063 1.310

0.031 0.408

1.069–3.978 0.691–2.481

Female: −607CC versus CA + AA Female: −137GG versus GC + CC

0.561 0.425

2.174 1.379

1.753 0.654

0.140 0.240

0.831–3.695 0.321–1.329

≤65: −607CC versus CA + AA ≤65: −137GG versus GC + CC

1.278 0.541

7.477 1.445

3.590 0.582

0.006 0.229

1.436–8.975 0.241–1.407

>65: −607CC versus CA + AA >65: −137GG versus GC + CC

0.358 0.173

1.064 0.545

1.430 1.189

0.302 0.461

0.725–2.824 0.751–1.884

N. Zhang et al. / Brain Research Bulletin 81 (2010) 590–594

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Table 5 Distribution of haplotype in IS patients and controls. Haplotype

IS (%)

Control (%)

2 -test single statistics

−607C/−137G −607C/−137C −607A/−137G −607A/−137C

369(45.5) 61(7.5) 299(36.9) 82(10.1)

279(38.4) 56(7.7) 290(39.9) 102(14.0)

tion of inflammatory molecules such as IFN-␥, IL-1␤, TNF-␣, and the inducible form of nitric-oxide synthase (iNOS) [9,18,22,35], which may contribute to neuroinflammation. IL-18 has been reported to contribute to ischemic brain injury [56]. Endothelial cell apoptosis has been shown to contribute to arteriosclerosis [46]. IL-18 participate the process in different way: lead to cell death in both immune and nonimmune cells via the Fas-Fas-L pathway [8,13], activate c-Jun N-terminal kinase (JNK) and mitogen activated protein kinase (MAPK) p38 [45] and then activate both intrinsic and extrinsic proapoptotic signaling pathways [16]. Analysis of the effect of IL-18 production on IS is complicated by the complexity of IS itself. For example, large artery atherosclerosis (LAA) subtypes are caused by arteriosclerosis and IL-18 is implicated in the disease. Many complicated factors exert influence on IS risk, such as age, gender, and other diseases. In CE subtypes, there are so many factors which can contribute to it, including atrial fibrillation, valvular heart disease, arrhythmia, age, hypertension [11,38] and rheavy drinking of alcohol [19]. Moreover, the sample of CE subtype may be not large enough, so further study will be necessary. This study also shows that the patients younger than 66 years more frequently had −607C allele than controls, but in elders we cannot find the significant difference between two groups. On one hand, it may arise from that the age itself just be a risk factor for developing IS. When age is increasing, the risk for developing IS would increase. The effect that IL-18 can work for the elders may be less than the youngers. On the other hand, it could be hypothesized that when the patients were older than 66 because perhaps there is greater mortality rate associated with patients with this allele. Recently, Bis et al. [5] investigated the possible role of IL-18 SNPs as genetic risk factors for MI and IS in Caucasian population and found that IL-18 gene polymorphisms were associated with cardiovascular outcomes and with MI risk, but not IS risk. In this study we did observe an association between IL-18 polymorphisms and IS risk in certain patients. The data associating IL-18 gene polymorphisms with IS risk seems controversial. However, there are differences between the studies. First, the IL-18 SNPs analyzed were different (rs 1946519, rs360718, rs2043055, rs360722, rs5744247, rs3882891 in Bis et al.’s studies, rs1946518, rs187238 in the present analysis). The two SNPs in IL-18 promotor have been proved to influence the production and the activation of IL-18 [15,23]. Second, the percentage of males in this study is about 60%, more than 40% in Bis et al.’s study. And we have found significant differences in males between cases and controls, but no difference in females, thus, the sex composing may influence the results. Third, we excluded subjects with the significant illnesse: T2DM, which also may contribute to the variance. Furthermore, the distribution of IL-18 functional polymorphisms may vary in different populations. In general, the frequencies of the −137G allele is 80–83% in Chinese [2,54,57], 72% in Caucasians [6], 66.1% in Switzerland [21], and 75.8% in Italy [39]. Our study, shows allele frequencies for −607C and −137G (C: 48%, G: 84.5%, respectively) similar to those found in Chinese [2,54,57]. Other studies have demonstrated an implication of the IL-18 gene polymorphisms in various disease, which are associated with inflammatory responses, such as T2DM, myocardial infarction, congestive heart failure, asthma, rheumatoid arthritis, and Alzheimer’s

2 -test global statistics



P

2

P

7.976 0.018 1.481 5.591

0.005 0.893 0.224 0.018

10.469

0.015

2

disease [18,20,27,36,44,54]. Inflammatory responses can play an important role in pathogenesis of these diseases, including IS. For example, the neuroinflammation and neurodegeneration may play an important role in the pathogenesis of AD, and rheumatoid arthritis is an accepted inflammatory joint disease. IL-18 has become a putative target in several immune-mediated diseases [17], and −607C allele may also be a target in future studies. Therefore, we tried our best to reduce the possibility that the association that has been identified is secondary to linkage to some other disease phenotype that covaries with IS. We excluded subjects with significant illnesses from our study at the beginning. Moreover, we used logistic regression to adjust for genetic predictors or potential confounders. In conclusion, our analysis demonstrated that the −607C alleles and the −607C/−137G haplotype are associated with increased the risk for developing IS. The data support the hypothesis that IL18 expression is involved in IS, suggesting that new therapeutic strategies designed to reduce IL-18 protein production or activity might be valuable for the prevention and treatment of IS. However, further studies with more subjects and/or other ethnicities will be needed before the conclusions of this study can be generalized. Conflict of interest None. Acknowledgements We are grateful to all of the subjects who kindly agreed to participate in this study. This work was supported by a grant from National Natural Science Foundation of China (30870884). References [1] J. Arimitsu, T. Hirano, S. Higa, M. Kawai, T. Naka, A. Ogata, Y. Shima, M. Fujimoto, T. Yamadori, K. Hagiwara, T. Ohgawara, Y. Kuwabara, I. Kawase, T. Tanaka, IL-18 gene polymorphisms affect IL-18 production capability by monocytes, Biochem. Biophys. Res. Commun. 342 (2006) 1413–1416. [2] J. Bai, Y. Zhang, M. Lin, X. Zeng, Z. Wang, J. Shen, L. Jiang, F. Gao, Q. Chen, Interleukin-18 gene polymorphisms and haplotypes in patients with oral lichen planus: a study in an ethnic Chinese cohort, Tissue Antigens 70 (2007) 390–397. [3] J. Balding, W.J. Livingstone, S.J. Pittock, L. Mynett-Johnson, T. Ahern, A. Hodgson, O.P. Smith, The IL-6 G-174C polymorphism may be associated with ischaemic stroke in patients without a history of hypertension, Ir. J. Med. Sci. 173 (2004) 200–203. [4] I. Banerjee, V. Gupta, T. Ahmed, M. Faizaan, P. Agarwal, S. Ganesh, Inflammatory system gene polymorphism and the risk of stroke: a case–control study in an Indian population, Brain Res. Bull. 75 (2008) 158–165. [5] J.C. Bis, S.R. Heckbert, N.L. Smith, A.P. Reiner, K. Rice, T. Lumley, L.A. Hindorff, K.D. Marciante, D.A. Enquobahrie, S.A. Monks, B.M. Psaty, Variation in inflammationrelated genes and risk of incident nonfatal myocardial infarction or ischemic stroke, Atherosclerosis 198 (2008) 166–173. [6] P. Bossù, A. Ciaramella, M.L. Moro, L. Bellincampi, S. Bernardini, G. Federici, A. Trequattrini, F. Macciardi, I. Spoletini, F. Di Iulio, C. Caltagirone, G. Spalletta, Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer’s disease, J. Neurol. Neurosurg. Psychiatry 78 (2007) 807–811. [7] B. Chandrasekar, S. Mummidi, A.J. Alente, D.N. Patel, S.R. Bailey, G.L. Freeman, M. Hatano, T. Tokuhisa, L.E. Jensen, The pro-atherogenic cytokine interleukin-18 induces CXCL16 expression in rat aortic smooth muscle cells via MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor 6, c-Src, phosphatidylinositol 3-kinase, Akt, c-Jun

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