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The SG13S114 polymorphism of the ALOX5AP gene is associated with ischemic stroke in Europeans: a meta-analysis of 8062 subjects

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Abstract

The association between ALOX5AP SG13S114 polymorphism and ischemic stroke (IS) susceptibility has extensively been investigated, especially in white populations; however, the results were inconclusive. Here, we perform a meta-analysis to clarify the effect of SG13S114 variant on the IS risk in Europeans. The Web of Science, PubMed, EMBASE, and Medline were searched up to August 1st, 2016. Data were extracted and the odd ratios (ORs) and 95% confidence intervals (CIs) were calculated by a fixed-effects or random-effects model. In total, 8 case control studies involved 8062 subjects were finally included in this meta-analysis. We observed a significantly decreased IS risk in persons carrying an A allele at the SG13S114 polymorphism compared with those with a T allele (A vs T, OR = 0.856, 95% CI = 0.797–0.919, p < 0.001). In addition, the results of sensitivity and cumulative meta-analysis indicated the robustness of our results. In addition, the publication bias was not detected using the funnel plot and Egger’s tests. In summary, the present meta-analysis suggested that the A allele at the ALOX5AP SG13S114 polymorphism is a protective factor for the IS in the Europeans. In addition, further studies with large sample size are needed to validate the association, as well as in other ethnic groups.

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References

  1. Feigin VL, Norrving B, George MG, Foltz JL, Roth GA, Mensah GA (2016) Prevention of stroke: a strategic global imperative. Nat Rev Neurol 12(9):501–512. doi:10.1038/nrneurol.2016.107

    Article  PubMed  Google Scholar 

  2. Bang OY, Ovbiagele B, Kim JS (2015) Nontraditional risk factors for ischemic stroke: an update. Stroke J Cereb Circ 46(12):3571–3578. doi:10.1161/STROKEAHA.115.010954

    Article  Google Scholar 

  3. Falcone GJ, Malik R, Dichgans M, Rosand J (2014) Current concepts and clinical applications of stroke genetics. Lancet Neurol 13(4):405–418. doi:10.1016/S1474-4422(14)70029-8

    Article  PubMed  Google Scholar 

  4. Yuan HP, Sun L, Li XH, Che FG, Zhu XQ, Yang F, Han J, Jia CY, Yang Z (2016) Association of adiponectin polymorphism with metabolic syndrome risk and adiponectin level with stroke risk: a meta-analysis. Sci Rep 6:31945. doi:10.1038/srep31945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ma Q, Yang Y, Na Y, Jin T, Xue Y, Shi Y, Li C, Zhang W (2016) IMPA2 polymorphisms and risk of ischemic stroke in a northwest Han Chinese population. Oncotarget. doi:10.18632/oncotarget.12133

    Google Scholar 

  6. Kumar A, Kumar P, Prasad M, Misra S, Kishor Pandit A, Chakravarty K (2016) Association between Apolipoprotein epsilon4 gene polymorphism and risk of ischemic stroke: a meta-analysis. Ann Neurosci 23(2):113–121. doi:10.1159/000443568

    Article  PubMed  PubMed Central  Google Scholar 

  7. Yan J, MG J, AM P (2016) Interleukin 6 promoter 174 G/C polymorphisms in acute ischemic stroke: G allele is protective but not associated with IL-6 levels or stroke outcome. J Neuroimmunol 293:22–27. doi:10.1016/j.jneuroim.2016.02.001

    Article  CAS  PubMed  Google Scholar 

  8. Hu X, Zan X, Xie Z, Li Y, Lin S, Li H, You C (2016) Association between plasminogen activator inhibitor-1 genetic polymorphisms and stroke susceptibility. Mol Neurobiol. doi:10.1007/s12035-015-9549-8

    Google Scholar 

  9. Evans JF, Ferguson AD, Mosley RT, Hutchinson JH (2008) What’s all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseases. Trends Pharmacol Sci 29(2):72–78. doi:10.1016/j.tips.2007.11.006

    Article  CAS  PubMed  Google Scholar 

  10. Kaushal R, Pal P, Alwell K, Haverbusch M, Flaherty M, Moomaw C, Sekar P, Kissela B, Kleindorfer D, Chakraborty R, Broderick J, Deka R, Woo D (2007) Association of ALOX5AP with ischemic stroke: a population-based case-control study. Hum Genet 121(5):601–607. doi:10.1007/s00439-007-0338-y

    Article  CAS  PubMed  Google Scholar 

  11. Meschia JF, Brott TG, Brown RD Jr, Crook R, Worrall BB, Kissela B, Brown WM, Rich SS, Case LD, Evans EW, Hague S, Singleton A, Hardy J (2005) Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Ann Neurol 58(3):351–361. doi:10.1002/ana.20585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Barral S, Fernandez-Cadenas I, Bis JC, Montaner J, Ikram AM, Launer LJ, Fornage M, Schmidt H, Brickman AM, Seshadri S, Mayeux R (2012) No association of ALOX5AP polymorphisms with risk of MRI-defined brain infarcts. Neurobiology of aging 33(3):629 e621–629 e623. doi:10.1016/j.neurobiolaging.2011.10.010

    Google Scholar 

  13. Bondarenko EA, Slominskii PA, Limborskaia SA, Shetova IM, Timofeev DY, Skvortsova VI (2011) Polymorphic variants of ALOX5AP gene and the risk of acute stroke development in the Russian population. Genetika 47(4):570–573

    CAS  PubMed  Google Scholar 

  14. Domingues-Montanari S, Fernandez-Cadenas I, del Rio-Espinola A, Corbeto N, Krug T, Manso H, Gouveia L, Sobral J, Mendioroz M, Fernandez-Morales J, Alvarez-Sabin J, Ribo M, Rubiera M, Obach V, Marti-Fabregas J, Freijo M, Serena J, Ferro JM, Vicente AM, Oliveira SA, Montaner J (2010) Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: a case-control, meta-analysis and functional study. Cerebrovasc Dis 29(6):528–537. doi:10.1159/000302738

    Article  CAS  PubMed  Google Scholar 

  15. Ye F, Liu NN, Zheng YQ, Zhang WJ, Wang CM, Xu Y, Den XL, Wang J (2014) Three polymorphisms of ALOX5AP and risk of ischemic stroke in Chinese: evidence from a meta-analysis. J Neurol Sci 336(1–2):93–98. doi:10.1016/j.jns.2013.10.013

    Article  CAS  PubMed  Google Scholar 

  16. Wang G, Liu R, Zhang J (2014) The arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene SG13S114 polymorphism and ischemic stroke in Chinese population: a meta-analysis. Gene 533(2):461–468. doi:10.1016/j.gene.2013.10.018

    Article  CAS  PubMed  Google Scholar 

  17. Ke X, Wu X, Guo H, Li Q (2015) Association of ALOX5AP rs10507391/SG13S114 A > T polymorphism with cerebral infarction in the Chinese population: a meta-analysis study. Int J Neurosci 125(10):726–732. doi:10.3109/00207454.2014.967769

    Article  CAS  PubMed  Google Scholar 

  18. Zintzaras E, Rodopoulou P, Sakellaridis N (2009) Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and risk of stroke: a HuGE gene-disease association review and meta-analysis. Am J Epidemiol 169(5):523–532. doi:10.1093/aje/kwn368

    Article  PubMed  Google Scholar 

  19. Trikalinos TA, Salanti G, Zintzaras E, Ioannidis JP (2008) Meta-analysis methods. Adv Genet 60:311–334. doi:10.1016/S0065-2660(07)00413-0

    PubMed  Google Scholar 

  20. Zintzaras E, Lau J (2008) Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches. J Clin Epidemiol 61(7):634–645. doi:10.1016/j.jclinepi.2007.12.011

    Article  PubMed  Google Scholar 

  21. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  PubMed  Google Scholar 

  22. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101

    Article  CAS  PubMed  Google Scholar 

  24. Bevan S, Dichgans M, Wiechmann HE, Gschwendtner A, Meitinger T, Markus HS (2008) Genetic variation in members of the leukotriene biosynthesis pathway confer an increased risk of ischemic stroke: a replication study in two independent populations. Stroke J Cereb Circ 39(4):1109–1114. doi:10.1161/STROKEAHA.107.491969

    Article  CAS  Google Scholar 

  25. Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, Thorsteinsdottir U, Samani NJ, Gudmundsson G, Grant SF, Thorgeirsson G, Sveinbjornsdottir S, Valdimarsson EM, Matthiasson SE, Johannsson H, Gudmundsdottir O, Gurney ME, Sainz J, Thorhallsdottir M, Andresdottir M, Frigge ML, Topol EJ, Kong A, Gudnason V, Hakonarson H, Gulcher JR, Stefansson K (2004) The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 36(3):233–239. doi:10.1038/ng1311

    Article  CAS  PubMed  Google Scholar 

  26. Helgadottir A, Gretarsdottir S, St Clair D, Manolescu A, Cheung J, Thorleifsson G, Pasdar A, Grant SF, Whalley LJ, Hakonarson H, Thorsteinsdottir U, Kong A, Gulcher J, Stefansson K, MacLeod MJ (2005) Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population. Am J Hum Genet 76(3):505–509. doi:10.1086/428066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kostulas K, Gretarsdottir S, Kostulas V, Manolescu A, Helgadottir A, Thorleifsson G, Gudmundsson LJ, Thorsteinsdottir U, Gulcher JR, Stefansson K, Hillert J (2007) PDE4D and ALOX5AP genetic variants and risk for ischemic cerebrovascular disease in Sweden. J Neurol Sci 263(1–2):113–117. doi:10.1016/j.jns.2007.06.042

    Article  CAS  PubMed  Google Scholar 

  28. Lemaitre RN, Rice K, Marciante K, Bis JC, Lumley TS, Wiggins KL, Smith NL, Heckbert SR, Psaty BM (2009) Variation in eicosanoid genes, non-fatal myocardial infarction and ischemic stroke. Atherosclerosis 204(2):e58–e63. doi:10.1016/j.atherosclerosis.2008.10.011

    Article  CAS  PubMed  Google Scholar 

  29. Lovkvist H, Smith JG, Luthman H, Hoglund P, Norrving B, Kristoffersson U, Jonsson AC, Lindgren AG (2008) Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region. Eur J Hum Genet EJHG 16(9):1117–1125. doi:10.1038/ejhg.2008.62

    Article  PubMed  Google Scholar 

  30. Quarta G, Stanzione R, Evangelista A, Zanda B, Di Angelantonio E, Marchitti S, Di Castro S, Di Vavo M, Volpe M, Rubattu S (2009) Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians. Eur J Hum Genet EJHG 17(11):1448–1453. doi:10.1038/ejhg.2009.71

    Article  CAS  PubMed  Google Scholar 

  31. Lohmussaar E, Gschwendtner A, Mueller JC, Org T, Wichmann E, Hamann G, Meitinger T, Dichgans M (2005) ALOX5AP gene and the PDE4D gene in a central European population of stroke patients. Stroke J Cereb Circ 36(4):731–736. doi:10.1161/01.STR.0000157587.59821.87

    Article  CAS  Google Scholar 

  32. Zee RY, Cheng S, Hegener HH, Erlich HA, Ridker PM (2006) Genetic variants of arachidonate 5-lipoxygenase-activating protein, and risk of incident myocardial infarction and ischemic stroke: a nested case-control approach. Stroke J Cereb Circ 37(8):2007–2011. doi:10.1161/01.STR.0000229905.25080.01

    Article  CAS  Google Scholar 

  33. Malik R, Traylor M, Pulit SL, Bevan S, Hopewell JC, Holliday EG, Zhao W, Abrantes P, Amouyel P, Attia JR, Battey TW, Berger K, Boncoraglio GB, Chauhan G, Cheng YC, Chen WM, Clarke R, Cotlarciuc I, Debette S, Falcone GJ, Ferro JM, Gamble DM, Ilinca A, Kittner SJ, Kourkoulis CE, Lemmens R, Levi CR, Lichtner P, Lindgren A, Liu J, Meschia JF, Mitchell BD, Oliveira SA, Pera J, Reiner AP, Rothwell PM, Sharma P, Slowik A, Sudlow CL, Tatlisumak T, Thijs V, Vicente AM, Woo D, Seshadri S, Saleheen D, Rosand J, Markus HS, Worrall BB, Dichgans M (2016) Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration. Neurology 86(13):1217–1226. doi:10.1212/WNL.0000000000002528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Szolnoki Z, Melegh B (2006) Gene-gene and gene-environment interplay represent specific susceptibility for different types of ischaemic stroke and leukoaraiosis. Curr Med Chem 13(14):1627–1634

    Article  CAS  PubMed  Google Scholar 

  35. Lin HF, Liao YC, Liou CW, Liu CK, Juo SH (2007) The phosphodiesterase 4D gene for early onset ischemic stroke among normotensive patients. J Thromb Haemost JTH 5(2):436–438. doi:10.1111/j.1538-7836.2007.02350.x

    Article  CAS  PubMed  Google Scholar 

  36. Munshi A, Roy S, Thangaraj K, Kaul S, Babu MS, Jyothy A (2012) Association of SNP41, SNP56 and a novel SNP in PDE4D gene with stroke and its subtypes. Gene 506(1):31–35. doi:10.1016/j.gene.2012.06.079

    Article  CAS  PubMed  Google Scholar 

  37. Brophy VH, Ro SK, Rhees BK, Lui LY, Lee JM, Umblas N, Bentley LG, Li J, Cheng S, Browner WS, Erlich HA (2006) Association of phosphodiesterase 4D polymorphisms with ischemic stroke in a US population stratified by hypertension status. Stroke J Cereb Circ 37(6):1385–1390. doi:10.1161/01.STR.0000221788.10723.66

    Article  CAS  Google Scholar 

  38. Staton JM, Sayer MS, Hankey GJ, Attia J, Thakkinstian A, Yi Q, Cole VJ, Baker R, Eikelboom JW (2006) Association between phosphodiesterase 4D gene and ischaemic stroke. J Neurol Neurosurg Psychiatry 77(9):1067–1069. doi:10.1136/jnnp.2006.092106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Feigin VL, Roth GA, Naghavi M, Parmar P, Krishnamurthi R, Chugh S, Mensah GA, Norrving B, Shiue I, Ng M, Estep K, Cercy K, Murray CJ, Forouzanfar MH (2016) Global burden of stroke and risk factors in 188 countries, during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet Neurol 15(9):913–924. doi:10.1016/S1474-4422(16)30073-4

    Article  PubMed  Google Scholar 

  40. O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, Mondo C, Damasceno A, Lopez-Jaramillo P, Hankey GJ, Dans AL, Yusoff K, Truelsen T, Diener HC, Sacco RL, Ryglewicz D, Czlonkowska A, Weimar C, Wang X, Yusuf S (2010) Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 376(9735):112–123. doi:10.1016/S0140-6736(10)60834-3

    Article  PubMed  Google Scholar 

  41. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, Amann M, Anderson HR, Andrews KG, Aryee M, Atkinson C, Bacchus LJ, Bahalim AN, Balakrishnan K, Balmes J, Barker-Collo S, Baxter A, Bell ML, Blore JD, Blyth F, Bonner C, Borges G, Bourne R, Boussinesq M, Brauer M, Brooks P, Bruce NG, Brunekreef B, Bryan-Hancock C, Bucello C, Buchbinder R, Bull F, Burnett RT, Byers TE, Calabria B, Carapetis J, Carnahan E, Chafe Z, Charlson F, Chen H, Chen JS, Cheng AT, Child JC, Cohen A, Colson KE, Cowie BC, Darby S, Darling S, Davis A, Degenhardt L, Dentener F, Des Jarlais DC, Devries K, Dherani M, Ding EL, Dorsey ER, Driscoll T, Edmond K, Ali SE, Engell RE, Erwin PJ, Fahimi S, Falder G, Farzadfar F, Ferrari A, Finucane MM, Flaxman S, Fowkes FG, Freedman G, Freeman MK, Gakidou E, Ghosh S, Giovannucci E, Gmel G, Graham K, Grainger R, Grant B, Gunnell D, Gutierrez HR, Hall W, Hoek HW, Hogan A, Hosgood HD 3rd, Hoy D, Hu H, Hubbell BJ, Hutchings SJ, Ibeanusi SE, Jacklyn GL, Jasrasaria R, Jonas JB, Kan H, Kanis JA, Kassebaum N, Kawakami N, Khang YH, Khatibzadeh S, Khoo JP, Kok C, Laden F, Lalloo R, Lan Q, Lathlean T, Leasher JL, Leigh J, Li Y, Lin JK, Lipshultz SE, London S, Lozano R, Lu Y, Mak J, Malekzadeh R, Mallinger L, Marcenes W, March L, Marks R, Martin R, McGale P, McGrath J, Mehta S, Mensah GA, Merriman TR, Micha R, Michaud C, Mishra V, Mohd Hanafiah K, Mokdad AA, Morawska L, Mozaffarian D, Murphy T, Naghavi M, Neal B, Nelson PK, Nolla JM, Norman R, Olives C, Omer SB, Orchard J, Osborne R, Ostro B, Page A, Pandey KD, Parry CD, Passmore E, Patra J, Pearce N, Pelizzari PM, Petzold M, Phillips MR, Pope D, Pope CA 3rd, Powles J, Rao M, Razavi H, Rehfuess EA, Rehm JT, Ritz B, Rivara FP, Roberts T, Robinson C, Rodriguez-Portales JA, Romieu I, Room R, Rosenfeld LC, Roy A, Rushton L, Salomon JA, Sampson U, Sanchez-Riera L, Sanman E, Sapkota A, Seedat S, Shi P, Shield K, Shivakoti R, Singh GM, Sleet DA, Smith E, Smith KR, Stapelberg NJ, Steenland K, Stockl H, Stovner LJ, Straif K, Straney L, Thurston GD, Tran JH, Van Dingenen R, van Donkelaar A, Veerman JL, Vijayakumar L, Weintraub R, Weissman MM, White RA, Whiteford H, Wiersma ST, Wilkinson JD, Williams HC, Williams W, Wilson N, Woolf AD, Yip P, Zielinski JM, Lopez AD, Murray CJ, Ezzati M, AlMazroa MA, Memish ZA (2012) A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2224–2260. doi:10.1016/S0140-6736(12)61766-8

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by Grants from the National Natural Science Foundation of China (No. 81171147) and Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (No. JX10231801).

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Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China

    Zhongjun Chen, Ronglan Zhu & Lixin Li

  2. Department of Neurosurgery, The Affiliated Huai’an Hospital of Xuzhou Medical College, No. 62 South Huaihai Road, Huai’an, 223002, China

    Zhongjun Chen, Jinyu Zheng & Wenguang Liu

  3. Department of Neurosurgery, Nanjing Brain Hospital Affiliated with Nanjing Medical University, 264 Guangzhou Road, Nanjing, 210029, Jiangsu, China

    Kun Yang

  4. Department of Neurosurgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, Jiangsu, China

    Kai Li

  5. Department of Neurosurgery, Sir Shaw Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China

    Baosheng Huang

  6. Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Xiaocheng Lu

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  1. Zhongjun Chen
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Chen, Z., Zheng, J., Liu, W. et al. The SG13S114 polymorphism of the ALOX5AP gene is associated with ischemic stroke in Europeans: a meta-analysis of 8062 subjects. Neurol Sci 38, 579–587 (2017). https://doi.org/10.1007/s10072-016-2804-6

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