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Misconceptions surrounding the genetic susceptibility to ischemic stroke
Journal of the Neurological Sciences 344 (2014) 221
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Misconceptions surrounding the genetic susceptibility to ischemic stroke
Dear Editor, I have read with interest a recent report by Ye and coworkers on the putative role of ALOX5AP variants in ischemic stroke [1]. In their report, the authors claim a significant effect of a common SNP on the phenotype under study based on earlier data from 11 case–control studies. However, this claim cannot be upheld in the light of substantial flaws. To begin with, the statistical approach taken is not supported by the concept of Mendelian inheritance. The authors have examined four genetic models per variant and obtained a significant association signal for SG13S114A/T after contrasting genotype frequencies of T carriers with frequencies of A carriers. They consider this a comparison of allelic effects which it is not. As T carriers (i.e. AT and TT genotypes) and A carriers (i.e. AT and AA genotypes) overlap, the respective calculations are obsolete. Ye et al. neither provide a rationale for selecting genetic models nor do they correct for the number of statistical tests performed. This augments the likelihood of a type-I error 20-fold. The meta-analysis is believed to significantly enhance the power of association results but power calculations are lacking. Multiple studies included in the analysis feature violations of the Hardy–Weinberg Equilibrium in control populations [2–5]. Moreover, the authors included a study with highly discrepant allele frequencies [4]. Other studies fail to specify which DNA strand was examined [5,6] rendering results uninformative for the canonical SG13S114A/T substitution. Unless strand information is provided, the risk and protective
http://dx.doi.org/10.1016/j.jns.2014.06.009 0022-510X/© 2014 Elsevier B.V. All rights reserved.
alleles at this site cannot be distinguished and can be read both as A, and as T. On the whole, the many inconsistencies encountered call for a careful re-examination of ALOX5AP in the context of the susceptibility to ischemic stroke. References [1] Ye F, Liu NN, Zheng YQ, Zhang WJ, Wang CM, Xu Y, et al. Three polymorphisms of ALOX5AP and risk of ischemic stroke in Chinese: evidence from a meta-analysis. J Neurol Sci 2014;336:93–8. [2] He YL, Zhu M, Jin XP, Zhou YL. Relationship of polymorphism of SG13S114A/T in ALOX5AP gene with atherosclerotic cerebral infarction. Zhejiang Da Xue Xue Bao Yi Xue Ban 2009;38:630–3. [3] Zhao J, Wang X, Xu J, Li N, Shang X, He Z, et al. Association of inflammatory response gene polymorphism with atherothrombotic stroke in Northern Han Chinese. Acta Biochim Biophys Sin (Shanghai) 2012;44:1023–30. [4] Gao Z, Tan G-P. Relationship between ALOX5AP gene single nucleotide polymorphism and stroke of Han population in Shenyang City. J Apoplexy Nerv Dis 2010;27:1022–6. [5] Zhang SY, Xu ML, Zhang CE, Qu ZY, Zhang BB, Zheng ZY, et al. Association of ALOX5AP gene single nucleotide polymorphisms and cerebral infarction in the Han population of northern China. BMC Med Genet 2012;13:61. [6] Lee JD, Lee TH, Huang YC, Chang YJ, Chang CH, Hsu HL, et al. ALOX5AP genetic variants and risk of atherothrombotic stroke in the Taiwanese population. J Clin Neurosci 2011;18:1634–8.
P.G. Sand Department of Psychiatry, University of Regensburg, Germany Department of Psychiatry, University of Regensburg, Universitaetsstrasse 84, 93053 Regensburg, Germany. Tel.: +49 941 941 8041; fax: +49 941 941 1235. E-mail address: [email protected]. 20 April 2014
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Misconceptions surrounding the genetic susceptibility to ischemic stroke
Dear Editor, I have read with interest a recent report by Ye and coworkers on the putative role of ALOX5AP variants in ischemic stroke [1]. In their report, the authors claim a significant effect of a common SNP on the phenotype under study based on earlier data from 11 case–control studies. However, this claim cannot be upheld in the light of substantial flaws. To begin with, the statistical approach taken is not supported by the concept of Mendelian inheritance. The authors have examined four genetic models per variant and obtained a significant association signal for SG13S114A/T after contrasting genotype frequencies of T carriers with frequencies of A carriers. They consider this a comparison of allelic effects which it is not. As T carriers (i.e. AT and TT genotypes) and A carriers (i.e. AT and AA genotypes) overlap, the respective calculations are obsolete. Ye et al. neither provide a rationale for selecting genetic models nor do they correct for the number of statistical tests performed. This augments the likelihood of a type-I error 20-fold. The meta-analysis is believed to significantly enhance the power of association results but power calculations are lacking. Multiple studies included in the analysis feature violations of the Hardy–Weinberg Equilibrium in control populations [2–5]. Moreover, the authors included a study with highly discrepant allele frequencies [4]. Other studies fail to specify which DNA strand was examined [5,6] rendering results uninformative for the canonical SG13S114A/T substitution. Unless strand information is provided, the risk and protective
http://dx.doi.org/10.1016/j.jns.2014.06.009 0022-510X/© 2014 Elsevier B.V. All rights reserved.
alleles at this site cannot be distinguished and can be read both as A, and as T. On the whole, the many inconsistencies encountered call for a careful re-examination of ALOX5AP in the context of the susceptibility to ischemic stroke. References [1] Ye F, Liu NN, Zheng YQ, Zhang WJ, Wang CM, Xu Y, et al. Three polymorphisms of ALOX5AP and risk of ischemic stroke in Chinese: evidence from a meta-analysis. J Neurol Sci 2014;336:93–8. [2] He YL, Zhu M, Jin XP, Zhou YL. Relationship of polymorphism of SG13S114A/T in ALOX5AP gene with atherosclerotic cerebral infarction. Zhejiang Da Xue Xue Bao Yi Xue Ban 2009;38:630–3. [3] Zhao J, Wang X, Xu J, Li N, Shang X, He Z, et al. Association of inflammatory response gene polymorphism with atherothrombotic stroke in Northern Han Chinese. Acta Biochim Biophys Sin (Shanghai) 2012;44:1023–30. [4] Gao Z, Tan G-P. Relationship between ALOX5AP gene single nucleotide polymorphism and stroke of Han population in Shenyang City. J Apoplexy Nerv Dis 2010;27:1022–6. [5] Zhang SY, Xu ML, Zhang CE, Qu ZY, Zhang BB, Zheng ZY, et al. Association of ALOX5AP gene single nucleotide polymorphisms and cerebral infarction in the Han population of northern China. BMC Med Genet 2012;13:61. [6] Lee JD, Lee TH, Huang YC, Chang YJ, Chang CH, Hsu HL, et al. ALOX5AP genetic variants and risk of atherothrombotic stroke in the Taiwanese population. J Clin Neurosci 2011;18:1634–8.
P.G. Sand Department of Psychiatry, University of Regensburg, Germany Department of Psychiatry, University of Regensburg, Universitaetsstrasse 84, 93053 Regensburg, Germany. Tel.: +49 941 941 8041; fax: +49 941 941 1235. E-mail address: [email protected]. 20 April 2014