Abstract
Recent genome-wide association studies have identified two variants rs10033464 and rs2200733 on chromosome 4q25, significantly associated with ischemic stroke risk. We conducted this study to investigate whether these two variants were associated with age at onset and prognosis of ischemic stroke in a Chinese population. Genotyping of rs10033464 and rs2200733 was performed by improved multiple ligase detection reaction. One-way ANOVA was used to compare the mean age of ischemic stroke onset for each variant. Combined effects of these two variants on age at ischemic stroke onset were then estimated. Kaplan-Meier method, log-rank test, and the Cox proportional hazards regression models were used to assess the effect of the two variants on ischemic stroke prognosis. A total of 914 ischemic stroke patients were included in the study. Rs10033464 and rs2200733 were not associated with ischemic stroke recurrence (P > 0.05). However, rs10033464 TT genotype was significantly correlated with early age of ischemic stroke onset (60.76 for GG, 61.74 for GT, 55.47 for TT, TT vs. GT: P = 0.043). Combined effects analysis revealed that mean age at ischemic stroke onset decreased with increasing genetic risk score (P = 0.038). The findings indicated that the chromosome 4q25 variants might associate with early age at onset of ischemic stroke. Further larger studies in other populations are warranted to validate our results.
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Lozano R, Naghavi M, Foreman K et al (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2095–2128
Strong K, Mathers C, Bonita R (2007) Preventing stroke: saving lives around the world. Lancet Neurol 6(2):182–187
Hassan A, Markus HS (2000) Genetics and ischaemic stroke. Brain J Neurol 123(Pt 9):1784–1812
Markus H (2004) Genes for stroke. J Neurol Neurosurg Psychiatry 75(9):1229–1231
Dichgans M (2007) Genetics of ischaemic stroke. Lancet Neurol 6(2):149–161
Jerrard-Dunne P, Cloud G, Hassan A, Markus HS (2003) Evaluating the genetic component of ischemic stroke subtypes: a family history study. Stroke J Cereb Circ 34(6):1364–1369
Luengo-Fernandez R, Gray AM, Rothwell PM, Oxford Vascular S (2012) A population-based study of hospital care costs during 5 years after transient ischemic attack and stroke. Stroke J Cereb Circ 43(12):3343–3351
Hankey GJ (2014) Secondary stroke prevention. Lancet Neurol 13(2):178–194
Lotta LA, Giusti B, Saracini C et al (2010) No association between chromosome 12p13 single nucleotide polymorphisms and early-onset ischemic stroke. J Thromb Haemost 8(8):1858–1860
Majumdar V, Nagaraja D, Karthik N, Christopher R (2010) Association of endothelial nitric oxide synthase gene polymorphisms with early-onset ischemic stroke in South Indians. J Atheroscler Thromb 17(1):45–53
Rubattu S, Giusti B, Lotta LA et al (2013) Association of a single nucleotide polymorphism of the NPR3 gene promoter with early onset ischemic stroke in an Italian cohort. Eur J Intern Med 24(1):80–82
Gretarsdottir S, Thorleifsson G, Manolescu A et al (2008) Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke. Ann Neurol 64(4):402–409
International Stroke Genetics C, Wellcome Trust Case Control C, Bellenguez C et al (2012) Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet 44(3):328–333
Liu X, Xu G, Wu W et al (2006) Subtypes and one-year survival of first-ever stroke in Chinese patients: the Nanjing Stroke Registry. Cerebrovasc Dis 22(2–3):130–136
Adams HP Jr, Bendixen BH, Kappelle LJ et al (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke J Cereb Circ 24(1):35–41
Coull AJ, Rothwell PM (2004) Underestimation of the early risk of recurrent stroke: evidence of the need for a standard definition. Stroke J Cereb Circ 35(8):1925–1929
Zhang Z, Xu G, Zhu W et al (2014) Chromosome 12p13 variants predict recurrence of ischaemic stroke in a Chinese population. Eur J Neurol Off J Eur Fed Neurol Soc 21(11):1400–1405
Thomas G, Sinville R, Sutton S et al (2004) Capillary and microelectrophoretic separations of ligase detection reaction products produced from low-abundant point mutations in genomic DNA. Electrophoresis 25(10–11):1668–1677
Shi L, Li C, Wang C et al (2009) Assessment of association of rs2200733 on chromosome 4q25 with atrial fibrillation and ischemic stroke in a Chinese Han population. Hum Genet 126(6):843–849
Lemmens R, Buysschaert I, Geelen V et al (2010) The association of the 4q25 susceptibility variant for atrial fibrillation with stroke is limited to stroke of cardioembolic etiology. Stroke J Cereb Circ 41(9):1850–1857
Wnuk M, Pera J, Jagiella J et al (2011) The rs2200733 variant on chromosome 4q25 is a risk factor for cardioembolic stroke related to atrial fibrillation in Polish patients. Neurol Neurochir Pol 45(2):148–152
Carty CL, Buzkova P, Fornage M et al (2012) Associations between incident ischemic stroke events and stroke and cardiovascular disease-related genome-wide association studies single nucleotide polymorphisms in the population architecture using genomics and epidemiology study. Circ Cardiovasc Genet 5(2):210–216
Cao YY, Ma F, Wang Y, Wang DW, Ding H (2013) Rs2200733 and rs10033464 on chromosome 4q25 confer risk of cardioembolic stroke: an updated meta-analysis. Mol Biol Rep 40(10):5977–5985
Sun L, Zhang Z, Xu J, Xu G, Liu X (2015) Chromosome 4q25 variants rs2200733, rs10033464, and rs1906591 contribute to ischemic stroke risk. Mol Neurobiol
Faucourt M, Houliston E, Besnardeau L, Kimelman D, Lepage T (2001) The pitx2 homeobox protein is required early for endoderm formation and nodal signaling. Dev Biol 229(2):287–306
Mommersteeg MT, Hoogaars WM, Prall OW et al (2007) Molecular pathway for the localized formation of the sinoatrial node. Circ Res 100(3):354–362
Chinchilla A, Daimi H, Lozano-Velasco E et al (2011) PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis. Circ Cardiovasc Genet 4(3):269–279
Martin RI, Babaei MS, Choy MK et al (2015) Genetic variants associated with risk of atrial fibrillation regulate expression of PITX2, CAV1, MYOZ1, C9orf3 and FANCC. J Mol Cell Cardiol 85:207–214
Gore-Panter SR, Hsu J, Hanna P et al (2014) Atrial fibrillation associated chromosome 4q25 variants are not associated with PITX2c expression in human adult left atrial appendages. PLoS One 9(1):e86245
Aguirre LA, Alonso ME, Badia-Careaga C et al (2015) Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP. BMC Biol 13:26
Acknowledgments
This work was supported by the National Natural Science Foundation of China (31200938, 81571148, 81501019, 81220108008). We thank Benjamin L. Kidder (Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA) for language editing of the manuscript.
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Written informed consent was obtained from all participates, and the study was approved by the Institutional Review Board of Jinling Hospital (Nanjing, China).
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The authors declare no conflict of interest.
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Xinfeng Liu is the first corresponding author and Zhizhong Zhang is the second corresponding author.
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Sun, L., Tian, L., Xu, J. et al. Chromosome 4q25 Variants and Age at Onset of Ischemic Stroke. Mol Neurobiol 54, 3388–3394 (2017). https://doi.org/10.1007/s12035-016-9903-5
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DOI: https://doi.org/10.1007/s12035-016-9903-5