Differences in brain-derived neurotrophic factor gene polymorphisms between acute ischemic stroke patients and healthy controls in the Han population of southwest China
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摘要
Single-nucleotide polymorphisms in the brain-derived neurotrophic factor gene may affect the secretion and function of brain-derived neurotrophic factor, thereby affecting the occurrence, severity and prognosis of ischemic stroke. This case-control study included 778 patients(475 males and 303 females, mean age of 64.0 ± 12.6 years) in the acute phase of ischemic stroke and 865 control subjects(438 males and 427 females, mean age of 51.7 ± 14.7 years) from the Department of Neurology, West China Hospital, Sichuan University, China between September 2011 and December 2014. The patients' severities of neurological deficits in the acute phase were assessed using the National Institutes of Health Stroke Scale immediately after admission to hospital. The ischemic stroke patients were divided into different subtypes according to the Trial of Org 10172 in Acute Stroke Treatment classification. Early prognosis was evaluated using the Modified Rankin Scale when the patients were discharged. Genomic DNA was extracted from peripheral blood of participants. Genotyping of rs7124442 and rs6265 was performed using Kompetitive Allele Specific polymerase chain reaction genotyping technology. Our results demonstrated that patients who carried the C allele of the rs7124442 locus had a lower risk of poor prognosis than the T allele carriers(odds ratio [OR] = 0.67; 95% confidence interval [CI]: 0.45–1.00; P = 0.048). The patients with the CC or TC genotype also exhibited lower risk than TT carriers(OR = 0.65; 95% CI: 0.42–1.00; P = 0.049). The AA genotype at the rs6265 locus was associated with the occurrence of ischemic stroke in patients with large-artery atherosclerosis(OR = 0.58; 95% CI: 0.37–0.90; P = 0.015). We found that the C allele(CC and TC genotypes) at the rs7124442 locus may be protective for the prognosis of ischemic stroke. The AA genotype at the rs6265 locus is likely a protective factor against the occurrence of ischemic stroke in patients with large-artery atherosclerosis. The study protocol was approved by the Ethics Committee of West China Hospital of Sichuan University, China(approval ID number 2008[4]) on July 25, 2008.
Single-nucleotide polymorphisms in the brain-derived neurotrophic factor gene may affect the secretion and function of brain-derived neurotrophic factor, thereby affecting the occurrence, severity and prognosis of ischemic stroke. This case-control study included 778 patients(475 males and 303 females, mean age of 64.0 ± 12.6 years) in the acute phase of ischemic stroke and 865 control subjects(438 males and 427 females, mean age of 51.7 ± 14.7 years) from the Department of Neurology, West China Hospital, Sichuan University, China between September 2011 and December 2014. The patients' severities of neurological deficits in the acute phase were assessed using the National Institutes of Health Stroke Scale immediately after admission to hospital. The ischemic stroke patients were divided into different subtypes according to the Trial of Org 10172 in Acute Stroke Treatment classification. Early prognosis was evaluated using the Modified Rankin Scale when the patients were discharged. Genomic DNA was extracted from peripheral blood of participants. Genotyping of rs7124442 and rs6265 was performed using Kompetitive Allele Specific polymerase chain reaction genotyping technology. Our results demonstrated that patients who carried the C allele of the rs7124442 locus had a lower risk of poor prognosis than the T allele carriers(odds ratio [OR] = 0.67; 95% confidence interval [CI]: 0.45–1.00; P = 0.048). The patients with the CC or TC genotype also exhibited lower risk than TT carriers(OR = 0.65; 95% CI: 0.42–1.00; P = 0.049). The AA genotype at the rs6265 locus was associated with the occurrence of ischemic stroke in patients with large-artery atherosclerosis(OR = 0.58; 95% CI: 0.37–0.90; P = 0.015). We found that the C allele(CC and TC genotypes) at the rs7124442 locus may be protective for the prognosis of ischemic stroke. The AA genotype at the rs6265 locus is likely a protective factor against the occurrence of ischemic stroke in patients with large-artery atherosclerosis. The study protocol was approved by the Ethics Committee of West China Hospital of Sichuan University, China(approval ID number 2008[4]) on July 25, 2008.
Single-nucleotide polymorphisms in the brain-derived neurotrophic factor gene may affect the secretion and function of brain-derived neurotrophic factor, thereby affecting the occurrence, severity and prognosis of ischemic stroke. This case-control study included 778 patients(475 males and 303 females, mean age of 64.0 ± 12.6 years) in the acute phase of ischemic stroke and 865 control subjects(438 males and 427 females, mean age of 51.7 ± 14.7 years) from the Department of Neurology, West China Hospital, Sichuan University, China between September 2011 and December 2014. The patients' severities of neurological deficits in the acute phase were assessed using the National Institutes of Health Stroke Scale immediately after admission to hospital. The ischemic stroke patients were divided into different subtypes according to the Trial of Org 10172 in Acute Stroke Treatment classification. Early prognosis was evaluated using the Modified Rankin Scale when the patients were discharged. Genomic DNA was extracted from peripheral blood of participants. Genotyping of rs7124442 and rs6265 was performed using Kompetitive Allele Specific polymerase chain reaction genotyping technology. Our results demonstrated that patients who carried the C allele of the rs7124442 locus had a lower risk of poor prognosis than the T allele carriers(odds ratio [OR] = 0.67; 95% confidence interval [CI]: 0.45–1.00; P = 0.048). The patients with the CC or TC genotype also exhibited lower risk than TT carriers(OR = 0.65; 95% CI: 0.42–1.00; P = 0.049). The AA genotype at the rs6265 locus was associated with the occurrence of ischemic stroke in patients with large-artery atherosclerosis(OR = 0.58; 95% CI: 0.37–0.90; P = 0.015). We found that the C allele(CC and TC genotypes) at the rs7124442 locus may be protective for the prognosis of ischemic stroke. The AA genotype at the rs6265 locus is likely a protective factor against the occurrence of ischemic stroke in patients with large-artery atherosclerosis. The study protocol was approved by the Ethics Committee of West China Hospital of Sichuan University, China(approval ID number 2008[4]) on July 25, 2008.
引文
Acute Ischemic Stroke Diagnosis and Treatment Writing Group of Cerebrovascular Disease in Neurology Branch of Chinese Medical Association(2010)The2010 China Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke.Zhonghua Shenjing Ke Zazhi 43:146-153.
Adams HP Jr,Bendixen BH,Kappelle LJ,Biller J, Love BB,Gordon DL,Marsh EE3rd(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 24:35-41.
Cheng B,Forkert ND,Zavaglia M,Hilgetag CC,Golsari A,Siemonsen S, Fiehler J,Pedraza S,Puig J,Cho TH,Alawneh J,Baron JC,Ostergaard L,Gerloff C,Thomalla G(2014)Influence of stroke infarct location on functional outcome measured by the modified rankin scale.Stroke 45:1695-1702.
Cramer SC,Procaccio V,GAIN Americas,GAIN International Study Investigators(2012)Correlation between genetic polymorphisms and stroke recovery:analysis of the GAIN Americas and GAIN International Studies.Eur J Neurol 19:718-724.
Egan MF,Kojima M,Callicott JH,Goldberg TE,Kolachana BS,Bertolino A,Zaitsev E,Gold B,Goldman D,Dean M,Lu B,Weinberger DR(2003)The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.Cell 112:257-269.
Failla MD,Conley YP,Wagner AK(2016)Brain-derived neurotrophic factor(BDNF)in traumatic brain injury-related mortality:interrelationships between genetics and acute systemic and central nervous system BDNF profiles.Neurorehabil Neural Repair 30:83-93.
Hohenadel MG,Thearle MS,Grice BA,Huang H,Dai MH,Tao YX,Hunter LA,Palaguachi GI,Mou Z,Kim RC,Tsang MM,Haack K,Voruganti VS,Cole SA,Butte NF,Comuzzie AG,Muller YL,Baier LJ,Krakoff J,Knowler WC,et al.(2014)Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants.Int J Obes(Lond)38:1068-1074.
Keshavarz P,Saberi A,Sharafshah A,Asgari K,Rezaei S(2016)Association of BDNF G196A gene polymorphism with ischemic stroke occurrence and its6-month outcome in an Iranian population.Top Stroke Rehabil 23:2 54-260.
Kim JM,Stewart R,Park MS,Kang HJ,Kim SW,Shin IS,Kim HR,Shin MG,Cho KH,Yoon JS(2012)Associations of BDNF genotype and promoter methylation with acute and long-term stroke outcomes in an East Asian cohort.PLoS One7:e61280.
Kim WS,Lim JY,Shin JH,Park HK, Tan SA,Park KU,Paik NJ(2013)Effect of the presence of brain-derived neurotrophic factor val(66)met polymorphism on the recovery in patients with acute subcortical stroke.Ann Rehabil Med 37:311-319.
Kotlega D,Peda B,Zembron-Lacny A,Golab-Janowska M,Nowacki P(2017)The role of brain-derived neurotrophic factor and its single nucleotide polymorphisms in stroke patients.Neurol Neurochir Pol 51:240-246.
Lee SH,Han JH,Choi JH,Huh EY,Kwon YK,Kaang BK(2003)The effect of brain-derived neurotrophic factor on neuritogenesis and synaptic plasticity in Aplysia neurons and the hippocampal cell line HiB5.Mol Cells 15:233-239.
Lyden P(2017)Using the National Institutes of Health Stroke Scale:a cautionary tale.Stroke 48:513-519.
Machalinski B,Lazewski-Banaszak P,Dabkowska E,Paczkowska E,Golab-Janowska M,Nowacki P(2012)The role of neurotrophic factors in regeneration of the nervous system.Neurol Neurochir Pol 46:579-590.
Mignone F,Gissi C,Liuni S,Pesole G(2002)Untranslated regions of mRNAs.Genome Biol 3:REVIEWS0004.
Mowla SJ,Farhadi HF,Pareek S,Atwal JK,Morris SJ,Seidah NG,Murphy RA(2001)Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor.J Biol Chem 276:12660-12666.
Orefice LL,Waterhouse EG,Partridge JG,Lalchandani RR,Vicini S,Xu B(2013)Distinct roles for somatically and dendritically synthesized brain-derived neurotrophic factor in morphogenesis of dendritic spines.J Neurosci 33:11618-11632.
Poo MM(2001)Neurotrophins as synaptic modulators.Nat Rev Neurosci 2:24-32.
Purcell S,Neale B,Todd-Brown K,Thomas L,Ferreira MA,Bender D,Maller J,Sklar P,de Bakker PI,Daly MJ,Sham PC(2007)PLINK:a tool set for whole-genome association and population-based linkage analyses.Am J Hum Genet81:559-575.
Qin L,Kim E,Ratan R,Lee FS,Cho S(2011)Genetic variant of BDNF(Val66Met)polymorphism attenuates stroke-induced angiogenic responses by enhancing anti-angiogenic mediator CD36 expression.J Neurosci 31:775-783.
Rostami E,Krueger F,Zoubak S,Dal Monte O,Raymont V,Pardini M,Hodgkinson CA,Goldman D,Risling M,Grafman J(2011)BDNF polymorphism predicts general intelligence after penetrating traumatic brain injury.PLoS One6:e27389.
Shi YY,He L(2005)SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci.Cell Res 15:97-98.
Shimizu E,Hashimoto K,Iyo M(2004)Ethnic difference of the BDNF 196G/A(val66met)polymorphism frequencies:the possibility to explain ethnic mental traits.Am J Med Genet B Neuropsychiatr Genet 126B:122-123.
Stanne TM,Tjarnlund-Wolf A,Olsson S,Jood K,Blomstrand C,Jern C(2014)Genetic variation at the BDNF locus:evidence for association with long-term outcome after ischemic stroke.PLoS One 9:e114156.
Wang W,Jiang B,Sun H,Ru X,Sun D,Wang L,Wang L,Jiang Y,Li Y,Wang Y,Chen Z,Wu S,Zhang Y,Wang D,Wang Y,Feigin VL(2017)Prevalence,incidence,and mortality of stroke in China:results from a nationwide population-based survey of 480 687 adults.Circulation 135:759-771.
Wurzelmann M,Romeika J,Sun D(2017)Therapeutic potential of brain-derived neurotrophic factor(BDNF)and a small molecular mimics of BDNF for traumatic brain injury.Neural Regen Res 12:7-12.
Zhao H,Alam A,San CY,Eguchi S,Chen Q,Lian Q,Ma D(2017)Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection:Recent developments.Brain Res 1665:1-21.
Zhao J,Wu H,Zheng L,Weng Y,Mo Y(2013)Brain-derived neurotrophic factor G196A polymorphism predicts 90-day outcome of ischemic stroke in Chinese:a novel finding.Brain Res 1537:312-318.
Adams HP Jr,Bendixen BH,Kappelle LJ,Biller J, Love BB,Gordon DL,Marsh EE3rd(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 24:35-41.
Cheng B,Forkert ND,Zavaglia M,Hilgetag CC,Golsari A,Siemonsen S, Fiehler J,Pedraza S,Puig J,Cho TH,Alawneh J,Baron JC,Ostergaard L,Gerloff C,Thomalla G(2014)Influence of stroke infarct location on functional outcome measured by the modified rankin scale.Stroke 45:1695-1702.
Cramer SC,Procaccio V,GAIN Americas,GAIN International Study Investigators(2012)Correlation between genetic polymorphisms and stroke recovery:analysis of the GAIN Americas and GAIN International Studies.Eur J Neurol 19:718-724.
Egan MF,Kojima M,Callicott JH,Goldberg TE,Kolachana BS,Bertolino A,Zaitsev E,Gold B,Goldman D,Dean M,Lu B,Weinberger DR(2003)The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.Cell 112:257-269.
Failla MD,Conley YP,Wagner AK(2016)Brain-derived neurotrophic factor(BDNF)in traumatic brain injury-related mortality:interrelationships between genetics and acute systemic and central nervous system BDNF profiles.Neurorehabil Neural Repair 30:83-93.
Hohenadel MG,Thearle MS,Grice BA,Huang H,Dai MH,Tao YX,Hunter LA,Palaguachi GI,Mou Z,Kim RC,Tsang MM,Haack K,Voruganti VS,Cole SA,Butte NF,Comuzzie AG,Muller YL,Baier LJ,Krakoff J,Knowler WC,et al.(2014)Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants.Int J Obes(Lond)38:1068-1074.
Keshavarz P,Saberi A,Sharafshah A,Asgari K,Rezaei S(2016)Association of BDNF G196A gene polymorphism with ischemic stroke occurrence and its6-month outcome in an Iranian population.Top Stroke Rehabil 23:2 54-260.
Kim JM,Stewart R,Park MS,Kang HJ,Kim SW,Shin IS,Kim HR,Shin MG,Cho KH,Yoon JS(2012)Associations of BDNF genotype and promoter methylation with acute and long-term stroke outcomes in an East Asian cohort.PLoS One7:e61280.
Kim WS,Lim JY,Shin JH,Park HK, Tan SA,Park KU,Paik NJ(2013)Effect of the presence of brain-derived neurotrophic factor val(66)met polymorphism on the recovery in patients with acute subcortical stroke.Ann Rehabil Med 37:311-319.
Kotlega D,Peda B,Zembron-Lacny A,Golab-Janowska M,Nowacki P(2017)The role of brain-derived neurotrophic factor and its single nucleotide polymorphisms in stroke patients.Neurol Neurochir Pol 51:240-246.
Lee SH,Han JH,Choi JH,Huh EY,Kwon YK,Kaang BK(2003)The effect of brain-derived neurotrophic factor on neuritogenesis and synaptic plasticity in Aplysia neurons and the hippocampal cell line HiB5.Mol Cells 15:233-239.
Lyden P(2017)Using the National Institutes of Health Stroke Scale:a cautionary tale.Stroke 48:513-519.
Machalinski B,Lazewski-Banaszak P,Dabkowska E,Paczkowska E,Golab-Janowska M,Nowacki P(2012)The role of neurotrophic factors in regeneration of the nervous system.Neurol Neurochir Pol 46:579-590.
Mignone F,Gissi C,Liuni S,Pesole G(2002)Untranslated regions of mRNAs.Genome Biol 3:REVIEWS0004.
Mowla SJ,Farhadi HF,Pareek S,Atwal JK,Morris SJ,Seidah NG,Murphy RA(2001)Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor.J Biol Chem 276:12660-12666.
Orefice LL,Waterhouse EG,Partridge JG,Lalchandani RR,Vicini S,Xu B(2013)Distinct roles for somatically and dendritically synthesized brain-derived neurotrophic factor in morphogenesis of dendritic spines.J Neurosci 33:11618-11632.
Poo MM(2001)Neurotrophins as synaptic modulators.Nat Rev Neurosci 2:24-32.
Purcell S,Neale B,Todd-Brown K,Thomas L,Ferreira MA,Bender D,Maller J,Sklar P,de Bakker PI,Daly MJ,Sham PC(2007)PLINK:a tool set for whole-genome association and population-based linkage analyses.Am J Hum Genet81:559-575.
Qin L,Kim E,Ratan R,Lee FS,Cho S(2011)Genetic variant of BDNF(Val66Met)polymorphism attenuates stroke-induced angiogenic responses by enhancing anti-angiogenic mediator CD36 expression.J Neurosci 31:775-783.
Rostami E,Krueger F,Zoubak S,Dal Monte O,Raymont V,Pardini M,Hodgkinson CA,Goldman D,Risling M,Grafman J(2011)BDNF polymorphism predicts general intelligence after penetrating traumatic brain injury.PLoS One6:e27389.
Shi YY,He L(2005)SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci.Cell Res 15:97-98.
Shimizu E,Hashimoto K,Iyo M(2004)Ethnic difference of the BDNF 196G/A(val66met)polymorphism frequencies:the possibility to explain ethnic mental traits.Am J Med Genet B Neuropsychiatr Genet 126B:122-123.
Stanne TM,Tjarnlund-Wolf A,Olsson S,Jood K,Blomstrand C,Jern C(2014)Genetic variation at the BDNF locus:evidence for association with long-term outcome after ischemic stroke.PLoS One 9:e114156.
Wang W,Jiang B,Sun H,Ru X,Sun D,Wang L,Wang L,Jiang Y,Li Y,Wang Y,Chen Z,Wu S,Zhang Y,Wang D,Wang Y,Feigin VL(2017)Prevalence,incidence,and mortality of stroke in China:results from a nationwide population-based survey of 480 687 adults.Circulation 135:759-771.
Wurzelmann M,Romeika J,Sun D(2017)Therapeutic potential of brain-derived neurotrophic factor(BDNF)and a small molecular mimics of BDNF for traumatic brain injury.Neural Regen Res 12:7-12.
Zhao H,Alam A,San CY,Eguchi S,Chen Q,Lian Q,Ma D(2017)Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection:Recent developments.Brain Res 1665:1-21.
Zhao J,Wu H,Zheng L,Weng Y,Mo Y(2013)Brain-derived neurotrophic factor G196A polymorphism predicts 90-day outcome of ischemic stroke in Chinese:a novel finding.Brain Res 1537:312-318.