李曉晴 劉水平 姜霽雯 袁鵬 鄭海亮

·論著·

DRD2基因多態(tài)性與冠狀動(dòng)脈旁路移植術(shù)后譫妄的關(guān)聯(lián)研究

李曉晴 劉水平 姜霽雯 袁鵬 鄭海亮

目的 研究DRD2基因多態(tài)性與冠狀動(dòng)脈旁路移植術(shù)后譫妄的相關(guān)性以及危險(xiǎn)因素。方法 以冠狀動(dòng)脈旁路移植手術(shù)住院患者為研究對(duì)象，連續(xù)納入手術(shù)患者150例，以《譫妄分級(jí)量表-98修訂版》作為譫妄診斷工具，分析術(shù)后譫妄的發(fā)生率和危險(xiǎn)因素；采用基因測序法確定DRD2的多態(tài)性，分析rs6275、ts6277多態(tài)性與譫妄的相關(guān)性。結(jié)果 術(shù)后譫妄發(fā)生率8.0%(12/150例)；組間單因素分析顯示腦梗死 (OR=0.784，95%CI 0.631～0.975，P=0.024)；手術(shù)持續(xù)時(shí)間(OR=2.251，95%CI 0.941～5.380，P=0.048)；體外循環(huán)時(shí)間(OR=1.057，95%CI 0.703～1.590，P=0.029)；ICU病房時(shí)間(OR=1.890，95%CI 1.201～2.973，P=0.005)差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；2組間rs6275基因型差異無統(tǒng)計(jì)學(xué)意義(OR=1.265，95%CI 0.697～2.303，P=0.651)；rs6277基因型2組間分布差異有統(tǒng)計(jì)學(xué)意義(OR=2.276，95%CI 1.142～4.523，P=0.049)；Logsistic多因素回歸分析顯示腦梗死(OR=1.861，95%CI 1.082～3.163，P=0.024)、ICU持續(xù)時(shí)間(OR=6.757，95%CI 2.376～19.267，P=0.001)、rs6277的CC基因型(OR=4.019，95%CI 1.395～12.341，P=0.012)是術(shù)后譫妄的危險(xiǎn)因素。結(jié)論 對(duì)術(shù)前合并腦梗死的高?；颊?，進(jìn)行DRD2基因篩查，有助于評(píng)估譫妄發(fā)生的可能性。

冠狀動(dòng)脈旁路移植術(shù)；術(shù)后譫妄；發(fā)生率；危險(xiǎn)因素

術(shù)后譫妄(postoperative delirium,POD)是在手術(shù)、麻醉后出現(xiàn)的急性、波動(dòng)性認(rèn)知功能障礙，是在患者易感素質(zhì)的基礎(chǔ)上，由圍手術(shù)期的多種因素共同作用所促發(fā)[1,2]。盡管心臟手術(shù)和麻醉技術(shù)日益成熟，POD仍是冠狀動(dòng)脈旁路移植術(shù)(coronary artery bypass grafting,CABG)術(shù)后神經(jīng)系統(tǒng)急性并發(fā)癥之一，POD不僅延長住院時(shí)間、增加醫(yī)療費(fèi)用、延緩功能恢復(fù)，最新研究顯示，術(shù)后譫妄還與術(shù)后持續(xù)認(rèn)知功能障礙(postoperative cognitive dysfunction,POCD)、癡呆(dementia)密切相關(guān)[3,4]。POD的發(fā)病機(jī)制尚不十分清楚，基因易感性和生物標(biāo)志物已成為譫妄研究的新熱點(diǎn)[5]。多巴胺受體阻斷劑能夠有效控制譫妄癥狀，使多巴胺能系統(tǒng)成為譫妄研究的候選基因之一[6]。本研究旨在探討多巴胺D2受體(dopamine D2 receptor,DRD2)與譫妄的相關(guān)性[7]，為早期預(yù)防提供依據(jù)。

1 資料與方法

1.1 一般資料 連續(xù)納入2014年1～12月北京安貞醫(yī)院心臟外科CABG手術(shù)的150例住院患者為研究對(duì)象，其中男95例，女55例；平均年齡(62.8±7.1)歲。

1.2 譫妄診斷標(biāo)準(zhǔn) 采用美國《精神疾病診斷與統(tǒng)計(jì)手冊(cè)-第五版》[8](《diagnostic and statistical manual-V,DSM-V》)的診斷標(biāo)準(zhǔn)，以譫妄分級(jí)量表-98修訂版(delirium rating scale-revised-98,DRS-R-98)[9]作為譫妄的診斷和鑒別診斷工具，該量表內(nèi)容分為兩部分：(1)3個(gè)診斷項(xiàng)目:包括“癥狀發(fā)生時(shí)間”“癥狀波動(dòng)性”和“軀體疾病”，鑒別診斷譫妄、癡呆、精神分裂癥等；(2)13個(gè)嚴(yán)重程度項(xiàng)目:包括“睡眠覺醒周期紊亂”、“感知障礙”、“妄想”、“情感易變性”、“言語”、“思維過程”、“精神運(yùn)動(dòng)性激越”、“精神運(yùn)動(dòng)性遲滯”、“注意力”、“短時(shí)記憶”、“定向障礙”、“長時(shí)記憶”和“視空間能力”。每個(gè)項(xiàng)目根據(jù)不同程度分為0～3分，累計(jì)積分，DRS-R-98≥12分則診斷譫妄。

1.3 研究方法

1.3.1 入選標(biāo)準(zhǔn)：①冠狀動(dòng)脈旁路移植術(shù)后，包括體外循環(huán)下行冠狀動(dòng)脈旁路移植手術(shù)(on-pump coronary artery bypass grafting,On-CABG)和非體外循環(huán)下行冠狀動(dòng)脈旁路移植手術(shù)(off-pump coronary artery bypass grafting,Off-CABG)；②符合譫妄的診斷標(biāo)準(zhǔn)， DRS-98≥12分；③術(shù)前無認(rèn)知功能障礙，簡易精神狀態(tài)檢查量表(Mini Mental State Examination,MMSE)評(píng)分：文盲≥17 分；小學(xué)≥20分；中學(xué)及以上≥24 分；④術(shù)前無焦慮、抑郁，醫(yī)院焦慮抑郁量表(hospital anxiety and depression scale，HADS)評(píng)分≤7分；⑤同意參加試驗(yàn)并簽署知情同意書。

1.3.2 排除標(biāo)準(zhǔn)：①術(shù)后發(fā)生腦卒中，包括缺血性及出血性腦卒中；②因其他因素引起術(shù)后意識(shí)障礙者；③嚴(yán)重視聽障礙，無法配合神經(jīng)系統(tǒng)查體、認(rèn)知功能測試及其他神經(jīng)系統(tǒng)功能評(píng)估；④同時(shí)進(jìn)行兩種及以上的心臟手術(shù)者。

1.3.3 觀察指標(biāo)：將觀察指標(biāo)分為三大類，分別為術(shù)前因素(既往病史和一般資料)，術(shù)中因素(手術(shù)過程)，術(shù)后因素(術(shù)后監(jiān)護(hù)室以及返回病房后)。術(shù)前因素包括年齡、性別、吸煙、飲酒、糖尿病、左心室射血分?jǐn)?shù)(left ventricular ejection fraction,LVEF)、高血壓、房顫(arterial fibrillation,AF)、腦梗死、腦出血。術(shù)中因素包括手術(shù)持續(xù)時(shí)間、麻醉持續(xù)時(shí)間、體外循環(huán)持續(xù)時(shí)間、術(shù)中平均動(dòng)脈壓(mean arterial pressure,MAP)、手術(shù)方式(體外循環(huán)下手術(shù)和非體外循環(huán)下手術(shù))。術(shù)后因素包括重癥監(jiān)護(hù)病房(intensive care unit,ICU)持續(xù)時(shí)間，機(jī)械通氣時(shí)間(controlled mechanical ventilation,CMV)，平均動(dòng)脈壓，血氧飽和度(arterial oxygen saturation,SaO2)，發(fā)熱，心率，血紅蛋白(hemoglobin,Hb)，術(shù)后疼痛采用視覺模擬疼痛評(píng)分法(visual analogue scale，VAS)。

1.3.4 分組：根據(jù)是否發(fā)生POD將研究對(duì)象分為研究組(譫妄組)12例和對(duì)照組(非譫妄組)138例。

1.3.5 多巴胺受體D2(dopamine D2 receptor,DRD2)基因型的測定:采用基因測序法確定研究對(duì)象的DRD2基因型。采用Promega DNA純化試劑盒抽提全血DNA，然后進(jìn)行DRD2基因PCR擴(kuò)增。DRD2 rs6275設(shè)計(jì)引物，上游：5’gccgactcaccgagaaca 3’；下游5’ggctgatgcctgggaact 3’。25 μl PCR擴(kuò)增反應(yīng)體系包括10×PCR緩沖液2.5 μl+2.5 mmol/L的dNTP混合液2 μl+上游引物(10 μmol/L)0.5 μl+下游引物(10 μmol/L)0.5 μl+DNA(200 ng/μl)2 μl +Taq DNA聚合酶(5 μg/μl)0.2 μl+ddH2O 17.3 μl=25 μl。循環(huán)條件：95℃ 5 min，(94℃ 30 s，51.8℃ 30 s，72℃ 30 s)共30個(gè)循環(huán)；最后72℃ 5 min，純化PCR產(chǎn)物。DRD2 rs6277設(shè)計(jì)引物，上游：5’gccgactcaccgagaaca 3’；下游5’ggctgatgcctgggaact 3’。25 μl PCR擴(kuò)增反應(yīng)體系包括10×PCR緩沖液2.5 μl+2.5 mmol/L的dNTP混合液2 μl+上游引物(10 μmol/L)0.5 μl+下游引物(10 μmol/L)0.5 μl+DNA(200 ng/μl)2 μl +Taq DNA聚合酶(5 μg/μl)0.2 μl+ddH2O 17.3 μl=25 μl。循環(huán)條件：95℃ 5 min，(94℃ 30 s，59.9℃ 30 s，72℃ 30 s)共30個(gè)循環(huán)；最后72℃ 5 min，純化PCR產(chǎn)物。擴(kuò)增產(chǎn)物進(jìn)行直接測序，采用DNA Star軟件比對(duì)，chromas軟件判斷基因型。

2 結(jié)果

2.1 POD的發(fā)生率和研究分組 納入150例研究對(duì)象，譫妄患者共12例為研究組；無譫妄患者138例為對(duì)照組。譫妄發(fā)生率8.0%。

2.2 組間單因素分析 將2組患者圍手術(shù)期指標(biāo)分為三大類型，即術(shù)前、術(shù)中和術(shù)后危險(xiǎn)因素，并對(duì)這三大類指標(biāo)進(jìn)行單因素分析。與POD發(fā)生有關(guān)的危險(xiǎn)因素包括既往腦梗死 (OR=0.784，95%CI 0.631～0.975，P=0.024)；手術(shù)持續(xù)時(shí)間(OR=2.251，95%CI 0.941～5.380，P=0.048)；體外循環(huán)時(shí)間(OR=1.057，95%CI 0.703～1.590，P=0.029)；ICU病房時(shí)間(OR=1.890，95%CI 1.201～2.973，P=0.005)，上述各因素對(duì)POD的影響差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。見表1～3。

表1 POD術(shù)前危險(xiǎn)因素分析

表2 POD術(shù)中危險(xiǎn)因素分析

表3 POD術(shù)后危險(xiǎn)因素分析

2.3 DRD2基因多態(tài)性與POD的關(guān)聯(lián)

2.3.1 rs6275和rs6277的基因頻率和基因型以及Hardy-Weinberg遺傳平衡檢驗(yàn)：DRD2位于染色體11q23，第7號(hào)外顯子的2個(gè)位點(diǎn)即rs6275和rs6277分別存在同義突變即939T>C和957C>T。rs6275等位基因C的頻率為43.7%，等位基因T的頻率為56.3%；三種基因型CC、CT、TT的頻率分別為15.3%、56.7%、28.0%。rs6277等位基因C的頻率為88.0%，等位基因T的頻率為12.0%；三種基因型CC、CT、TT的頻率分別為78.7%、18.7%、2.6%。經(jīng)Hardy-Weinberg平衡定律檢驗(yàn)，rs6275和rs6277的基因型頻率的分布符合遺傳平衡(P>0.05)，樣本來自同一孟德爾群體。見表4、5。

表4 rs6275和rs6277的基本特征

表5 rs6275和rs6277位點(diǎn)基因頻率及基因型分布 例(%)

2.3.2 2組中rs6275和rs6277基因和基因型頻率的結(jié)果:2組間rs6275等位基因頻率差異無統(tǒng)計(jì)學(xué)意義(OR=1.056，95%CI 0.727～1.733，P=0.775)；rs6275基因型2組間分布差異亦無統(tǒng)計(jì)學(xué)意義(OR=1.265，95%CI 0.697～2.303，P=0.651)。2組間rs6277等位基因頻率差異有統(tǒng)計(jì)學(xué)意義(OR=3.857，95%CI 1.727～8.663，P=0.001)；rs6277基因型2組間分布差異有統(tǒng)計(jì)學(xué)意義(OR=2.276，95%CI 1.142～4.523，P=0.049)。見表6。

表6 2組中rs6275和rs6277基因和基因型頻率比較 例(%)

2.3.3 多因素回歸分析：多因素Logistic逐步回歸分析結(jié)果顯示，與POD發(fā)生有關(guān)的因素包括腦梗死、ICU持續(xù)時(shí)間、rs6277的CC基因型。見表7。

表7 POD的Logsistic多因素回歸分析結(jié)果

3 討論

POD是CABG常見的并發(fā)癥之一，與圍手術(shù)期的多種因素有關(guān)[10]。腦血管病是發(fā)生POD的高危因素。術(shù)前“認(rèn)知正常(cognitively healthy)”的患者，頭部核磁檢查可以發(fā)現(xiàn)腦白質(zhì)疏松(white matter hyperintensity or leukoaraiosis)、腔隙性梗死(lacunar infarction)等多種腦小血管病變(cerebral small vessel disease,SVD)[11]，腦血管病變導(dǎo)致神經(jīng)元損失、突觸數(shù)目減少、神經(jīng)環(huán)路受損、認(rèn)知障礙發(fā)生閾值降低，在此基礎(chǔ)上，CABG手術(shù)應(yīng)激可誘發(fā)系統(tǒng)性炎性反應(yīng)，增加血腦屏障通透性，炎性因子TNF等進(jìn)一步誘發(fā)急性腦損傷，導(dǎo)致乙酰膽堿、五羥色胺、多巴胺等神經(jīng)遞質(zhì)失衡，產(chǎn)生譫妄[12]。

POD與ICU病房觀察時(shí)間延長有關(guān)。ICU時(shí)間長與手術(shù)時(shí)間長、創(chuàng)傷大、術(shù)后并發(fā)癥等多種因素有關(guān)，對(duì)中樞神經(jīng)系統(tǒng)等重要器官的影響亦增加；ICU也是一種特殊環(huán)境，常有機(jī)械輔助通氣、肢體約束、留置胃管尿管、密切監(jiān)測護(hù)理等，容易誘發(fā)譫妄[13]。

本研究首創(chuàng)性的觀察了多巴胺受體基因多態(tài)性與術(shù)后譫妄的關(guān)聯(lián)性。多巴胺是重要的神經(jīng)遞質(zhì)，多巴胺與乙酰膽堿神經(jīng)遞質(zhì)失衡是譫妄的發(fā)病機(jī)制之一[14]。腦內(nèi)有三條主要的多巴胺能神經(jīng)通路，分別是黑質(zhì)紋狀體通路、中腦邊緣系統(tǒng)通路以及漏斗結(jié)節(jié)通路。多巴胺遞質(zhì)與多巴胺受體(dopamine receptors， DRs)結(jié)合，發(fā)揮調(diào)節(jié)運(yùn)動(dòng)、認(rèn)知、學(xué)習(xí)、記憶、情感、內(nèi)分泌功能的重要作用。多巴胺受體有五種亞型D1～D5。最近的薈萃分析、橫斷面流行病學(xué)研究以及基因多態(tài)性研究結(jié)果均提示多巴胺受體基因與譫妄、酒精依賴、精神分裂癥、神經(jīng)退行性疾病有關(guān)[15]。多巴胺D2受體(dopamine receptor D2,DRD2)編碼基因位于染色體11q22-q24，其單核苷酸多態(tài)性(single nucleotide polymorphism,SNP)成為目前的研究熱點(diǎn)。本研究首創(chuàng)性的觀察了DRD2基因位于第七外顯子的兩種同義突變r(jià)s6275(C/T)和rs6277(C/T)[16,17]與術(shù)后譫妄的關(guān)系。我們發(fā)現(xiàn)rs6277的C等位基因是術(shù)后譫妄的危險(xiǎn)因素(P=0.001，OR=3.857，95%CI 1.727～8.663)。雖然rs6277(C/T)是同義突變，表達(dá)的氨基酸相同，但是細(xì)胞研究顯示C/T等位基因的差異顯著影響DRD2的mRNA的穩(wěn)定性和表達(dá)數(shù)量；健康志愿者的人體試驗(yàn)進(jìn)一步顯示紋狀體、皮質(zhì)、丘腦不同腦區(qū)域的多巴胺受體的親和性和密度受rs6277(C/T)突變影響，C/C純合子的DRD2親和性最強(qiáng)，T/T純合子的親和性最弱[18-20]。據(jù)此推測rs6277(C/T)突變通過增加多巴胺能神經(jīng)活性，導(dǎo)致多巴胺與乙酰膽堿遞質(zhì)失衡，進(jìn)而增加譫妄發(fā)生的易感性。國內(nèi)外對(duì)于rs6277(C/T)與譫妄的相關(guān)性研究均為之甚少，因此需要更大規(guī)模的病例對(duì)照(case-control)研究以及更細(xì)化的表型分層，進(jìn)一步確認(rèn)rs6277與譫妄的相關(guān)性。

國外對(duì)rs6275(C/T)多態(tài)性的研究集中在精神分裂癥[21]、偏頭痛[22]、語言障礙[23]、藥物濫用[24]等方面。在與譫妄的關(guān)聯(lián)研究中，有關(guān)rs6275的陽性報(bào)道極少，本研究亦未發(fā)現(xiàn)rs6275(C/T)與術(shù)后譫妄相關(guān)。

藥物遺傳學(xué)研究顯示，DRD2基因多態(tài)性可能與藥物治療的不良反應(yīng)相關(guān)[25-27]，因此，對(duì)術(shù)前合并腦梗死的高?；颊撸M(jìn)行DRD2基因篩查，有助于評(píng)估譫妄發(fā)生的可能性，對(duì)指導(dǎo)藥物治療，提高術(shù)后管理水平具有一定的應(yīng)用價(jià)值。

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Correlation between dopamine D2 receptor gene polymorphism and postoperative delirium in patients undergoing coronary artery bypass grafting

LIXiaoqing,LIUShuiping,JIANGJiwen,etal.

DepartmentofNeurology,AnzhenHospitalAffiliatedtoCapitalMedicalUniversity,Beijing100029,China

Objective To investigate the correlation between dopamine D2 receptor (DRD2) gene polymorphism and postoperative delirium in patients undergoing coronary artery bypass grafting (CABG), and to analyze the risk factors of postoperative delirium.Methods A total 150 patients who underwent coronary artery bypass grafting were enrolled in the study. The incidence rate and risk factors of postoperative delirium were analyzed by taking 《Delirium rating scale 98 revised edition》as diagnosis criteria for delirium,moreover, DRD2 genotypes were detected by gene sequencing.The correlation between rs6275,rs6277 polymorphism and delirium was analyzed.Results The incidence rate of postoperative delirium was 8.0% (12/150).The interclass univariate Logistic regression analysis results showed there were significant differences in cerebral infarction (OR=0.784，95%CI 0.631～0.975,P<0.05),surgery duration (OR=2.251,95%CI 0.941～5.380,P<0.05), extracorporeal circulation time (OR=1.057,95%CI 0.703～1.590,P<0.05)and intensive care unit duration (OR=1.890,95%CI 1.201～2.973,P<0.01). However there were no significant differences in frequencies of genotype and alleles of rs6275 polymorphism between case group and control group (OR=1.265,95%CI 0.697～2.303,P>0.05),but there were significant differences in frequencies of genotype and alleles of rs6277 polymorphism between the two groups (OR=2.276, 95%CI 1.142～4.523,P<0.05). The Logistic multifactor stepwise regression analysis showed that cerebral infarction, ICU duration and CC genotype of rs6277 were risk factors of postoperative delirium (P<0.01 orP<0.05).Conclusion To perform DRD2 gene screening in cerebral infarction patients with high risk factors may be helpful for prevention of occurrence of postoperative delirium.

coronary artery bypass grafting; postoperative delirium; incidence rate; risk factors

10.3969/j.issn.1002-7386.2017.15.001

項(xiàng)目來源：北京市自然科學(xué)基金項(xiàng)目(編號(hào)：1152003)

100029 北京市，首都醫(yī)科大學(xué)附屬北京安貞醫(yī)院(李曉晴、劉水平、姜霽雯、袁鵬)；首都醫(yī)科大學(xué)附屬北京世紀(jì)壇醫(yī)院醫(yī)學(xué)工程處(鄭海亮)

鄭海亮，100038 北京市，首都醫(yī)科大學(xué)附屬北京世紀(jì)壇醫(yī)院醫(yī)學(xué)工程處；

E-mail:15811197824@163.com

R 614

A

1002-7386(2017)15-2245-05

2016-09-27)