甄艷鳳,劉興宇,房輝,徐剛,楊岳,孫雪玲,張谷月,張丹丹,許靜,周蕾
錳超氧化物歧化酶基因rs4880位點多態(tài)性與2型糖尿病發(fā)生及認(rèn)知功能的相關(guān)性研究
甄艷鳳,劉興宇,房輝,徐剛,楊岳,孫雪玲,張谷月,張丹丹,許靜,周蕾
目的探討錳超氧化物歧化酶(MnSOD)基因rs4880位點多態(tài)性與2型糖尿病(T2DM)發(fā)生及認(rèn)知功能的相關(guān)性。方法選取2008年3月—2010年3月唐山工人醫(yī)院住院治療的T2DM患者450例為病例組,同期于北京某社區(qū)招募無T2DM者512例為對照組。檢測受試者空腹血糖(FPG)及三酰甘油(TG)、總膽固醇(TC)、高密度脂蛋白膽固醇(HDL-C)、低密度脂蛋白膽固醇(LDL-C)臨床表型。采用重復(fù)性成套神經(jīng)心理狀態(tài)測驗量表(RBANS)評價受試者認(rèn)知功能。采用限制性片段長度多態(tài)性PCR技術(shù)檢測MnSOD基因rs4880位點多態(tài)性。結(jié)果MnSOD基因rs4880位點基因型為TT、CT和CC。兩組rs4880位點基因型及等位基因頻率分布比較,差異均無統(tǒng)計學(xué)意義(P>0.05)。兩組女性受試者rs4880位點基因型分布比較,差異有統(tǒng)計學(xué)意義(P<0.05);其中,CT基因型受試者發(fā)生T2DM的風(fēng)險是TT基因型的2.188倍〔95%CI(1.413,3.388)〕。兩組女性受試者rs4880位點等位基因頻率分布比較,差異有統(tǒng)計學(xué)意義(P<0.05);其中,C等位基因發(fā)生T2DM的風(fēng)險是T等位基因的1.926倍〔95%CI (1.310,2.830)〕。兩組男性受試者rs4880位點基因型及等位基因頻率分布比較,差異均無統(tǒng)計學(xué)意義(P>0.05)。病例組rs4880位點多態(tài)性與TC、LDL-C及胰島素抵抗指數(shù)(HOMA-IR)相關(guān)(P<0.05),而未發(fā)現(xiàn)與FPG、TG、HDL-C相關(guān)(P>0.05)。病例組rs4880位點多態(tài)性與RBANS延遲記憶相關(guān)(P<0.05),而未發(fā)現(xiàn)與即刻記憶、視覺廣度、言語功能、注意及總分相關(guān)(P>0.05)。結(jié)論MnSOD基因rs4880位點CT、C是女性T2DM發(fā)病的危險基因型和等位基因,T2DM患者RBANS延遲記憶評分與MnSOD基因rs4880位點多態(tài)性有關(guān)。
糖尿病,2型;錳超氧化物歧化酶;rs4880位點;多態(tài)性,單核苷酸;重復(fù)性成套神經(jīng)心理狀態(tài)測驗量表;認(rèn)知障礙
甄艷鳳,劉興宇,房輝,等.錳超氧化物歧化酶基因rs4880位點多態(tài)性與2型糖尿病發(fā)生及認(rèn)知功能的相關(guān)性研究[J].中國全科醫(yī)學(xué),2015,18(32):3939-3943.[www.chinagp.net]
Zhen YF,Liu XY,F(xiàn)ang H,et al.Relationship between MnSOD-rs4880 polymorphism and the development of type 2 diabetes aswell as cognitive function[J].Chinese General Practice,2015,18(32):3939-3943.
2型糖尿病(T2DM)患者常合并認(rèn)知功能損傷[1-2],而其發(fā)生的確切機制尚不明確。研究顯示,T2DM的發(fā)生與氧化應(yīng)激有關(guān)[3],而腦內(nèi)神經(jīng)元對氧化應(yīng)激尤為敏感,氧化應(yīng)激狀態(tài)下線粒體內(nèi)活性氧(ROS)水平升高,導(dǎo)致腦組織損傷。錳超氧化物歧化酶(MnSOD)是清除ROS的第一線關(guān)鍵性抗氧化防御酶,有研究發(fā)現(xiàn)MnSOD基因編碼區(qū)rs4880位點多態(tài)性可致MnSOD活性降低[4],同時,rs4880位點多態(tài)性與精神分裂癥患者認(rèn)知功能障礙相關(guān)[5]。因此,本研究通過探討rs4880位點多態(tài)性與T2DM發(fā)生及認(rèn)知功能的關(guān)系,為臨床指導(dǎo)T2DM患者認(rèn)知功能損傷的預(yù)防和治療提供依據(jù)。
1.1研究對象選取2008年3月—2010年3月唐山工人醫(yī)院住院治療的T2DM患者450例為病例組,其中男232例,女218例;平均年齡(55.0±13.4)歲;受教育年限(9.8±1.6)年。患者均符合1999年世界衛(wèi)生組織T2DM診斷標(biāo)準(zhǔn)[6]。排除標(biāo)準(zhǔn):(1)存在腦血管疾病史,如腦血栓、腦出血等;(2)有影響認(rèn)知功能的中樞性神經(jīng)損傷疾病病史,如顱腦創(chuàng)傷、腫瘤、癡呆等;(3)有影響認(rèn)知功能的嚴(yán)重聽力、視力及肢體功能障礙;(4)藥物濫用和依賴或乙醇溶液依賴;(5)不同意參加本研究。
另同期于北京某社區(qū)招募無T2DM者512例為對照組,其中男264例,女248例;平均年齡(55.5 ±12.6)歲;受教育年限(11.4±2.6)年。兩組性別、年齡、受教育年限比較,差異無統(tǒng)計學(xué)意義(χ2性別=0.004,t年齡=2.017,t受教育年限=2.309;P>0.05)。本研究經(jīng)本院醫(yī)學(xué)倫理委員會批準(zhǔn),受試者簽署知情同意書。
1.2方法
1.2.1血糖及血脂檢測病例組患者于入院次日清晨抽取靜脈血5ml,3000r/min離心10min,檢測血清空腹血糖(FPG)及血脂〔三酰甘油(TG)、總膽固醇
(TC)、高密度脂蛋白膽固醇(HDL-C)、低密度脂蛋白膽固醇(LDL-C)〕水平。電化學(xué)發(fā)光法檢測空腹胰島素(FINS)水平,計算胰島素抵抗指數(shù)(HOMAIR)=FPG×FINS/22.5。
1.2.2認(rèn)知功能評定采用重復(fù)性成套神經(jīng)心理狀態(tài)測驗量表(RBANS)[7]評價受試者認(rèn)知功能。RBANS包括即刻記憶、視覺廣度、言語功能、注意、延遲記憶5個分量表,張保華等[8]對451例北京城鄉(xiāng)健康居民調(diào)查顯示,該量表Cronbach'sα系數(shù)為0.90,重測信度為0.90。本研究參與調(diào)查的3位研究者均經(jīng)過培訓(xùn),各研究者RBANS總分相關(guān)系數(shù)(ICC)大于0.8。
1.2.3基因型測定抽取受試者外周靜脈血3ml,以2000r/min低溫離心10min,棄上清液,使用博邁德中量血DNA提取試劑盒提取基因組DNA。MnSOD基因rs4880位點多態(tài)性依據(jù)引物設(shè)計原則,應(yīng)用Primer5引物設(shè)計軟件設(shè)計引物,引物序列如下:上游:5'-ACCAGCAGGCAGCTGGCGCCGG-3',下游:5'-GCGTTGATGTGAGGTTCCAG-3'。PCR總反應(yīng)體系25.0 μl,其中含45ng模板DNA,引物(10pmol/μl)4.0 μl,dNTPs(2mmol/L)1.0μl,MgCl2(25mmol/μl) 1.5μl,10×PCRbuffer2.5μl,1UTaqDNA聚合酶,以上PCR試劑均來自于大連寶生物有限公司。PCR反應(yīng)參數(shù):95℃預(yù)變性5min,95℃變性30s,54.5℃退火30s,72℃延伸1min,共30個循環(huán),72℃終末延伸10min。PidI限制性內(nèi)切酶來自美國Fermentas公司。酶切后產(chǎn)物經(jīng)2.8%瓊脂糖電泳,UVP凝膠圖像分析管理系統(tǒng)查看結(jié)果,進行分型。
1.3統(tǒng)計學(xué)方法采用SPSS16.0統(tǒng)計軟件進行統(tǒng)計分析,采用Hardy-Weinberg遺傳平衡定律檢驗樣本的群體代表性;計量資料以(±s)表示,組間比較采用t檢驗;計數(shù)資料以相對數(shù)表示,組間比較采用χ2檢驗。采用Unphased3.1.4軟件分析基因型與臨床表型、RBANS評分的相關(guān)性。以P<0.05為差異有統(tǒng)計學(xué)意義。
2.1MnSOD基因rs4880位點基因型PCR產(chǎn)物經(jīng)酶切后可分為3個片段,即18 bp、89 bp純和型CC,107 bp野生型TT,18 bp、89 bp和107 bp雜合型CT (見圖1)。
圖1 MnSOD基因rs4880位點多態(tài)性酶切產(chǎn)物電泳圖Figure 1 Electrophoresis of enzyme-digested product of MnSOD-rs4880 polymorphism
2.2rs4880位點基因型及等位基因頻率分布病例組與對照組基因型頻率分布符合Hardy-Weinberg遺傳平衡定律(χ2=0.284,P=0.594),具有群體代表性。兩組rs4880位點基因型及等位基因頻率分布比較,差異均無統(tǒng)計學(xué)意義(P>0.05,見表1)。兩組女性受試者rs4880位點基因型分布比較,差異有統(tǒng)計學(xué)意義(P<0.05);其中,CT基因型受試者發(fā)生T2DM的風(fēng)險是TT基因型的2.188倍〔95%CI(1.413,3.388)〕。兩組女性受試者rs4880位點等位基因頻率分布比較,差異有統(tǒng)計學(xué)意義(P<0.05);其中,C等位基因發(fā)生T2DM的風(fēng)險是T等位基因的1.926倍〔95%CI(1.310,2.830),見表2〕。兩組男性受試者rs4880位點基因型及等位基因頻率分布比較,差異均無統(tǒng)計學(xué)意義(P>0.05,見表3)。
表1 兩組rs4880位點基因型及等位基因頻率分布比較〔n(%)〕Table 1 Comparison of genotype and allele frequency of rs4880 sitebetween the two groups
表2 兩組女性受試者rs4880位點基因型及等位基因頻率分布比較〔n(%)〕Table 2 Comparison of genotype and allele frequency of rs4880 site in female subjects between the two groups
表3 兩組男性受試者rs4880基因型及等位基因頻率分布比較〔n(%)〕Table3 Comparison of genotype distribution and allele frequency of rs4880 site in male subjects between the two groups
2.3病例組rs4880位點多態(tài)性與T2DM臨床表型的相關(guān)性病例組rs4880位點多態(tài)性與TC、LDL-C及HOMA-IR相關(guān)(P<0.05),而未發(fā)現(xiàn)與FPG、TG、HDL-C相關(guān)(P>0.05,見表4)。
表4 病例組rs4880位點多態(tài)性與臨床表型的相關(guān)性分析(±s)Table 4 Correlation between rs4880 site polymorphism and clinical phenotypes in case group
表4 病例組rs4880位點多態(tài)性與臨床表型的相關(guān)性分析(±s)Table 4 Correlation between rs4880 site polymorphism and clinical phenotypes in case group
注:FPG=空腹血糖,TG=三酰甘油,TC=總膽固醇,HDL-C =高密度脂蛋白膽固醇,LDL-C=低密度脂蛋白膽固醇,HOMA-IR =胰島素抵抗指數(shù)
基因型例數(shù)FPG (mmol/L) 8 4.6±3.4 CT 56 9.3±3.2 1.9±1.3 4.8±1.1 1.1±0.3 2.6±0.9 3.5±2.3 CC 6 10.4±3.7 1.4±0.7 4.0±0.6 1.0±0.3 2.4±0.9 2.8±1.0 χ2 TG (mmol/L) TC (mmol/L) HDL-C (mmol/L)HOMA-IR TT 170 9.5±3.9 2.1±1.7 5.4±1.4 1.2±0.3 2.9±0. LDL-C (mmol/L)值0.762 0.274 0.037 0.160 0.028 0.012 0.092 1.199 4.826 1.971 4.354 5.346 P值
2.4病例組rs4880位點多態(tài)性與RBANS評分的相關(guān)性病例組rs4880位點多態(tài)性與RBANS延遲記憶相關(guān)(P<0.05),而未發(fā)現(xiàn)與即刻記憶、視覺廣度、言語功能、注意及總分相關(guān)(P>0.05,見表5)。
表5 病例組rs4880位點多態(tài)性與RBANS評分的相關(guān)性分析(±s,分)Table 5 Correlation between rs4880 site polymorphism and RBANS scores in case group
表5 病例組rs4880位點多態(tài)性與RBANS評分的相關(guān)性分析(±s,分)Table 5 Correlation between rs4880 site polymorphism and RBANS scores in case group
基因型例數(shù)即刻記憶視覺廣度言語功能注意延遲記憶總分TT 170 67.7±14.7 83.1±13.3 84.9±14.5 82.9±16.7 75.2±11.5 73.0±13.4 CT 56 68.6±15.2 80.4±13.8 83.7±14.2 80.7±16.1 77.6±12.0 72.0±13.7 CC 6 72.4±22.6 85.0±14.0 86.8±17.4 72.8±22.6 88.2±14.1 74.2±20.7 χ20.254 1.492 0.025 2.301 6.213 0.262 P值值0.620 0.222 0.874 0.129 0.024 0.609
MnSOD基因定位于染色體6q25[9],含5個外顯子及4個內(nèi)含子,對線粒體內(nèi)氧自由基的清除發(fā)揮重要作用。但MnSOD只有從胞質(zhì)轉(zhuǎn)移至線粒體才能發(fā)揮其清除氧自由基的作用,若轉(zhuǎn)移過程受到阻礙,線粒體內(nèi)氧自由基由于清除不足而蓄積,導(dǎo)致氧化應(yīng)激的發(fā)生,造成細(xì)胞損傷。MnSOD啟動子區(qū)的突變會使編碼序列發(fā)生變化,這可能是減弱MnSOD抗氧化作用的原因之一。MnSOD啟動子區(qū)的線粒體靶向序列(MTS)編碼含24個氨基酸的信號肽,此信號肽的作用是引導(dǎo)MnSOD由胞質(zhì)轉(zhuǎn)移至線粒體[10]。rs4880位點位于MnSOD基因啟動子的編碼區(qū),其多態(tài)性指第47位核苷酸,即編碼區(qū)第9位密碼子GCT中的C堿基突變?yōu)門堿基,從而使密碼子變?yōu)镚TT,致使MnSOD信號肽第16位氨基酸由丙氨酸替換為纈氨酸[11],氨基酸的替換使其編碼的信號肽空間結(jié)構(gòu)發(fā)生變化,由α-螺旋結(jié)構(gòu)變?yōu)棣拢郫B。α-螺旋構(gòu)象具有雙親和性,可引導(dǎo)MnSOD從胞質(zhì)轉(zhuǎn)移入線粒體,但β-折疊可影響信號肽和線粒體內(nèi)膜相關(guān)受體的正確識別,使MnSOD從胞質(zhì)轉(zhuǎn)移入線粒體的速率降低,繼而影響MnSOD在線粒體抗氧化作用的發(fā)揮[10]。
本研究發(fā)現(xiàn),病例組和對照組MnSOD基因rs4880位點基因型及等位基因頻率均無差異,與在日本[12]進行的研究結(jié)果一致,但與在俄羅斯[13]、印度[14]進行的研究結(jié)果不同。本研究納入受試者與日本人群[12]均以TT基因型為主,而俄羅斯、德國、瑞典、立陶宛、芬蘭等白種人CC、CT基因型和C等位基因比例較高[15],提示MnSOD基因rs4880位點多態(tài)性具有種族差異。
本研究對性別分層分析發(fā)現(xiàn),女性T2DM患者rs4880位點基因型及等位基因頻率分布與健康對照組比較,差異具有統(tǒng)計學(xué)意義,攜帶CT基因型的女性患T2DM的風(fēng)險是TT基因型的2.188倍,CT基因型為女性T2DM發(fā)病的危險基因型;攜帶C等位基因的女性患T2DM的風(fēng)險是T等位基因的1.926倍,等位基因C為女性T2DM發(fā)病的危險因素。Hiroi等[16]體外研究證實,MnSOD在線粒體的活性CC型>CT型>TT型。本研究中,女性T2DM患者基因型以TT為主,推測MnSOD基因型為TT時,MnSOD轉(zhuǎn)運至線粒體的能力降低,線粒體內(nèi)MnSOD的水平及活性下降,清除ROS能力下降,ROS水平升高,從而導(dǎo)致胰島素抵抗,最終引起T2DM的發(fā)生。
本研究發(fā)現(xiàn),T2DM患者LDL-C、TC水平與MnSOD基因rs4880位點多態(tài)性有關(guān)。有文獻報道,MnSOD基因與人類致動脈粥樣硬化(AS)性脂蛋白表型和LDL-C水平升高有關(guān)[17],提示MnSOD雖不參與脂代謝,但其基因多態(tài)性與血脂間存在某種關(guān)聯(lián),其機制尚不清楚。本研究同樣發(fā)現(xiàn),T2DM患者HOMA-IR與MnSOD基因rs4880位點多態(tài)性有關(guān),提示MnSOD基因可能是通過胰島素抵抗參與T2DM的發(fā)生過程。
本研究結(jié)果顯示,T2DM患者RBANS延遲記憶評分與MnSOD基因rs4880位點多態(tài)性有關(guān)。氧化應(yīng)激參與T2DM的發(fā)生過程,高血糖狀態(tài)下的ROS水平升高是胰島素抵抗的重要觸發(fā)器[18]。腦內(nèi)神經(jīng)元對氧化應(yīng)激尤其敏感,氧化應(yīng)激狀態(tài)下線粒體內(nèi)ROS水平升高,而MnSOD是清除ROS的第一線關(guān)鍵性抗氧化防御酶,T2DM患者MnSOD抗氧化防御能力下降[19],因此腦組織發(fā)生神經(jīng)退行性改變,引起認(rèn)知功能損傷。氧化損傷與β-淀粉樣蛋白的形成密切相關(guān)[20],β-淀粉樣蛋白具有神經(jīng)毒性,損傷神經(jīng)元,影響其功能。氧化應(yīng)激是神經(jīng)退行性疾病的重要發(fā)病機制,如阿爾茨海默病(AD)、海綿狀腦病、帕金森病[21]。
綜上所述,MnSOD基因rs4880位點CT、C是女性發(fā)生T2DM的危險基因型和等位基因,T2DM患者RBANS延遲記憶評分與MnSOD基因rs4880位點多態(tài)性有關(guān)。
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(本文編輯:吳立波)
Relationship Between M nSOD-rs4880 Polym orphism and the Developm ent of Type 2 Diabetes as W ell as CognitiveFunction
ZHEN Yan-feng,LIU Xing-yu,F(xiàn)ANG Hui,et al.The Second Department of Endocrine,Tangshan Gongren Hospital,Tangshan 063000,China
Objective To investigate the relationship between Manganese superoxide dismutase(MnSOD)-rs4880 polymorphism and the development of type 2 diabetes(T2DM)aswell as cognitive function.M ethods We enrolled 450 T2DM patients who were hospitalized in Tangshan Gongren Hospital from March 2008 to March 2010 as the case group,and we enrolled another 512 personswithout T2DM thatwere recruited from a community in Beijing in the same period as the control group.We collected the clinical phenotype data including FPG,TG,TC,HDL-C and LDL-C.The Repeatable Battery for the Assessment of Neuropsychological Status(RBANS)was applied to assess the cognitive function of the subjects,and RFLP-PCR was used to detect MnSOD-rs4880 polymorphism.Results MnSOD-rs4880 has three genotypes:TT,CT and CC.There was no significantdifference both in distribution ofgenotype and allele frequency between the two groups(P>0.05).Significant difference was found in genotype distribution of this site in female subjects between the two groups(P<0.05);subjectswith CTgenotype had 2. 188 times higher risk to develop T2DM than TT genotype carriers〔95% CI (1. 413,3. 388) 〕. Significantdifference was also found in allele frequency of rs4880 site in female subjects between the two groups (P < 0. 05) ; subjects whocarried C allele had 1. 926 times higher risk to develop T2DM than T allele carriers〔95%CI (1. 310,2. 830) 〕. There was nosignificant difference both in the distribution of genotype and allele frequency of rs4880 site in male subjects between the twogroups (P > 0. 05) . Association was found between rs4880 site polymorphism and TC,LDL - C and HOMA - IR (P < 0. 05) ,while no association was found between rs4880 site polymorphism and FPG,TG and HDL - C (P > 0. 05) . The rs4880 sitepolymorphism was found associated with RBANS delayed memory (P < 0. 05) ,while no association was found between MnSOD- rs4880 polymorphism and immediate memory,visuospatial /constructional,language,attention and the total score (P >0. 05) . Conclusion CT and C are risk genotype and allele for females to develop T2DM,and MnSOD - rs4880 polymorphismis associated with RBANS delayed memory score of T2DM patients.
Diabetes mellitus,type 2; Manganese superoxide dismutase; rs4880 site; Polymorphism,singlenucleotide; RBANS; Cognition disorders
R 587.1
A
10.3969/j.issn.1007-9572.2015.32.011
河北省自然科學(xué)基金資助項目(H2015105083)
063000河北省唐山市,唐山工人醫(yī)院內(nèi)分泌二科(甄艷鳳,房輝,楊岳,孫雪玲,張谷月,張丹丹,許靜,周蕾),神經(jīng)外科(劉興宇),燒傷科(徐剛)
房輝,063000河北省唐山市,唐山工人醫(yī)院內(nèi)分泌二科;E-mail:fanghui@medmail.com.cn
2015-01-08;
2015-08-24)