曹嵐，李志強(qiáng)，師詠勇，劉赟

研究報(bào)告

端粒長(zhǎng)度與2型糖尿?。好系聽栯S機(jī)化研究與多基因風(fēng)險(xiǎn)評(píng)分分析

曹嵐1,3，李志強(qiáng)2,3，師詠勇3，劉赟4

1. 上海市婦幼保健中心，上海 200062 2. 青島大學(xué)生物醫(yī)學(xué)研究院(暨上海交通大學(xué)Bio-X研究院青島分院)，青島 266003 3. 上海交通大學(xué)Bio-X研究院，遺傳發(fā)育與精神神經(jīng)疾病教育部重點(diǎn)實(shí)驗(yàn)室，上海 200030 4. 復(fù)旦大學(xué)生物醫(yī)學(xué)研究院，上海 200032

多項(xiàng)觀察性研究表明，端粒長(zhǎng)度縮短與2型糖尿病(type 2 diabetes, T2D)之間存在關(guān)聯(lián)。然而，傳統(tǒng)觀察性研究結(jié)果常受到混雜因素和反向因果關(guān)聯(lián)的影響，端粒長(zhǎng)度與T2D是否存在因果關(guān)聯(lián)尚不明確。本研究在中國(guó)漢族人群中利用孟德爾隨機(jī)化(Mendelian randomization, MR)和多基因風(fēng)險(xiǎn)評(píng)分(polygenic risk score, PRS)方法探索端粒長(zhǎng)度與T2D的因果關(guān)系。MR研究選取8個(gè)與端粒長(zhǎng)度相關(guān)的獨(dú)立遺傳變異作為工具變量，利用2632例中國(guó)漢族人群T2D全基因組關(guān)聯(lián)研究(genome-wide association study, GWAS)數(shù)據(jù)，檢驗(yàn)遺傳預(yù)測(cè)的端粒長(zhǎng)度與T2D的關(guān)系。利用中國(guó)漢族人群GWAS數(shù)據(jù)，采用PRS分析評(píng)價(jià)端粒長(zhǎng)度PRS與T2D的關(guān)系。MR研究共納入1318例T2D患者和1314例正常對(duì)照，逆方差加權(quán)、MR-Egger回歸、簡(jiǎn)單中位數(shù)和加權(quán)中位數(shù)法估計(jì)的OR值分別為0.78 (95%: 0.36~1.68,= 0.522)、0.23 (95%: 0.01~7.64,= 0.412)、0.60 (95%: 0.28~ 1.28,= 0.185)和0.64 (95%: 0.31~1.33,= 0.233)，遺傳預(yù)測(cè)的較長(zhǎng)端粒長(zhǎng)度與T2D之間不存在關(guān)聯(lián)。PRS分析未發(fā)現(xiàn)端粒長(zhǎng)度PRS與T2D顯著關(guān)聯(lián)的一致結(jié)果。本研究采用MR和PRS方法未發(fā)現(xiàn)端粒長(zhǎng)度與T2D具有因果關(guān)聯(lián)，后續(xù)研究中增大樣本量有助于得出更可靠的結(jié)論。

孟德爾隨機(jī)化；多基因風(fēng)險(xiǎn)評(píng)分；端粒長(zhǎng)度；2型糖尿病

過去幾十年中，糖尿病患病率和病例數(shù)在全球范圍內(nèi)持續(xù)升高[1]。2017年，全球有約4.51億成人患有糖尿病[2]，而中國(guó)估計(jì)有超過1億成人患糖尿病[3]。2型糖尿病(type 2 diabetes, T2D)是一種由遺傳和環(huán)境因素相互作用導(dǎo)致的復(fù)雜疾病[4~6]。T2D的患病率隨年齡增加而上升[7]。糖尿病及其并發(fā)癥給患者家庭和國(guó)家造成了巨大的衛(wèi)生經(jīng)濟(jì)負(fù)擔(dān)。

端粒是真核細(xì)胞染色體末端的DNA-蛋白質(zhì)復(fù)合體，其功能是維持染色體的完整性[8]。由于DNA末端不能完全復(fù)制，正常體細(xì)胞端粒會(huì)隨著細(xì)胞分裂逐漸縮短，導(dǎo)致細(xì)胞老化[9]。細(xì)胞老化是生物老化的重要方面，而端粒長(zhǎng)度是細(xì)胞老化的重要標(biāo)志物。端粒長(zhǎng)度經(jīng)常在白細(xì)胞中進(jìn)行測(cè)量。白細(xì)胞端粒長(zhǎng)度(leukocyte telomere length, LTL)具有遺傳性，遺傳度在36%~84%之間[10]。

多項(xiàng)觀察性研究表明，LTL縮短與T2D之間存在關(guān)聯(lián)[11,12]。最近，關(guān)于LTL與T2D的meta分析顯示縮短的端粒長(zhǎng)度與T2D顯著相關(guān)[13,14]。然而，端粒長(zhǎng)度縮短可能是受到疾病或治療影響并發(fā)生在疾病診斷之后，共同的環(huán)境因素也可能既影響端粒長(zhǎng)度又影響糖尿病風(fēng)險(xiǎn)，導(dǎo)致偏倚的效應(yīng)估計(jì)。

近年，隨著全基因組關(guān)聯(lián)研究(genome-wide association study, GWAS)的大量應(yīng)用，孟德爾隨機(jī)化(Mendelian randomization, MR)和多基因風(fēng)險(xiǎn)評(píng)分(polygenic risk score, PRS)等方法被日益廣泛用于發(fā)現(xiàn)疾病病因以及因果推斷[15~19]。相比傳統(tǒng)的觀察性流行病學(xué)研究，MR研究和PRS分析不會(huì)受到常見混雜因素的影響，且因果時(shí)序合理。本研究旨在通過MR和PRS方法在中國(guó)漢族人群中檢驗(yàn)端粒長(zhǎng)度與T2D的因果關(guān)系。

1 材料與方法

1.1 研究對(duì)象

研究對(duì)象來(lái)自中國(guó)漢族人群T2D GWAS的2632名上海居民，包括1318例T2D患者和1314例正常對(duì)照。T2D患者均符合WHO糖尿病診斷標(biāo)準(zhǔn)，選取同一地區(qū)空腹血糖(fasting plasma glucose, FPG)< 6.1 mmol/L人群作為正常對(duì)照[20]。所有2632名研究對(duì)象均應(yīng)用定量PCR測(cè)量外周血LTL并進(jìn)行中國(guó)漢族人群LTL GWAS[21]。以上研究已獲中國(guó)科學(xué)院上海生命科學(xué)研究院倫理委員會(huì)批準(zhǔn)(批準(zhǔn)號(hào)：ER- SIBS-250701)，研究對(duì)象均已簽署知情同意書。

1.2 孟德爾隨機(jī)化研究

采用MR方法評(píng)估遺傳預(yù)測(cè)的端粒長(zhǎng)度與T2D的關(guān)系。MR是將與暴露相關(guān)聯(lián)的遺傳變異作為工具變量以推斷暴露與結(jié)局因果關(guān)聯(lián)的一種方法[22]。本研究采用以下標(biāo)準(zhǔn)篩選與端粒長(zhǎng)度相關(guān)的遺傳變異：(1)在已發(fā)表的端粒長(zhǎng)度GWAS研究中達(dá)到全基因組顯著性水平(<5×10?8)；(2)在中國(guó)人群中的最小等位基因頻率(minor allele frequency, MAF)>1%；(3)被選擇的遺傳變異間不存在明顯的連鎖不平衡(2<0.01)。符合標(biāo)準(zhǔn)(1)的遺傳變異共16個(gè)。同時(shí)符合標(biāo)準(zhǔn)(1)和標(biāo)準(zhǔn)(2)的遺傳變異共12個(gè)。本研究最終篩選到8個(gè)遺傳變異作為工具變量，并獲取相關(guān)的信息，包括與較長(zhǎng)端粒長(zhǎng)度相關(guān)的等位基因、MAF、效應(yīng)估計(jì)值()、標(biāo)準(zhǔn)誤和值。使用已發(fā)表端粒長(zhǎng)度GWAS中工具變量與端粒長(zhǎng)度的效應(yīng)估計(jì)值()和標(biāo)準(zhǔn)誤以及2632名中國(guó)漢族人群T2D GWAS中工具變量與T2D的效應(yīng)估計(jì)值()和標(biāo)準(zhǔn)誤計(jì)算因果效應(yīng)。本研究采用4種MR方法：逆方差加權(quán)(inverse-variance weighted, IVW)、MR-Egger回歸、簡(jiǎn)單中位數(shù)(simple median estimator, SME)和加權(quán)中位數(shù)(weighted median estimator, WME)法。此外，通過MR-Egger的截距項(xiàng)評(píng)估工具變量是否存在多效性。所有的分析均采用R (version 3.4.0, R Foundation)的軟件包‘MendelianRandomization’進(jìn)行。

1.3 多基因風(fēng)險(xiǎn)評(píng)分分析

采用PRS分析檢驗(yàn)遺傳預(yù)測(cè)的端粒長(zhǎng)度與T2D的關(guān)系。PRS分析利用GWAS匯總數(shù)據(jù)在人群中構(gòu)建個(gè)體遺傳評(píng)分[23,24]。本研究將2632名研究對(duì)象隨機(jī)分為兩組，1316名T2D患者或者正常對(duì)照進(jìn)行T2D GWAS，1316名研究對(duì)象進(jìn)行LTL GWAS。LTL GWAS的研究對(duì)象與T2D GWAS的研究對(duì)象沒有重疊。本研究中端粒長(zhǎng)度PRS的構(gòu)建基于1316名中國(guó)人群LTL GWAS的匯總數(shù)據(jù)。采用PRSice軟件[25](http://prsice.info/)進(jìn)行數(shù)據(jù)處理和分析，在T2D GWAS研究的1316個(gè)個(gè)體中計(jì)算多個(gè)值閾值(P= 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5)的端粒長(zhǎng)度PRS。PRS分析采用Bonferroni法進(jìn)行多重檢驗(yàn)校正，校正后顯著性閾值設(shè)為0.05/7 = 0.007。

2 結(jié)果與分析

2.1 端粒長(zhǎng)度與T2D的孟德爾隨機(jī)化研究

2.1.1 工具變量信息

根據(jù)本研究工具變量篩選標(biāo)準(zhǔn)，最終篩選到8個(gè)獨(dú)立的遺傳變異作為工具變量[26~28]。表1列出了8個(gè)遺傳變異的相關(guān)信息，包括所在染色體、臨近基因、效應(yīng)等位基因、MAF、與端粒長(zhǎng)度關(guān)聯(lián)的系數(shù)、與T2D關(guān)聯(lián)的系數(shù)等。其中，6個(gè)遺傳變異與端粒長(zhǎng)度和T2D具有相反的效應(yīng)方向，1個(gè)遺傳變異與T2D關(guān)聯(lián)的值小于0.05。

2.1.2 孟德爾隨機(jī)化研究結(jié)果

IVW、MR-Egger回歸、SME和WME法的OR值分別為0.78 (95%: 0.36~1.68,= 0.522)、0.23 (95%: 0.01~7.64,= 0.412)、0.60 (95%: 0.28~ 1.28,= 0.185)、0.64 (95%: 0.31~1.33，= 0.233)，表明遺傳預(yù)測(cè)的較長(zhǎng)端粒長(zhǎng)度與T2D之間不存在關(guān)聯(lián)。此外，MR-Egger回歸的截距為0.110 (95%: –0.198~0.417,= 0.485)，表明工具變量不存在多效性(圖1)。

進(jìn)一步根據(jù)年齡將研究對(duì)象分為≤60歲和>60歲兩層。在≤60歲的研究對(duì)象中，IVW法的OR值為0.60 (95%: 0.27~1.33,= 0.211)。在>60歲的研究對(duì)象中，IVW法的OR值為1.22 (95%: 0.36~ 4.08,= 0.751)。在各層均未發(fā)現(xiàn)遺傳預(yù)測(cè)的較長(zhǎng)端粒長(zhǎng)度與T2D具有關(guān)聯(lián)。

表1 與端粒長(zhǎng)度相關(guān)的遺傳變異

SNP：single-nucleotide polymorphism，單核苷酸多態(tài)性；Chr：染色體；效應(yīng)等位基因：與較長(zhǎng)端粒長(zhǎng)度相關(guān)的等位基因；MAF：最小等位基因頻率，來(lái)自既往GWAS研究；T2D：2型糖尿??；：效應(yīng)估計(jì)值；“*”表示增加一個(gè)效應(yīng)等位基因時(shí)端粒長(zhǎng)度的增加量(kb)。

圖1 不同孟德爾隨機(jī)化方法分析結(jié)果

T2D：2型糖尿??；IVW：逆方差加權(quán)法；SME：簡(jiǎn)單中位數(shù)法；WME：加權(quán)中位數(shù)法。

2.2 端粒長(zhǎng)度與T2D的多基因風(fēng)險(xiǎn)評(píng)分分析

在1316名T2D或健康對(duì)照人群中構(gòu)建端粒長(zhǎng)度PRS以檢驗(yàn)端粒長(zhǎng)度PRS與T2D的關(guān)系。僅有一個(gè)值閾值的端粒長(zhǎng)度PRS與T2D存在關(guān)聯(lián)(= 0.015)，但經(jīng)過Bonferroni校正后，此關(guān)聯(lián)無(wú)統(tǒng)計(jì)學(xué)意義(圖2)。

3 討論

到目前為止，多項(xiàng)觀察性研究表明端粒長(zhǎng)度縮短與T2D之間存在關(guān)聯(lián)。本課題組前期在4016例中國(guó)漢族人群中進(jìn)行的一項(xiàng)病例對(duì)照研究也發(fā)現(xiàn)較短的LTL與T2D相關(guān)(OR = 1.52, 95%: 1.23~1.88,= 0.0001)[29]。最近，一項(xiàng)關(guān)于端粒長(zhǎng)度與T2D的meta分析顯示縮短的端粒長(zhǎng)度與T2D的關(guān)聯(lián)有統(tǒng)計(jì)學(xué)意義(OR = 1.117, 95%: 1.002~1.246,= 0.045)[13]。D’Mello等[14]進(jìn)行的meta分析也顯示縮短的LTL與T2D有關(guān)聯(lián)關(guān)系(OR = 1.37, 95%: 1.10~1.72)。端粒孟德爾隨機(jī)化合作組織[30]于2017年發(fā)表的MR研究未發(fā)現(xiàn)遺傳預(yù)測(cè)的較長(zhǎng)端粒長(zhǎng)度與T2D存在關(guān)聯(lián)，但卻發(fā)現(xiàn)遺傳預(yù)測(cè)的較長(zhǎng)端粒長(zhǎng)度降低1型糖尿病的風(fēng)險(xiǎn)(OR = 0.71, 95%: 0.51~0.98,= 0.04)。本研究采用MR和PRS方法，在中國(guó)漢族人群中評(píng)估端粒長(zhǎng)度和T2D的因果關(guān)系，沒有發(fā)現(xiàn)遺傳預(yù)測(cè)的較長(zhǎng)端粒長(zhǎng)度和T2D存在任何顯著關(guān)聯(lián)。

圖2 端粒長(zhǎng)度PRS與T2D的關(guān)聯(lián)

本研究中MR分析選取的工具變量均為歐洲人群發(fā)現(xiàn)的與端粒長(zhǎng)度相關(guān)的遺傳變異。本課題組在前期的研究中驗(yàn)證了歐洲人群發(fā)現(xiàn)的附近位點(diǎn)rs12696304和rs16847897在中國(guó)漢族人群中與LTL相關(guān)(= 4.5×10–3和9.5×10–5)[31]。此外，在中國(guó)漢族人群GWAS研究中發(fā)現(xiàn)上的位點(diǎn)rs2736100與端粒長(zhǎng)度相關(guān)(= 1.93×10–5)[21]，該發(fā)現(xiàn)與歐洲人群研究結(jié)果一致[26]。一項(xiàng)在亞洲人群進(jìn)行的MR研究也表明歐洲人群發(fā)現(xiàn)的端粒長(zhǎng)度相關(guān)遺傳變異可以有效應(yīng)用于亞洲人群[32]。

在傳統(tǒng)的病例對(duì)照研究中，端粒長(zhǎng)度縮短可能發(fā)生在疾病診斷之后并由疾病或治療導(dǎo)致，故其結(jié)果常受反向因果關(guān)聯(lián)的干擾，影響其論證因果關(guān)系的能力。本研究中遺傳預(yù)測(cè)的端粒長(zhǎng)度與抽血、疾病診斷時(shí)間無(wú)關(guān)，遺傳變異先于疾病的發(fā)生，符合因果推斷中“先因后果”的時(shí)序性要求。此外，本研究運(yùn)用遺傳預(yù)測(cè)的端粒長(zhǎng)度，有利于將影響端粒長(zhǎng)度的遺傳因素與非遺傳因素進(jìn)行區(qū)分。常見影響端粒長(zhǎng)度的非遺傳因素包括衰老、氧化損傷等。

與其他研究相比，本研究具有以下優(yōu)勢(shì)：(1)選取與端粒長(zhǎng)度相關(guān)的8個(gè)獨(dú)立的遺傳變異作為工具變量，避免連鎖不平衡對(duì)因果估計(jì)結(jié)果的影響；(2)采用了多種MR方法。本研究也存在局限性：LTL GWAS和T2D GWAS的樣本量較小，PRS分析的把握度較低。

綜上所述，本研究在中國(guó)漢族人群中采用MR和PRS方法未發(fā)現(xiàn)端粒長(zhǎng)度與T2D具有因果關(guān)聯(lián)。后續(xù)研究中發(fā)現(xiàn)更多新的端粒長(zhǎng)度相關(guān)遺傳變異并增大樣本量有助于得出更可靠的結(jié)論。

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Telomere length and type 2 diabetes: Mendelian randomization study and polygenic risk score analysis

Lan Cao1,3, Zhiqiang Li2,3, Yongyong Shi3, Yun Liu4

Recent epidemiological studies suggest an association between shorter telomere length and higher risk for type 2 diabetes (T2D). However, results from observational studies are susceptible to confounding and reverse causation, and it is not clear whether there is a causal association between telomere length and T2D. Using Mendelian randomization (MR) and polygenic risk score (PRS) approaches, we had evaluated the causal effect of telomere length on T2D in the Chinese Han population. Using 8 telomere-length associated genetic variants as instrumental variables, an analysis of genetically predicted telomere length and T2D risk was performed in the MR study based on data from a T2D genome-wide association study (GWAS) in 2632 individuals (1318 cases and 1314 controls). We also applied a PRS approach to investigate the causal relationship using Chinese GWAS data. The inverse-variance weighted, MR-Egger regression, simple median, and weighted median methods yielded no evidence of association between genetically predicted longer telomere length and risk of T2D (OR = 0.78, 95%: 0.36 ~ 1.68,= 0.522; OR = 0.23, 95%: 0.01 ~ 7.64,= 0.412; OR = 0.60, 95%: 0.28 ~ 1.28,= 0.185; OR = 0.64, 95%: 0.31 ~ 1.33，= 0.233; respectively). Further, PRS analysis did not produce consistent genetic overlap between telomere length and T2D. Accordingly, this study found no evidence supporting a causal association between telomere length and T2D. Further studies with larger cohorts could yield more reliable results and conclusions.

Mendelian randomization; polygenic risk score; telomere length; type 2 diabetes

2020-03-18;

2020-05-22

上海市衛(wèi)生和計(jì)劃生育委員會(huì)科研課題項(xiàng)目(編號(hào)：20164Y0163)資助[Supported by Foundation of Shanghai Municipal Health Commission (No. 20164Y0163)]

曹嵐，博士，研究方向：復(fù)雜疾病的遺傳學(xué)。E-mail: caolan@sjtu.edu.cn

曹嵐。

10.16288/j.yczz.20-077

2020/9/2 11:40:03

URI: https://kns.cnki.net/kcms/detail/11.1913.R.20200901.1436.001.html

(責(zé)任編委: 陳雁)