用以评估和校准人类生物学年龄的表观遗传学时钟的构建  

An epigenetic clock model for assessing the human biological age of healthy aging

作　　者：倪晓琳 原慧萍[1] 焦娟 王钊平 苏华斌 吕渊[4] 庞国防[4] 张为[4] 孙亮[1] 胡才友[4] 杨泽[1] Ni Xiaolin;Yuan Huiping;Jiao Juan;Wang Zhaoping;Su Huabin;Lyu Yuan;Pang Guofang;Zhang Wei;Sun Liang;Hu Caiyou;Yang Ze(The Key Laboratory of Geriatrics,Beijing Institute of Geriatrics,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing Hospital/National Center of Gerontology of National Health Commission,Beijing 100730,China;Clinical Lab,the Seventh Medical Center of Chinese People′s Liberation Army General Hospital,Beijing 100700,China;Department of Prevention and Health Protection,Jiangbin Hospital,Guangxi Zhuang Autonomous Region,Nanning 530021,China;Neurological Department,Jiangbin Hospital,Guangxi Zhuang Autonomous Region,Nanning 530021,China)

机构地区：[1]北京医院,国家老年医学中心,国家卫生健康委北京老年医学研究所,国家卫生健康委老年医学重点实验室,中国医学科学院老年医学研究院,北京100730 [2]中国解放军总医院第七医学中心检验科,北京100700 [3]广西壮族自治区江滨医院预防保健科,南宁530021 [4]广西壮族自治区江滨医院神经内科,南宁530021

出　　处：《中华医学杂志》2022年第2期119-124,共6页National Medical Journal of China

基　　金：国家自然科学基金(9184910151,81870552,81400790,81460203,31760299,81571385,91849132,81872096);国家重点研发计划(2018YFC2000400);广西自然科学基金(2014GXNSFDA118028、2018GXNSFAA138156、桂科自0991198);广西壮族自治区卫生和计划生育委员会自筹经费科研课题(Z20170162);北京医院创新项目(BJ-2018-139);中国医学科学院研究院基金(2018RC330003)。

摘　　要：目的构建适用于评估和校准人类生物学年龄的表观遗传学时钟模型。方法于2019年7月1日至11月30日从广西壮族自治区长寿队列选取186名研究对象,于2020年10月1日至12月31日从解放军总医院第七医学中心体检人群选取124名研究对象。采用自制问卷收集人口学特征、家族疾病史等资料,通过体格检查测量对象的心率和血压,采集空腹外周静脉血,分别检测空腹血糖(FBG)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)和端粒长度,采用靶向甲基化位点测序检测EDARADD cg09809672、IPO8 cg19722847、NHLRC1 cg22736354、P2RX6 cg05442902和SCGN cg06493994基因位点的甲基化水平。排除DNA甲基化和端粒长度检测质量控制不合格的54名对象,最终对256名对象资料进行分析。分析不同年龄段甲基化水平变化情况,采用多重线性回归法构建生物学年龄预测模型,采用Kendal秩相关分析评价年龄差值[即(公历年龄-生物学年龄)]与端粒长度的相关性,比较各年龄组不同年龄差值对象的健康相关指标。结果对象年龄的M(Q1,Q3)为67(51,91)岁,其中女性166名(64.84%)。随年龄增加,基因位点甲基化水平分别呈下降(EDARADD cg09809672、IPO8 cg19722847和P2RX6 cg05442902)和上升趋势(NHLRC1 cg22736354和SCGN cg06493994)(均P<0.05)。所构建的生物学年龄预测模型为:Y=-53.121×EDARADD cg09809672-137.564×IPO8 cg19722847+141.040×NHLRC1 cg22736354-67.893×P2RX6 cg05442902+149.547×SCGN cg06493994+4.592×sex+64.185(R2=0.86,P<0.001),式中Y为生物学年龄,方程各项依次为5个基因位点甲基化水平、性别(男性=1,女性=2)和截距。年龄差值与端粒长度Kendall秩相关系数为0.731(P<0.001)。与年龄差值<0的对象相比,年龄差值≥0的对象未成年期收缩压较高[分别为(88.50±8.89)和(109.83±9.48)mmHg,1 mmHg=0.133 kPa],青壮年期TC较低[分别为(5.48±0.23)和(3.98±0.54)mmol/L],TG较低[分别为Objective To construct an epigenetic clock model for assessing and calibrating human biological age.Methods Convenience sampling was used to select 186 subjects from the longevity cohort of Guangxi Zhuang Antonornous Region from July 1 to November 30,2019,and 124 subjects from the physical examination population of the Seventh Medical Center of the PLA General Hospital from October 1 to December 31,2020.Self-designed questionnaire was applied to collect demographic characteristics and family history of disease.Physical examination was applied to determine heart rate and blood pressure.Fasting peripheral venous blood was drawn for determination of fasting plasma glucose,plasma total cholesterol,triglyceride,plasma high-density lipoprotein cholesterol,plasma low-density lipoprotein cholesterol and telomere length.Methylation levels of EDARADD cg09809672,IPO8 cg19722847,NHLRC1 cg22736354,P2RX6 cg05442902 and SCGN cg06493994 were detected by targeted methylation site sequencing.A total of 54 subjects with unqualified quality control of DNA methylation and telomere length were excluded,and 256 subjects′data were finally analyzed.Trend test was used for the change of methylation level among different ages groups,multiple linear regression method was used to build prediction models of biological age.Kendal rank correlation analysis was used to evaluate the correlation of age gap(Gregorian calendar age minus biological age)with telomere length.Independent sample t-test was used to compare the health-related indicators between subjects with different age gap within different age groups.Results The M(Q1,Q3)of age of subjects were 67(51,91)years old,including 166 females(64.84%).With increase of age,the methylation levels of gene loci were decreased(EDARADD cg09809672,IPO8 cg19722847 and P2RX6 cg05442902)and increased(NHLRC1 cg22736354 and SCGN cg06493994)(all P values<0.05).The established biological age prediction model was as follows:Y=-53.121×EDARADD cg09809672-137.564×IPO8 cg19722847+141.040×NHLRC1 cg22736354-67.8

关 键 词：DNA甲基化 时间生物学现象 生物学年龄 表观遗传学时钟 生物信息学分析 

分 类 号：R394[医药卫生—医学遗传学]