端粒长度与2型糖尿病：孟德尔随机化研究与多基因风险评分分析

doi:10.16288/j.yczz.20-077

遗传 ›› 2020, Vol. 42 ›› Issue (9): 882-888.doi: 10.16288/j.yczz.20-077

端粒长度与2型糖尿病：孟德尔随机化研究与多基因风险评分分析

曹岚^1,³, 李志强^2,³, 师咏勇³, 刘赟⁴

^1. 上海市妇幼保健中心,上海 200062
^2. 青岛大学生物医学研究院(暨上海交通大学Bio-X研究院青岛分院),青岛 266003
^3. 上海交通大学Bio-X研究院,遗传发育与精神神经疾病教育部重点实验室,上海 200030
^4. 复旦大学生物医学研究院,上海 200032;

收稿日期:2020-03-18 修回日期:2020-05-22 出版日期:2020-09-20 发布日期:2020-08-28
作者简介:曹岚,博士,研究方向：复杂疾病的遗传学。E-mail: caolan@sjtu.edu.cn
基金资助:
上海市卫生和计划生育委员会科研课题项目资助编号(20164Y0163)

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

Lan Cao^1,³, Zhiqiang Li^2,³, Yongyong Shi³, Yun Liu⁴

^1. Shanghai Center for Women and Children’s Health, Shanghai 200062, China;
^2. The Affiliated Hospital of Qingdao University, The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao 266003, China
^3. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China
^4. Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;

Received:2020-03-18 Revised:2020-05-22 Online:2020-09-20 Published:2020-08-28
Supported by:
Supported by Foundation of Shanghai Municipal Health Commission No(20164Y0163)

摘要/Abstract

摘要：

多项观察性研究表明,端粒长度缩短与2型糖尿病(type 2 diabetes, T2D)之间存在关联。然而,传统观察性研究结果常受到混杂因素和反向因果关联的影响,端粒长度与T2D是否存在因果关联尚不明确。本研究在中国汉族人群中利用孟德尔随机化(Mendelian randomization, MR)和多基因风险评分(polygenic risk score, PRS)方法探索端粒长度与T2D的因果关系。MR研究选取8个与端粒长度相关的独立遗传变异作为工具变量,利用2632例中国汉族人群T2D全基因组关联研究(genome-wide association study, GWAS)数据,检验遗传预测的端粒长度与T2D的关系。利用中国汉族人群GWAS数据,采用PRS分析评价端粒长度PRS与T2D的关系。MR研究共纳入1318例T2D患者和1314例正常对照,逆方差加权、MR-Egger回归、简单中位数和加权中位数法估计的OR值分别为0.78 (95% CI: 0.36~1.68, P = 0.522)、0.23 (95% CI: 0.01~7.64, P = 0.412)、0.60 (95% CI: 0.28~ 1.28, P = 0.185)和0.64 (95% CI: 0.31~1.33, P = 0.233),遗传预测的较长端粒长度与T2D之间不存在关联。PRS分析未发现端粒长度PRS与T2D显著关联的一致结果。本研究采用MR和PRS方法未发现端粒长度与T2D具有因果关联,后续研究中增大样本量有助于得出更可靠的结论。

关键词: 孟德尔随机化, 多基因风险评分, 端粒长度, 2型糖尿病

Abstract:

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% CI: 0.36 ~ 1.68, P = 0.522; OR = 0.23, 95% CI: 0.01 ~ 7.64, P = 0.412; OR = 0.60, 95% CI: 0.28 ~ 1.28, P = 0.185; OR = 0.64, 95% CI: 0.31 ~ 1.33,P = 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.

Key words: Mendelian randomization, polygenic risk score, telomere length, type 2 diabetes

曹岚, 李志强, 师咏勇, 刘赟. 端粒长度与2型糖尿病：孟德尔随机化研究与多基因风险评分分析[J]. 遗传, 2020, 42(9): 882-888.

Lan Cao, Zhiqiang Li, Yongyong Shi, Yun Liu. Telomere length and type 2 diabetes: Mendelian randomization study and polygenic risk score analysis[J]. Hereditas(Beijing), 2020, 42(9): 882-888.

图/表 3

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SNP	Chr.	临近基因	效应等位基因	MAF	端粒长度		T2D
SNP	Chr.	临近基因	效应等位基因	MAF	β^*	P值	β	P值
rs10936599	3	TERC	C	0.252	0.117	2.54×10^-31	-0.038	0.53
rs2736100	5	TERT	C	0.486	0.094	4.38×10^-19	-0.053	0.37
rs7675998	4	NAF1	G	0.217	0.090	4.35×10^-16	-0.077	0.32
rs4387287	10	OBFC1	A	NA	0.100	2.33×10^-11	-0.114	0.17
rs8105767	19	ZNF208	G	0.291	0.058	1.11×10^-09	-0.027	0.69
rs755017	20	RTEL1	G	0.131	0.074	6.71×10^-09	0.095	0.12
rs3027234	17	CTC1	C	0.179	0.057	2.29×10^-08	-0.323	0.04
rs11125529	2	ACYP2	A	0.142	0.067	4.48×10^-08	0.135	0.08

端粒长度与2型糖尿病：孟德尔随机化研究与多基因风险评分分析

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

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