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

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。

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.