The Association Study Of Telomerase TERT Gene Genetic Variation And Telomere Length With The Genetic Susceptibility To Cerebral Small Vessel Disease

Objective:Observational studies have found that telomerase TERT gene and short leucocytetelomere length（LTL）may be related to the occurrence and development of cerebrovascular diseases.However,it is still unclear whether telomerase gene variation increases the risk of cerebral small vessel disease（CSVD）and whether there is a causal association between LTL and CSVD.Methods:Based on analysis of genome-wide association GWAS database published studies,as well as selection of telomerase TERT gene minor allele frequency of 5%or more of five single nucleotide polymorphisms（SNPs）,in 307 patients with CSVD and320 healthy controls in the TERT genotyping and LTL determination,through four kinds of genetic model to evaluate the relationship between SNPs and CSVD risk.The first MR analysis of CSVD was performed by selecting SNPs associated with LTL and PRS constructed based on multiple SNPs as genetic instrumental variables（Ⅳ）,and the causal relationship between LTL and CSVD risk was predicted.Results:A total of 307 case groups and 320 healthy subjects were included as controls.In case group the mean age,body weight and body mass index（BMI）,smoking,blood pressure,blood glucose,low density lipoprotein and homocysteinewere significantly higher than those in control group（P<0.05）.There were no significant differences in gender,height,triglyceride,cholesterol,alcohol consumption,or exercise between the two groups.Allele model analysis showed that the allele frequency of TERT gene rs2853676（P=0.001）and rs2075786（P=0.006）was significantly different between the case group and the control group.Correlation analysis of genetic model showed two significant SNP loci:rs2075786 co-dominant model genotype"A/A"and dominant model genotype"A/G"and"A/A"and log-additive model genotype,rs2853676co-dominant model genotype"C/T"and dominant model genotype"T/T"and log-additive model genotype may be significantly associated with increased risk of CSVD.The genotype"A/G"of the superdominant model of rs2736122 showed significant differences only after correction for age,sex,smoking,drinking and exercise.Further analysis of LTL results showed that there was a negative correlation between LTL and age,and there was a significant difference between the case group and the control group（P<0.001）.MR analysis of 3 SNPs showed a causal association between short LTL and increased risk of CSVD.In addition,short LTL genetic prediction（calculated by PRS）was strongly associated with increased risk of CSVD(OR=0.30,95%CI:0.16-0.56,P=1.84×10^-4).Conclusion:Studies based on Chinese Han population showed that hypertension,hyperglycemia,low density lipoprotein and homocysteine,smoking and other factors may be independent risk factors for cerebrovascular disease.Allelic model analysis and multiple genetic model analysis showed that genetic variation of TERT gene could increase the risk of CSVD.In addition,leukocyte telomere length（LTL）was negatively correlated with age,and there was no correlation between LTL length and sex difference.By using LTL-related SNPs as instrumental variables and using MR method to construct individual polygenic genetic risk score（PRS）,we found that there is a causal association between LTL and CSVD,and short LTL may be a potential causal risk factor for CSVD.