Differential Analysis Of Genetic And Risk Factors For Stanford Type A And B Aortic Dissection In A Chinese Han Population

【Background】Aortic dissection(AD)is a common but one of the most destructive cardiovascular diseases,with an aggressive onset,difficult diagnosis,high mortality rate and poor prognosis.Stanford type A aortic dissection is usually more aggressive than Stanford type B,and sudden death from AD rupture is more commonly encountered in forensic pathology practice with Stanford type A.In this study,whole-exome gene sequencing was performed on 49 non-syndromic AD samples,and the common single nucleotide polymorphism(SNP)of 142 AD-related genes from the test results were screened and analyzed,and the first ADrelated SNP-based risk prediction model for Stanford A AD was established.The first ADrelated SNP-based risk prediction model for Stanford type A AD was developed,which provides a new idea to clarify the differences in genetic mechanisms of different Stanford types of AD.In addition,the sequencing results of 22 of these 49 AD cases were screened for pathogenic mutations,and this time we continued to analyze the pathogenic mutations in the results of 27 additional AD samples to accumulate information on AD pathogenic mutations.This study complement the non-syndromic AD-positive causative loci and ADassociated common SNP loci in the Chinese Han population.And informing the prediction of risk for more severe AD phenotype(Stanford type A)in high-risk populations in clinical and forensic pathology practice【Purpose of the study】The objectives of our research were to analyze single nucleotide polymorphisms associated with aortic dissection and to explore the variability in the distribution of common variants in different Stanford types of AD,to construct a Stanford type A AD risk model,to screen for pathogenic mutations,and to broaden the spectrum of pathogenic mutations in aortic dissection.【Methods】(1)AD sample collection and whole-exome sequencing: biological samples of sporadic AD cases were collected and genomic DNA was extracted for whole-exome sequencing.(2)Screening of single nucleotide polymorphisms associated with aortic dissection:Using the whole exome sequencing results of 2573 healthy people as controls,common SNPs with minor allele frequency(MAF)less than 0.05 were screened to compare the variability of AD-associated gene SNPs between AD and control groups,and the variability of distribution between different Stanford type AD and control groups.(3)Comparison of differential distribution of genetic polymorphisms in different types of AD and risk modeling: using Stanford type A AD as the case group and Stanford type B AD as the control group,the susceptibility of common SNPs to different Stanford types of AD was assessed using dominant and recessive models,and multivariate logistic regression models were established by combining SNPs with basic clinical information.(4)Screening of positive pathogenic variants: selection of pathogenic and likely pathogenic variants in 142 AD-related genes from the sequencing results of 27 AD cases.【Results】(1)A total of 39 SNPs were found to have significantly different allele frequency distributions between the AD group and the healthy population control group,including 13 SNPs with different distributions between the Stanford type A AD group and the healthy population control group,12 SNPs with different distributions between the Stanford type B AD group and the healthy population control group,and 1 SNP with a higher MAF in both types of AD than in the healthy population control group.(2)4 SNPs(rs13180243、rs16918110、rs2274963、rs77254078)with significantly different distribution in different Stanford types of AD were screened and combined with gender,age,hypertension,smoking,and drinking as independent variables to construct a Stanford A type logistic regression risk model with an area under the curve of 0.907.(3)Whole-exome sequencing data from 27 AD cases were analyzed,and 19 positive variants were screened,12 of which were de novo variants.【Conclusion】(1)The genotype-positive diagnosis rate was 53.06%(26/49)among 49 AD patients.(2)Thirty-nine common SNPs differed between the AD group and healthy population controls,including 4 SNPs between the Stanford type A AD group and Stanford type B AD group,which were combined with clinical data to construct the Stanford type A entrapment risk model.(3)A total of 41 positive mutations were screened in 49 AD patients,including 23 de novo variants,and 2 de novo variants were identified in 2 AD patients each.The mean age of onset was younger in the "positive mutation AD group" than in the "negative mutation AD group".