Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection  

作　　者：Zongzhe Li Chengming Zhou Lun Tan Peng Chen Yanyan Cao Chenze Li Xianqing Li Jiangtao Yan Hesong Zeng Dao-Wu Wang Dao-Wen Wang 

机构地区：[1]Division of Cardiology,Departments of Internal Medicine and Genetic Diagnosis Center,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology [2]Department of Cardiology,the First Affiliated Hospital,Nanjing Medical University

出　　处：《Science China(Life Sciences)》2017年第1期57-65,共9页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(91439203);National Key Basic Research Program of China(2012CB518004,2012CB517801)

摘　　要：Aortic dissection （AD） is a devastating, heterogeneous condition of aorta. The homeostasis between collagens and matrix metalloproteases （MMPs）/tissue inhibitors of MMPs （TIMPs） system in the extracellular matrix plays an important role for structure and functions of aorta. However, our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited. We analyzed all yet known coding human genes of collagens （45 genes）, MMPs/TIMPs （27 genes） in 702 sporadic AD patients and in 163 matched healthy controls, by using massively targeted next-generation and Sanger sequencing. To define the pathogenesis of potential disease-causing candidate genes, we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats. We identified 257 pathogenic or likely pathogenic variants which involved 88.89% （64/72） genes in collagens-MMPs/TIMPs system and accounted for 31.05% （218/702） sporadic AD patients. In them, 84.86% patients （185/218） carried one variant, 12.84% two variants and 2.30% more than two variants. Importantly, we identified 52 novel probablY pathogenic loss-of-function （LOF） variants （20 nonsense, 16 frameshift, 14 splice sites, one stop-loss, one initiation codon） in 11.06% （50/452） AD patients, which were absent in 163 controls （P=2.5-10-5）. Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems. The Col5a2-/- rats manifested growth retardation and aortic dysplasia. Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis.Aortic dissection(AD) is a devastating,heterogeneous condition of aorta.The homeostasis between collagens and matrix metalloproteases(MMPs)/tissue inhibitors of MMPs(TIMPs) system in the extracellular matrix plays an important role for structure and functions of aorta.However,our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited.We analyzed all yet known coding human genes of collagens(45 genes),MMPs/TIMPs(27genes) in 702 sporadic AD patients and in 163 matched healthy controls,by using massively targeted next-generation and Sanger sequencing.To define the pathogenesis of potential disease-causing candidate genes,we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats.We identified 257 pathogenic or likely pathogenic variants which involved 88.89%(64/72) genes in collagens-MMPs/TIMPs system and accounted for 31.05%(218/702) sporadic AD patients.In them,84.86%patients(185/218) carried one variant,12.84%two variants and 2.30%more than two variants.Importantly,we identified 52 novel probably pathogenic loss-of-function(LOF) variants(20 nonsense,16 frameshift,14 splice sites,one stop-loss,one initiation codon) in 11.06%(50/452) AD patients,which were absent in 163controls(P=2.5×10^(-5)).Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems.The Col5α2^(-/-) rats manifested growth retardation and aortic dysplasia.Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis.

关 键 词：aortic dissection COLLAGEN matrix metalloproteinase next-generation sequencing genetic diagnosis 

分 类 号：R543.1[医药卫生—心血管疾病]