title: Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection.
abstract: 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.
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Zongzhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Chengming
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Lun
authors.initials: L
authors.lastname: Tan
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Chenze
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Xianqing
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Yan
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Hesong
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China. dwwang@tjh.tjmu.edu.cn.
authors.forename: Dao-Wu
authors.initials: DW
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. david37212@hotmail.com.
authors.forename: Dao-Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000818:Animals; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics*; D001018:Aortic Diseases / Q000235:genetics; D001483:Base Sequence; D003094:Collagen / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D017423:Sequence Analysis, RNA; D013895:Thoracic Arteries / Q000473:pathology; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D003094:Collagen; D020782:Matrix Metalloproteinases
keywords: aortic dissection; collagen; genetic diagnosis; matrix metalloproteinase; next-generation sequencing