PMID- 27975164 OWN - NLM STAT- MEDLINE DCOM- 20170721 LR - 20170817 IS - 1869-1889 (Electronic) IS - 1674-7305 (Linking) VI - 60 IP - 1 DP - 2017 Jan TI - Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection. PG - 57-65 LID - 10.1007/s11427-016-0333-3 [doi] AB - 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=2.5x10(-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. FAU - Li, Zongzhe AU - Li Z AD - 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. FAU - Zhou, Chengming AU - Zhou C AD - 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. FAU - Tan, Lun AU - Tan L AD - 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. FAU - Chen, Peng AU - Chen P AD - 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. FAU - Cao, Yanyan AU - Cao Y AD - 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. FAU - Li, Chenze AU - Li C AD - 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. FAU - Li, Xianqing AU - Li X AD - 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. FAU - Yan, Jiangtao AU - Yan J AD - 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. FAU - Zeng, Hesong AU - Zeng H AD - 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. FAU - Wang, Dao-Wu AU - Wang DW AD - Department of Cardiology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China. dwwang@tjh.tjmu.edu.cn. FAU - Wang, Dao-Wen AU - Wang DW AD - 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. LA - eng PT - Journal Article DEP - 20161213 PL - China TA - Sci China Life Sci JT - Science China. Life sciences JID - 101529880 RN - 0 (Tissue Inhibitor of Metalloproteinases) RN - 9007-34-5 (Collagen) RN - EC 3.4.24.- (Matrix Metalloproteinases) RN - Aortic Aneurysm, Familial Thoracic 1 SB - IM MH - Animals MH - Aortic Aneurysm, Thoracic/*genetics MH - Aortic Diseases/genetics MH - Base Sequence MH - Collagen/*genetics MH - Female MH - Gene Expression Profiling MH - Gene Knockout Techniques MH - Genetic Predisposition to Disease/*genetics MH - Humans MH - Male MH - Matrix Metalloproteinases/*genetics MH - *Mutation MH - Pedigree MH - Rats, Sprague-Dawley MH - Reverse Transcriptase Polymerase Chain Reaction MH - Risk Factors MH - Sequence Analysis, RNA MH - Thoracic Arteries/pathology MH - Tissue Inhibitor of Metalloproteinases/genetics OTO - NOTNLM OT - aortic dissection OT - collagen OT - genetic diagnosis OT - matrix metalloproteinase OT - next-generation sequencing EDAT- 2016/12/16 06:00 MHDA- 2017/07/22 06:00 CRDT- 2016/12/16 06:00 PHST- 2016/10/09 00:00 [received] PHST- 2016/11/01 00:00 [accepted] PHST- 2016/12/16 06:00 [pubmed] PHST- 2017/07/22 06:00 [medline] PHST- 2016/12/16 06:00 [entrez] AID - 10.1007/s11427-016-0333-3 [pii] AID - 10.1007/s11427-016-0333-3 [doi] PST - ppublish SO - Sci China Life Sci. 2017 Jan;60(1):57-65. doi: 10.1007/s11427-016-0333-3. Epub 2016 Dec 13.