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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

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Front. Med.    2021, Vol. 15 Issue (3) : 438-447    https://doi.org/10.1007/s11684-020-0826-1
RESEARCH ARTICLE
Identification of COL3A1 variants associated with sporadic thoracic aortic dissection: a case--control study
Yanghui Chen1,2, Yang Sun1,2, Zongzhe Li1,2, Chenze Li1,2, Lei Xiao1,2, Jiaqi Dai1,2, Shiyang Li1,2,3, Hao Liu1,2, Dong Hu1,2, Dongyang Wu1,2, Senlin Hu1,2, Bo Yu1,2, Peng Chen1,2, Ping Xu4, Wei Kong5, Dao Wen Wang1,2()
1. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2. Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan 430030, China
3. The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi 832008, China
4. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
5. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
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Abstract

Thoracic aortic dissection (TAD) without familial clustering or syndromic features is known as sporadic TAD (STAD). So far, the genetic basis of STAD remains unknown. Whole exome sequencing was performed in 223 STAD patients and 414 healthy controls from the Chinese Han population (N = 637). After population structure and genetic relationship and ancestry analyses, we used the optimal sequence kernel association test to identify the candidate genes or variants of STAD. We found that COL3A1 was significantly relevant to STAD (P = 7.35 × 10−6) after 10 000 times permutation test (P = 2.49 × 10−3). Moreover, another independent cohort, including 423 cases and 734 non-STAD subjects (N = 1157), replicated our results (P = 0.021). Further bioinformatics analysis showed that COL3A1 was highly expressed in dissected aortic tissues, and its expression was related to the extracellular matrix (ECM) pathway. Our study identified a profile of known heritable TAD genes in the Chinese STAD population and found that COL3A1 could increase the risk of STAD through the ECM pathway. We wanted to expand the knowledge of the genetic basis and pathology of STAD, which may further help in providing better genetic counseling to the patients.
Keywords sporadic thoracic aortic dissection      exome sequencing      gene COL3A1      case–control study      extracellular matrix     
Corresponding Author(s): Dao Wen Wang   
Just Accepted Date: 26 April 2021   Online First Date: 28 May 2021    Issue Date: 18 June 2021
 Cite this article:   
Yanghui Chen,Yang Sun,Zongzhe Li, et al. Identification of COL3A1 variants associated with sporadic thoracic aortic dissection: a case--control study[J]. Front. Med., 2021, 15(3): 438-447.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0826-1
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I3/438
Type A (n = 130) Type B (n = 90)
Clinical characteristics
Male (%) 104 (80.00) 71 (78.89)
Age (year) 50.72±10.35 51.46±9.81
BMI (kg/m2) 24.93±4.47 24.61±4.36
SBP (mmHg) 141.00±40.00 148.00±33.50
DBP (mmHg) 78.00±20.00 85.00±18.25
Epidemiology
Smoking (%) 37 (27.46) 23 (25.56)
Drinking (%) 23 (17.69) 11 (21.11)
Hypertension (%) 77 (59.23) 41 (45.56)
Diagnostic imaging
CT/CTA (%) 130 (100) 90 (100)
Echocardiography (%) 121 (93.08) 82 (91.11)
Blood serum laboratory tests
WBC (×109/L) 12.34±5.63 9.66±4.92
Hb (g/L) 132.50±21.00 130.50±26.00
GLU (mmol/L) 7.42±1.84 6.78±1.79
AST (IU/L) 21.00±19.00 16.00±15.50
ALT (IU/L) 21.50±27.50 19.00±10.25
BUN (mmol/L) 7.26±4.12 5.52±2.89
Cr (µmol/L) 96.00±50.00 77.00±31.75
TC (mmol/L) 3.78±1.21 3.95±1.00
TG (mmol/L) 1.03±0.64 1.08±0.82
LDL (mmol/L) 2.48±0.87 2.47±0.92
HDL (mmol/L) 1.07±0.38 1.09±0.43
Extent of aortic dissection n = 124 n = 90
Supra-aortic vessels (%) 121 (97.58) −
Arch (%) 121 (97.58) −
Descending thoracic aorta (%) 117 (94.35) 82 (91.11)
Abdominal aorta (%) 88 (70.97) 80 (88.89)
Superior mesenteric artery (%) 33 (26.61) 20 (22.22)
Left renal artery (%) 49 (39.52) 21 (23.33)
Right renal artery (%) 30 (24.19) 23 (25.56)
Iliac arteries (%) 49 (39.52) 37 (41.11)
Echocardiography n = 124 n = 90
Ascending aortic dimension (mm) 40.00±7.25 37.00±4.50
Dilation of aortic dimension (%) 94 (77.69) 36 (43.33)
Ejection fraction (%) 60.00±5.00 60.00±2.00
Ejection fraction<50% (%) 5 (4.13) 0 (0)
Tab.1  Clinical characteristics of all STAD cases
Fig.1  Variants in genes putatively associated with HTAD. All rare functional damaging variants (missense variants, frame shift variants, and nonsense variants) in the exome are shown. Each bar represents one of the individuals, and each row represents a gene. The colors represent different types of variants and clinical phenotypes. The top bar plot indicates the number of functional variants in each person.
Fig.2  Gene-based associated test identified COL3A1 in STAD. (A) Procedure of variant filtering for gene-based associated test. (B) Heatmap showing the P value of candidate genes by SKAT-O in discovery cohorts; + indicates that cases carried more of the rare deleterious variants, and − indicates that controls carried more. (C) Mutation needle plot of COL3A1 rare deleterious variants.
Subject Age Gender Type Amino acid Exon MAF in 1000 Genomes (EAS) MAF in ExAC (EAS) MAF in gnomAD
ADx086 36 F B p.P566L 24 0.006 0.0038 0.0035
ADx099 46 M A p.A1045T 43 0.0069 0.0053 0.0055
ADx203 49 M B p.A1045T 43 0.0069 0.0053 0.0055
ADx219 43 M A p.P566L 24 0.006 0.0038 0.0035
ADx477 50 M A p.A1045T 43 0.0069 0.0053 0.0055
ADx506 49 M A p.P566L 24 0.006 0.0038 0.0035
ADx540 63 M B p.P566L 24 0.006 0.0038 0.0035
ADx629 33 M A p.P566L 24 0.006 0.0038 0.0035
ADx692 64 M B p.R413Q 18 ND 0.0002 0.0002
ADx720 57 F B p.R1100H 45 ND 0.0002 0.0002
ADx736 53 M A p.G888C 39 ND ND ND
ADx823 55 M A p.P566L 24 0.006 0.0038 0.0035
ADx825 54 M A p.R1255H 48 ND 0 0
ADx826 49 M A p.P566L 24 0.006 0.0038 0.0035
Tab.2  Details of rare deleterious variants from COL3A1 in the STAD population
Fig.3  COL3A1 analysis in GSE52093 and the GTEx database. (A) COL3A1 expression in whole body organ and data from the GTEx database. (B) COL3A1 overexpressed in aorta with dissection from GSE52093. TAD refers to dissected aorta from TAD patients; normal means aorta without dissection from non-TAD individuals. (C) Volcano plot showing the results of GSEA using GSE52093 case data. The right shows the top 10 pathways enriched in COL3A1 high level. COL3A1 high level refers to the significant pathway enriched by COL3A1 high-level associated genes, COL3A1 low level refers to the significant pathway enriched by COL3A1 low-level associated genes, and stable refers to insignificant pathway. (D) GSEA results revealing that the ECM pathway was highly enriched in COL3A1-overexpressed genes that are highly expressed when COL3A1 is also highly expressed and data from the GTEx database.
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