Format

Send to

Choose Destination
Mol Genet Genomics. 2016 Feb;291(1):79-92. doi: 10.1007/s00438-015-1090-y. Epub 2015 Jul 14.

Identification of rare variants in TNNI3 with atrial fibrillation in a Chinese GeneID population.

Author information

1
Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
2
Central Hospital of Suizhou City, Suizhou, 441300, China.
3
Xiang Yang Central Hospital, Xiangyang, 441021, China.
4
Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
5
Department of Molecular Cardiology, Center for Cardiovascular Genetics, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
6
Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
7
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
8
Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. cheng.mian@icloud.com.
9
Key Laboratory of Molecular Biophysics of the Ministry of Education, Center for Human Genome Research and Cardio-X Institute, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China. qkwang@hust.edu.cn.
10
Department of Molecular Cardiology, Center for Cardiovascular Genetics, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA. qkwang@hust.edu.cn.

Abstract

Despite advances by genome-wide association studies (GWAS), much of heritability of common human diseases remains missing, a phenomenon referred to as 'missing heritability'. One potential cause for 'missing heritability' is the rare susceptibility variants overlooked by GWAS. Atrial fibrillation (AF) is the most common arrhythmia seen at hospitals and increases risk of stroke by fivefold and doubles risk of heart failure and sudden death. Here, we studied one large Chinese family with AF and hypertrophic cardiomyopathy (HCM). Whole-exome sequencing analysis identified a mutation in TNNI3, R186Q, that co-segregated with the disease in the family, but did not exist in >1583 controls, suggesting that R186Q causes AF and HCM. High-resolution melting curve analysis and direct DNA sequence analysis were then used to screen mutations in all exons and exon-intron boundaries of TNNI3 in a panel of 1127 unrelated AF patients and 1583 non-AF subjects. Four novel missense variants were identified in TNNI3, including E64G, M154L, E187G and D196G in four independent AF patients, but no variant was found in 1583 non-AF subjects. All variants were not found in public databases, including the ExAC Browser database with 60,706 exomes. These data suggest that rare TNNI3 variants are associated with AF (P = 0.03). TNNI3 encodes troponin I, a key regulator of the contraction-relaxation function of cardiac muscle and was not previously implicated in AF. Thus, this study may identify a new biological pathway for the pathogenesis of AF and provides evidence to support the rare variant hypothesis for missing heritability.

KEYWORDS:

Atrial fibrillation (AF); Cardiac troponin I; Hypertrophic cardiomyopathy; TNNI3 mutations; Whole exome sequencing

PMID:
26169204
PMCID:
PMC4713376
DOI:
10.1007/s00438-015-1090-y
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center