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The genetic variation rs12143842 in NOS1AP increases idiopathic ventricular tachycardia risk in Chinese Han populations.

ABSTRACT: Genome-wide association studies identified that the common T of rs12143842 in NOS1AP is associated with a QT/QTc interval in European populations. In this study, we test the association between the variation rs12143842 in NOS1AP and idiopathic ventricular tachycardia (IVT). A case-control association study examining rs12143842 was performed in two independent cohorts. The Northern cohort enrolled 277 IVT patients and 728 controls from a Chinese Gene ID population. The Central cohort enrolled 301 IVT patients and 803 matched controls. Genotyping was performed using high-resolution melt analysis. The minor T allele of the rs12143842 SNP was significantly associated with decreased IVT risk in the Northern cohort (adjusted P?=?0.024, OR 0.71(0.52~0.96)), and this association was replicated in an independent Central Gene ID cohort (adjusted P?=?0.029, OR 0.78 (0.62~0.97)). The association was more significant in the combined population (adjusted P?=?0.001, OR 0.76 (0.64~0.90)). The P values for the genotypic association were significant for the dominant (P?

SUBMITTER: Zhang R

PROVIDER: S-EPMC5567283 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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The genetic variation rs12143842 in NOS1AP increases idiopathic ventricular tachycardia risk in Chinese Han populations.

Zhang Ronfeng R Chen Feifei F Yu Honjiu H Gao Lianjun L Yin Xiaomeng X Dong Yingxue Y Yang Yanzong Y Xia Yunlong Y

Scientific reports 20170821 1

Genome-wide association studies identified that the common T of rs12143842 in NOS1AP is associated with a QT/QTc interval in European populations. In this study, we test the association between the variation rs12143842 in NOS1AP and idiopathic ventricular tachycardia (IVT). A case-control association study examining rs12143842 was performed in two independent cohorts. The Northern cohort enrolled 277 IVT patients and 728 controls from a Chinese Gene ID population. The Central cohort enrolled 301 ...[more]

PMID: 28827735

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Project description:BackgroundVentricular tachycardia (VT) is a major cause of sudden cardiac death (SCD). Clinical investigations can sometimes fail to identify the underlying cause of VT and the event is classified as idiopathic (iVT). VT contributes significantly to the morbidity and mortality in patients with coronary artery disease (CAD) and dilated cardiomyopathy (DCM). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility screening for disease-predisposing variants could improve VT diagnostics and prevent SCD in patients.MethodsNinety-two patients diagnosed with coronary heart disease (CHD), DCM, or iVT were included in our study. We evaluated genetic profiles and variants in known cardiac risk genes by targeted next generation sequencing (NGS) using a newly designed custom panel of 96 genes. We hypothesized that shared morphological and phenotypical features among these subgroups may have an overlapping molecular base. To our knowledge, this was the first study of the deep sequencing of 96 targeted cardiac genes in Kazakhstan. The clinical significance of the sequence variants was interpreted according to the guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015. The ClinVar and Varsome databases were used to determine the variant classifications.ResultsTargeted sequencing and stepwise filtering of the annotated variants identified a total of 307 unique variants in 74 genes, totally 456 variants in the overall study group. We found 168 mutations listed in the Human Genome Mutation Database (HGMD) and another 256 rare/unique variants with elevated pathogenic potential. There was a predominance of high- to intermediate pathogenicity variants in LAMA2, MYBPC3, MYH6, KCNQ1, GAA, and DSG2 in CHD VT patients. Similar frequencies were observed in DCM VT, and iVT patients, pointing to a common molecular disease association. TTN, GAA, LAMA2, and MYBPC3 contained the most variants in the three subgroups which confirm the impact of these genes in the complex pathogenesis of cardiomyopathies and VT. The classification of 307 variants according to ACMG guidelines showed that nine (2.9%) variants could be classified as pathogenic, nine (2.9%) were likely pathogenic, 98 (31.9%) were of uncertain significance, 73 (23.8%) were likely benign, and 118 (38.4%) were benign. CHD VT patients carry rare genetic variants with increased pathogenic potential at a comparable frequency to DCM VT and iVT patients in genes related to sarcomere function, nuclear function, ion flux, and metabolism.ConclusionsIn this study we showed that in patients with VT secondary to coronary artery disease, DCM, or idiopathic etiology multiple rare mutations and clinically significant sequence variants in classic cardiac risk genes associated with cardiac channelopathies and cardiomyopathies were found in a similar pattern and at a comparable frequency.

Dataset Information

The genetic variation rs12143842 in NOS1AP increases idiopathic ventricular tachycardia risk in Chinese Han populations.

Publications

The genetic variation rs12143842 in NOS1AP increases idiopathic ventricular tachycardia risk in Chinese Han populations.

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