Functional variants in the LC3B gene promoter in acute myocardial infarction

Coronary artery disease (CAD) including acute myocardial infarction (AMI) is an inflammatory and metabolic disease mainly caused by atherosclerosis. Dysfunctional autophagy has been associated with abnormal lipid metabolism and inflammation. In previous studies, we have reported altered autophagic activity in AMI patients. As autophagy-related protein 5 (ATG5) is a core protein in autophagy, we speculated that altered ATG5 level may contribute to CAD and AMI development. In this study, the promoter of the ATG5 gene was genetically and functionally investigated in large groups of AMI patients (n = 378) and ethnic-matched healthy controls (n = 386). The results showed that a total of 15 genetic variants including 6 single-nucleotide polymorphisms (SNPs) in the ATG5 gene promoter were found in this study population. A novel deletion variant (g.106326168_70delTCT) and an SNP [g.106325757C > G (rs190825454)] were found in one 66-year-old male patient with non-ST-segment elevated AMI, but in none of controls. In cultured HEK-293 and H9c2 cells, the deletion variant significantly decreased the transcriptional activity of the ATG5 gene promoter (P<0.01). In contrast, the genetic variants either identified only in controls or found in both AMI patients and controls did not affect the transcriptional activity of the ATG5 gene promoter (P>0.05). Furthermore, an electrophoretic mobility shift assay showed that the deletion variant evidently affected the binding of a transcription factor. Therefore, the genetic variant identified in AMI may affect the activity of the ATG5 gene promoter and change the ATG5 level, contributing to AMI as a rare risk factor.

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Genetic variants of VEGFR-1 gene promoter in acute myocardial infarction

Human Genomics ◽

10.1186/s40246-019-0243-1 ◽

2019 ◽

Vol 13 (1) ◽

Cited By ~ 1

Author(s):

Haihua Wang ◽

Shufang Zhang ◽

Na Wang ◽

Jie Zhang ◽

Mingkai Chen ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Genetic Variants ◽

Intracellular Signaling ◽

Transcriptional Activity ◽

Complex Disease ◽

Cardiac Fibrosis ◽

Gene Promoter ◽

Common Complex Disease ◽

Mobility Shift

Abstract Background Coronary artery disease (CAD) including acute myocardial infarction (AMI) is a common complex disease caused by atherosclerosis. Vascular epithelial growth factor receptor-1 (VEGFR-1) stimulates angiogenesis and vascular permeability, and functions as a decoy to sequester VEGF and prevent initiation of intracellular signaling. VEGFR-1 knockout mice exhibit significantly higher mortality due to heart failure, cardiac hypertrophy, and cardiac dysfunction. An evident increase in macrophage infiltration and cardiac fibrosis are also observed after transverse aortic constriction. Therefore, VEGFR-1 gene variants may be involved in CAD. In this study, VEGFR-1 gene promoter was genetically and functionally analyzed in large cohorts of AMI patients and ethnic-matched controls. Results A total of 16 DNA sequence variants (DSVs) including six single-nucleotide polymorphisms (SNPs) were found in the VEGFR-1 gene promoter and 5′-untranslated region. Five novel DSVs and one SNP were only identified in AMI patients group. These DSVs and SNP significantly altered the transcriptional activity of the VEGFR-1 gene promoter in both HEK-293 and H9c2 cells (P < 0.05). Further electrophoretic mobility shift assay indicated that the DSVs and SNPs evidently affected the binding of transcription factors. Conclusions The genetic variants in VEGFR-1 gene identified in AMI patients may alter the transcriptional activity of the VEGFR-1 gene promoter and change VEGFR-1 level, contributing to AMI development.

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Higher DNA methylation of ABO gene promoter is associated with acute myocardial infarction in a hospital-based population in Karachi

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.36.3.1406 ◽

2020 ◽

Vol 36 (3) ◽

Author(s):

Farzana Abubakar Yousuf ◽

Khawar Kazmi ◽

Junaid Iqbal ◽

Nikhat Ahmed ◽

Mohammad Perwaiz Iqbal

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Dna Methylation ◽

Methylation Status ◽

Gene Promoter ◽

P Value ◽

Healthy Controls ◽

Pakistani Population ◽

Age Range ◽

Relationship Of

Objective: To find out if there is any relationship of methylation status of ABO gene promoter with the risk of acute myocardial infarction (AMI) in a hospital-based Pakistani population in Karachi, Pakistan. Methods: A case control study comprising of 39 adult AMI patients (both males and females; age range 30-70 years) and 39 normal healthy controls (both males and females and similar age range) nested in a large study (to see the relationship of ABO genotypes with AMI) was designed to investigate the methylation status of ABO gene promoter and its association with AMI. The study was carried out at the Aga Khan University, Karachi during July 2018 to June 2019. DNA isolated from samples of AMI patients and normal healthy controls were converted into bisulphite DNA using a kit method. Methylation specific polymerase chain reaction was carried out to determine the methylation status of ABO gene promoter in both cases and controls. Logistic regression was used to find out any association between increased methylation status of ABO gene promoter and risk of AMI. Results: A significantly higher percentage of DNA methylation of the ABO gene promoter was observed in AMI patients as compared to normal healthy controls (82.1% vs. 35.9%; p value <0.001). This higher methylation status of ABO gene promoter was associated with AMI and the odds of AMI in this population were more than 6-fold in subjects with methylated gene promoter compared to those with unmethylated gene promoter after adjusting with age and waist circumference [AOR (95% CI) = 6.27 (1.76-22.3); p value = 0.005]. Conclusion: The ABO gene promoter’s hypermethylation appears to be increasing the risk of AMI in a hospital-based Pakistani population in Karachi, Pakistan. doi: https://doi.org/10.12669/pjms.36.3.1406 How to cite this:Yousuf FA, Kazmi K, Iqbal J, Ahmed N, Iqbal MP. Higher DNA methylation of ABO gene promoter is associated with acute myocardial infarction in a hospital-based population in Karachi. Pak J Med Sci. 2020;36(3):---------. doi: https://doi.org/10.12669/pjms.36.3.1406 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Identification and functional analysis of genetic variants in TBX5 gene promoter in patients with acute myocardial infarction

BMC Cardiovascular Disorders ◽

10.1186/s12872-019-1237-6 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Shuai Wang ◽

Jie Zhang ◽

Xiaohui He ◽

Yexin Zhang ◽

Jing Chen ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Transcription Factors ◽

Complex Disease ◽

Cultured Cells ◽

Normal Population ◽

Gene Promoter ◽

Epidemiological Studies ◽

Common Complex Disease ◽

Tbx5 Gene

Abstract Background Coronary artery disease (CAD), including acute myocardial infarction (AMI), is a common complex disease. Although a great number of genetic loci and variants for CAD have been identified, genetic causes and underlying mechanisms remain largely unclear. Epidemiological studies have revealed that CAD incidence is strikingly higher in patients with congenital heart disease than that in normal population. T-box transcription factors play critical roles in embryonic development. In particular, TBX5 as a dosage-sensitive regulator is required for cardiac development and function. Thus, dysregulated TBX5 gene expression may be involved in CAD development. Methods TBX5 gene promoter was genetically and functionally analysed in large groups of AMI patients (n = 432) and ethnic-matched healthy controls (n = 448). Results Six novel heterozygous DNA sequence variants (DSVs) in the TBX5 gene promoter (g.4100A > G, g.4194G > A, g.4260 T > C, g.4367C > A, g.4581A > G and g.5004G > T) were found in AMI patients, but in none of controls. These DSVs significantly changed the activity of TBX5 gene promoter in cultured cells (P < 0.05). Furthermore, three of the DSVs (g.4100A > G, g.4260 T > C and g.4581A > G) evidently modified the binding sites of unknown transcription factors. Conclusions The DSVs identified in AMI patients may alter TBX5 gene promoter activity and change TBX5 level, contributing to AMI development as a rare risk factor.

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Genetic Variants and Functional Analyses of the ATG16L1 Gene Promoter in Acute Myocardial Infarction

Frontiers in Genetics ◽

10.3389/fgene.2021.591954 ◽

2021 ◽

Vol 12 ◽

Author(s):

Falan Han ◽

Shuchao Pang ◽

Zhaoqing Sun ◽

Yinghua Cui ◽

Bo Yan

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Transcription Factors ◽

Electrophoretic Mobility ◽

Transcriptional Activity ◽

Gene Promoter ◽

Luciferase Reporter ◽

Mobility Shift ◽

Genotype Frequencies ◽

Promoter Mutations

BackgroundAcute myocardial infarction (AMI), a common complex disease caused by an interaction between genetic and environmental factors, is a serious type of coronary artery disease and is also a leading cause of death worldwide. Autophagy-related 16-like 1 (ATG16L1) is a key regulatory factor of autophagy and plays an important role in induced autophagy. In the cardiovascular system, autophagy is essential to preserve the homeostasis and function of the heart and blood vessels. No studies have hitherto examined the association between AMI and ATG16L1 gene promoter.MethodsWe conducted a case-control study, using polymerase chain reaction and sequencing techniques, dual luciferase reporter assay, and electrophoretic mobility shift assay, to analyze genetic and functional variation in the ATG16L1 gene promoter between AMI and controls. A variety of statistical analyses were used to analyze the allele and genotype frequencies and the relationship between single-nucleotide polymorphisms (SNPs) and AMI.ResultsIn all, 10 SNPs and two DNA-sequence variants (DSVs) were identified in 688 subjects, and three ATG16L1 gene promoter mutations [g.233250693 T > C (rs185213911), g.233250946 G > A (rs568956599), g.233251133 C > G (rs1301744254)] that were identified in AMI patients significantly altered the transcriptional activity of ATG16L1 gene promoter in HEH2, HEK-293, and H9c2 cells (P < 0.05). Further electrophoretic mobility shift assays indicated that the SNPs affected the binding of transcription factors (P < 0.01).ConclusionATG16L1 gene promoter mutations in AMI patients may affect the binding of transcription factors and change the transcriptional activity of the ATG16L1 gene, changing the level of autophagy and contributing to the occurrence and development of AMI as rare and low-frequency risk factors.

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