Abstract
Long-term primary prevention of myocardial infarction faces challenges, but genetic risk assessment may change this dynamic. We sought for genetic risk loci influencing myocardial infarction and underlying pathomechanisms. AS-PCR used for mutation detection (STAT4_ rs3024839 and IL22_ rs2227483) and confirmed positives by sequencing and Digital PCR. STAT4 and IL22 mRNA levels and chromatin accessibility at SNP sites were evaluated. We assessed SNPs for association with myocardial underlying comorbidities as well as their predictive performance ability. The population flow-sorted CD4+ FOXP3+ Tregs and the level of Foxp3 mRNA were measured and TGF-β1 quantified using ELISA and intracellular staining assay. Immunophenotyping used to identify p53 expression, pro-inflammatory monocytes and circulating endothelial cells. More than 99% samples were positive for mutations. Significant differences in the mutated allele and genotype frequencies were identified at a p value cutoff of 0.05. Analyses identified SNPs as risk factors for comorbid factors with the ability in distinguishing high and low-risk individuals (AUC > 0.9). Differentially accessible chromatin regions influencing STAT4 and IL22 expression were found in risk loci. Lower circulating CD4+ FOXP3+Tregs, Foxp3 expression decline, decreasing TGF-β1 level, increased p53 level, inflammatory state and endothelial dysfunction were further validated. Discovered genotypes open novel opportunities for MI prediction.
Data availability
The datasets generated and/or analyzed during the current study are available in the [dbSNP] repository [http://www.ncbi.nlm.nih.gov/SNP]” and SNPs can be searched for using the dbSNP ID (rs3024839 (https://www.ncbi.nlm.nih.gov/snp/?term=rs3024839) and rs2227483 (https://www.ncbi.nlm.nih.gov/snp/?term=rs2227483)).
Abbreviations
- MI:
-
Myocardial infarction
- SNP:
-
Single nucleotide polymorphism
- HWE:
-
Hardy–Weinberg equilibrium
- ECG:
-
Electrocardiograph
- cTnI:
-
Cardiac troponin-I
- CK-MB:
-
Creatine kinase MB fraction
- STEMI:
-
ST elevation MI
- NSTEMI:
-
Non-ST elevation MI
- EDTA:
-
Ethylenediaminetetraacetic acid
- AS-PCR:
-
Allele-specific polymerase chain reaction
- ARMS:
-
Amplification refractory mutation system
- dPCR:
-
Digital PCR
- FAM:
-
6-Carboxyfluorescein
- VIC:
-
2′-Chloro-7′phenyl-1,4-dichloro-6-carboxy-fluorescein
- AUC:
-
Area under the curve
- ROC:
-
Receiver operating characteristic
- RT-qPCR:
-
Reverse transcription-quantitative PCR
- PI:
-
Propidium iodide
- TGF-β1:
-
Transforming growth factor-β1
- ELISA:
-
Enzyme-linked immunosorbent assay
- CECs:
-
Circulating endothelial cells
- ORs:
-
Odds ratios
- CIs:
-
Confidence intervals
- Fst:
-
F-statistics
- PCA:
-
Principal component analysis
- MFI:
-
Mean fluorescent intensity
- CVD:
-
Cardiovascular diseases
- GRS:
-
Genetic risk score
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Special thanks to the hospitals healthcare workers and all other staffs.
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Naeimi S & Khashei Varnamkhasti K, designed the study and critically reviewed the manuscript. Khosravi Nezhad Z, Dehghani F, Molavizade S, Khanifar H, Ashrafi M, Azhdari M, Faghih Abbasi M, Baratvand G, Khashei Varnamkhasti K, Naeimi R, Khashei Varnamkhasti S, Hemati E, performed formal analysis. Naeimi S & Khashei Varnamkhasti K, administrated project. Methodology; Naeimi S, Khashei Varnamkhasti K & Molavizade S. Khashei Varnamkhasti K, wrote the manuscript. The final manuscript has been approved by all authors. .
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This study was conducted in accordance with the approved institutional guidelines of the Islamic Azad University-Kazerun Branch in Iran. All participants signed the informed consent form and their data were anonymized prior to analysis. The Ethics Committee of the Islamic Azad University-Kazerun Branch in Iran approved this study and all experimental protocols (IR.IAU.KAU.REC.1398.045).
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Khosravi Nezhad, Z., Dehghani, F., Molavizade, S. et al. The rs3024839 and rs2227483 polymorphisms with immune pathomechanism offers a starting point for diagnosis and susceptibility testing of myocardial infarction. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39886-6
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DOI: https://doi.org/10.1038/s41598-026-39886-6
