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Next-generation sequencing of prolidase gene identifies novel and common variants associated with low prolidase in coronary artery ectasia

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Abstract

Background

Decreased collagen biosynthesis and increased collagenolysis can cause ectasia progression in the arterial walls. Prolidase is a key enzyme in collagen synthesis; a decrease in prolidase activity or level may decrease collagen biosynthesis, which may contribute to ectasia formation. Considering that, the variations in PEPD gene encoding prolidase enzyme were evaluated by analyzing next-generation sequencing (NGS) for the first time together with known risk factors in coronary artery ectasia (CAE) patients.

Methods

Molecular analysis of the PEPD gene was performed on genomic DNA by NGS in 76 CAE patients and 76 controls. The serum levels of prolidase were measured by the sandwich-ELISA technique.

Results

Serum prolidase levels were significantly lower in CAE group compared to control group, and it was significantly lower in males than females in both groups (p < 0.001). On the other hand, elevated prolidase levels were observed in CAE patients in the presence of diabetes (p < 0.001), hypertension (p < 0.05) and hyperlipidemia (p < 0.05). Logistic regression analysis demonstrated that the low prolidase level (p < 0.001), hypertension (p < 0.02) and hyperlipidemia (p < 0.012) were significantly associated with increased CAE risk. We identified four missense mutations in the PEPD gene, namely G296S, T266A, P365L and S134C (novel) that could be associated with CAE. The pathogenicity of these mutations was predicted to be “damaging” for G296S, S134C and P365L, but “benign” for T266A. We also identified a novel 5′UTR variation (Chr19:34012748 G>A) in one patient who had a low prolidase level. In addition, rs17570 and rs1061338 common variations of the PEPD gene were associated with low prolidase levels in CAE patients, while rs17569 variation was associated with high prolidase levels in both CAE and controls (p < 0.05).

Conclusions

Our findings indicate that the low serum prolidase levels observed in CAE patients is significantly associated with PEPD gene variations. It was concluded that low serum prolidase level and associated PEPD mutations may be potential biomarkers for the diagnosis of CAE.

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Data availability

The datasets generated during and analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank our patients and healthy control subjects who participated in the study.

Funding

The present study was supported by a Grant from the Scientific Research Projects Coordination Unit of Istanbul University (Project Nos.: TDK-2018-31311 and TYO-2019-32124).

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Authors and Affiliations

  1. Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey

    Kubra Cigdem Pekkoc-Uyanik, Ezgi Irmak Aslan, Fatih Yanar, Oguz Ozturk & Hulya Yilmaz-Aydogan

  2. Department of Medical Biology, Faculty of Medicine, Halic University, Istanbul, Turkey

    Kubra Cigdem Pekkoc-Uyanik

  3. Department of Cardiology, Institute of Cardiology, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Onur Kilicarslan, Ozgur Selim Ser, Serhan Ozyildirim & Ahmet Yildiz

  4. Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey

    Fatih Yanar

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Contributions

KCP-U: Methodology, Investigation, Writing-original draft. EIA: Investigation, Validation. AY: Conceptualization, data curation. OK: Clinic examinations. OSS: Clinic examinations. SO: Clinic examinations. FY: Data analysis and manuscript preparation. OO: Supervision and formal analysis. HY-A: Funding acquisition, Project administration, Methodology, Writing-review&editing. All authors read and approved the final manuscript.

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Correspondence to Hulya Yilmaz-Aydogan.

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The study was in accordance with the Declaration of Helsinki for medical research involving human subjects. The protocol was approved by the Ethics Committee of the Istanbul University, Istanbul Faculty of Medicine (Approval Number: 2018/714).

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Pekkoc-Uyanik, K.C., Aslan, E.I., Kilicarslan, O. et al. Next-generation sequencing of prolidase gene identifies novel and common variants associated with low prolidase in coronary artery ectasia. Mol Biol Rep 50, 1349–1365 (2023). https://doi.org/10.1007/s11033-022-08142-1

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