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PPIA rs6850: A > G single-nucleotide polymorphism is associated with raised plasma cyclophilin A levels in patients with coronary artery disease

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Abstract

Plasma level of cyclophilin A is a promising marker of vascular disease in patients with type 2 diabetes. Genetic variants in the peptidylprolyl isomerase A gene, encoding human cyclophilin may alter protein synthesis thus affecting its activity, function, and circulating plasma levels. We examined the effect of single-nucleotide polymorphisms (SNPs) within the PPIA gene on plasma levels of cyclophilin A and coupled this with status of vascular disease in patients with and without type 2 diabetes in 212 South Indian subjects. The regulatory region of PPIA gene was sequenced for SNPs. The association of SNPs with known blood markers of type 2 diabetes and coronary artery disease such as HbA1c, low- and high-density lipoproteins, triglycerides, fasting and postprandial blood sugar levels, and cyclophilin A were probed. We identified three SNPs namely, rs6850: A > G; (AG/−) c.*227_*228delAG and (−/T) c.*318_*319insT. Welchs two-sample t test indicated an association of SNP rs6850: A > G, located at the 5′ UTR region with increased plasma levels of cyclophilin A in patients with coronary artery disease and with coronary artery disease associated with diabetes. The presence of rs6850: A > G variant was significantly associated with coronary artery disease irrespective of whether the patients had diabetes or not. In silico analysis of the sequence using different tools and matrix libraries did not predict any significant differential binding sites for rs6850: A > G, c.*227_*228delAG and c.*318_*319insT. Our results indicate that the SNP rs6850: A > G is associated with increased risk for elevated plasma levels of cyclophilin A and coronary artery disease in patients with and without type 2 diabetes.

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Abbreviations

PPIA:

Peptidyl-prolyl isomerase A

CAD:

Coronary artery disease

DM:

Diabetes mellitus

DM + CAD:

Diabetes mellitus + coronary artery disease

UTR:

Untranslated region

EDTA:

Ethylene diamine tetra acetic acid

ELISA:

Enzyme-linked immunosorbent assay

FBS:

Fasting blood sugar

HbA1c:

Glycated hemoglobin

HDL:

High-density lipoprotein

LDL:

Low-density lipoprotein

Tris HCl:

Tris hydrochloric acid

NaCl:

Sodium chloride

SDS:

Sodium dodecyl sulfate

TRANSFAC:

Transcription Factor database

ANOVA:

Analysis of variance

CI:

Confidence intervals

OR:

Odds ratios

CPBP:

Core promoter binding protein

LEF-1:

Lymphoid enhancer-binding factor-1

VSMCs:

Vascular smooth muscle cells

GWAS:

Genome-wide association study

TFBS:

Transcription factor binding sites

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Acknowledgments

This work was supported by Indian Council of Medical Research, Ministry of Health, Government of India (No 5/4/1-4/2013/NCD-II). Financial support from Director, Rajiv Gandhi Centre for Biotechnology is also acknowledged.

Authors contributions

VA drafted the manuscript and carried out all molecular biology experiments; RK designed, analyzed, and interpreted statistical data. VKA and RG performed bioinformatics analysis and interpreted data. DG and SS were involved in acquisition of data and drafting the manuscript. KRS, NSP, and AM contributed to design of the study and acquisition of data. CCK and SR were equally involved in conceiving the study, its design, interpretation of results, and critically reviewed and revised the manuscript before submission. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India

    A. Vinitha, A. Vivekanand, G. Reshmi, G. Divya, S. Sumi, C. C. Kartha & Surya Ramachandran

  2. Achutha Menon Centre, SCTIMST, Thiruvananthapuram, India

    V. Raman Kutty

  3. PRS Hospital, Thiruvananthapuram, India

    K. R. Santosh

  4. Indian Institute of Diabetes, Thiruvananthapuram, India

    N. S. Pratapachandran

  5. The Madras Medical Mission, Chennai, India

    Mullassari S. Ajit

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  1. A. Vinitha
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Correspondence to C. C. Kartha or Surya Ramachandran.

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Vinitha, A., Kutty, V.R., Vivekanand, A. et al. PPIA rs6850: A > G single-nucleotide polymorphism is associated with raised plasma cyclophilin A levels in patients with coronary artery disease. Mol Cell Biochem 412, 259–268 (2016). https://doi.org/10.1007/s11010-015-2632-7

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  • DOI: https://doi.org/10.1007/s11010-015-2632-7

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