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TNFRSF11B gene polymorphisms increased risk of peripheral arterial occlusive disease and critical limb ischemia in patients with type 2 diabetes

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Abstract

Aims

Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. OPG has been hypothesized to modulate vascular functions; however, its role in mediating atherosclerosis is controversial. Epidemiological data in patients with cardiovascular disease (CVD) indicate that OPG serum levels are associated with several inflammatory markers, myocardial infarction events, and calcium scores, suggesting that OPG may be causative for CVD.

Methods

The present study aimed to evaluate whether the OPG gene (TNFRSF11B) polymorphisms are involved in the development of peripheral arterial occlusive disease (PAOD) and critical limb ischemia (CLI) in patients with type 2 diabetes. This genetic association study included 402 diabetic patients (139 males and 263 females) with peripheral arterial occlusive disease and 567 diabetic subjects without peripheral arterial occlusive disease (208 males and 359 females). The T245G, T950C, and G1181C polymorphisms of the OPG gene were analyzed by polymerase chain reaction and restriction fragment length polymorphism.

Results

We found that the T245G, T950C, and G1181C gene polymorphisms of the OPG gene were significantly (27.9 vs. 12.2 %, P < 0.01; 33.6 vs. 10.4 %, P < 0.01 and 24.4 vs. 12.7 %, P < 0.01, respectively) and independently (adjusted OR 4.97 (3.12–6.91), OR 7.02 (4.96–11.67), and OR 2.85 (1.95–4.02), respectively) associated with PAOD. We also found that these three polymorphisms act synergistically in patients with PAOD and are associated with different levels of risk for PAOD and CLI, depending on the number of high-risk genotypes carried concomitantly by a given individual.

Conclusion

The TNFRSF11B gene polymorphisms under study are associated with PAOD, and synergistic effects between these genotypes might be potential markers for the presence and severity of atherosclerotic disorders.

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Conflict of interest

Federico Biscetti, Carlo Filippo Porreca, Flavio Bertucci, Giuseppe Straface, Angelo Santoliquido, Paolo Tondi, Flavia Angelini, Dario Pitocco, Luca Santoro, Antonio Gasbarrini, Raffaele Landolfi, and Andrea Flex declare that they have no conflict of interest.

Human and Animal Rights disclosure

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).

Informed consent disclosure

Informed consent was obtained from all patients for being included in the study.

Author information

Authors and Affiliations

  1. Institute of Rheumatology and Affine Sciences, Catholic University School of Medicine, Rome, Italy

    Federico Biscetti

  2. Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy

    Federico Biscetti, Carlo Filippo Porreca, Flavio Bertucci, Angelo Santoliquido, Paolo Tondi, Dario Pitocco, Antonio Gasbarrini, Raffaele Landolfi & Andrea Flex

  3. Laboratory of Vascular Biology and Genetics, Catholic University School of Medicine, Rome, Italy

    Federico Biscetti, Carlo Filippo Porreca, Flavio Bertucci, Flavia Angelini, Antonio Gasbarrini & Andrea Flex

  4. Vascular Medicine and Atherothrombosis Laboratory, Department of Experimental Medicine, Sapienza University of Rome, Polo Pontino, Italy

    Giuseppe Straface

  5. Department of Internal Medicine, Complesso Integrato Columbus, School of Medicine, Rome, Italy

    Luca Santoro

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  1. Federico Biscetti
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  2. Carlo Filippo Porreca
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  3. Flavio Bertucci
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  12. Andrea Flex
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Corresponding author

Correspondence to Andrea Flex.

Additional information

Managed by Antonio Secchi.

Federico Biscetti and Carlo Filippo Porreca have contributed equally to this study.

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Biscetti, F., Porreca, C.F., Bertucci, F. et al. TNFRSF11B gene polymorphisms increased risk of peripheral arterial occlusive disease and critical limb ischemia in patients with type 2 diabetes. Acta Diabetol 51, 1025–1032 (2014). https://doi.org/10.1007/s00592-014-0664-1

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