Associations and interactions between variants in selenoprotein genes, selenoprotein levels and the development of abdominal aortic aneurysm, peripheral arterial disease, and heart failure

PLoS One. 2018 Sep 6;13(9):e0203350. doi: 10.1371/journal.pone.0203350. eCollection 2018.

Abstract

Background: Little is known on the role of selenoprotein genes in cardiovascular disease. This study examines the associations of the SEPP1, SELENOS, TXNRD1, TXNRD2, GPX4, and SOD2 polymorphisms and selenoprotein P (SeP) and thioredoxin concentrations with the development of abdominal aortic aneurysm (AAA) and aortoiliac occlusive disease (AOID), as well as their influence on cardiac phenotype.

Methods: 564 patients with AAA, 400 patients with AIOD, and 543 controls were enrolled and characterized for coronary artery disease, myocardial infarction, and systolic heart failure (HF) occurrence. In AAA, the coexistence of peripheral arterial disease (PAD) was examined. Genotypes were determined using TaqMan-based assays. Selenoprotein concentration was assessed using the ELISA method.

Results: The SELENOS rs34713741T, SEPP1 rs3877899A, and GPX4 rs713041T alleles were related to a 30-60% increase in the AIOD/PAD risk in the recessive or dominant model (all associations at P < .05). The SEPP1 rs3877899A allele was a protective factor for the development of AAA without concomitant PAD (OR = 0.68 for the dominant model, P = .014), but not AAA with concomitant PAD. The cumulative two-locus effects of selenoprotein genes on the AAA/AIOD risk were observed, including the multiplicative interaction between the SELENOS rs34713741T and GPX4 rs713041T alleles (both in the recessive model) affecting the AIOD risk (OR = 5.27, P = .001) and its clinical phenotype. Coexistence of HF in aortic diseases was related to both the SEPP1 rs7579A allele (OR = 1.83 for carriers, P = .013) and increased SeP concentrations; SeP level ≥8.5 mg/mL caused a 3.5-fold increase in the risk of HF. In AAA, SeP levels were correlated with BMI (r = -0.575, P < .0001).

Conclusions: Our results provide evidence that selenoprotein polymorphisms constitute a risk factor for HF and peripheral atherosclerosis, but prevent the development of AAA. Excessive weight might result in reduced antioxidant reserve efficiency in AAA. Validation studies are required to establish whether SeP concentration may be a marker for HF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aortic Aneurysm, Abdominal / blood*
  • Aortic Aneurysm, Abdominal / genetics*
  • Case-Control Studies
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Glutathione Peroxidase / genetics
  • Heart Failure / blood
  • Heart Failure / genetics*
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Peripheral Arterial Disease / blood*
  • Peripheral Arterial Disease / genetics*
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Selenoprotein P / blood
  • Selenoprotein P / genetics
  • Selenoproteins / blood*
  • Selenoproteins / genetics*

Substances

  • Membrane Proteins
  • SELENOP protein, human
  • SELENOS protein, human
  • Selenoprotein P
  • Selenoproteins
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Glutathione Peroxidase

Grants and funding

The work has been supported by the National Science Centre in Poland under grant no. NN403250440 (RS, ES) and the Poznan University of Medical Sciences under grant nos. 502-14-02214335-10268 (JT, ES) and 502-01-02214335-05962 (GO, ES). The Camillo Di Croce award for the best presentation on familial and/or genetic aspects of aneurysms during the 4th International Meeting on Aortic Diseases in Belgium (awarded to ES).