A functional interleukin-1 receptor antagonist polymorphism influences atherosclerosis development. The interleukin-1beta:interleukin-1 receptor antagonist balance in atherosclerosis

Circ J. 2009 Aug;73(8):1531-6. doi: 10.1253/circj.cj-08-1150. Epub 2009 Jul 3.


Background: Interleukin (IL)-beta plays a central role in inflammation and atherosclerosis, but levels of IL-1beta, its natural antagonist, IL-1Ra, and their balance in human atherosclerotic lesions, are unknown. Knowledge of protein levels in atherosclerosis and the influence of a functional IL-1Ra polymorphism would increase the understanding of atherosclerosis pathogenesis.

Methods and results: Fresh and endotoxin-stimulated explanted human atherosclerotic and normal arteries were analyzed for IL-1beta, IL-1Ra and IL-1 receptor 1 (IL-1R1) using TaqMan PCR and enzyme-linked immunosorbent assay. Two hundred forty-three survivors of a first myocardial infarction were genotyped for a polymorphism in IL-1Ra and their coronary atherosclerosis analyzed by using coronary angiography. Levels of IL-1beta, IL-1Ra and IL-1R1 mRNA were significantly increased in atherosclerotic arteries compared with normal arteries. Endotoxin stimulation increased IL-1beta levels more than IL-1Ra levels (ie, promoted a pro-inflammatory state). A polymorphism in IL-1Ra known to increase levels of IL-1Ra was associated with decreased mean coronary artery plaque area.

Conclusions: Activation of innate immunity changed the balance between IL-1beta and IL-1Ra in atherosclerotic arteries towards a more pro-inflammatory state. In line with this, the presence of an IL-1Ra intron 2 polymorphism known to increase IL-1Ra levels, and possibly the IL-1Ra:IL-1beta ratio, was associated with reduced coronary atherosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arteries / chemistry
  • Atherosclerosis / etiology*
  • Atherosclerosis / genetics
  • Endotoxins / pharmacology
  • Female
  • Humans
  • Immunity, Innate
  • Inflammation / etiology
  • Interleukin 1 Receptor Antagonist Protein / analysis
  • Interleukin 1 Receptor Antagonist Protein / genetics*
  • Interleukin-1beta / analysis
  • Interleukin-1beta / genetics*
  • Male
  • Middle Aged
  • Myocardial Infarction / genetics
  • Polymorphism, Genetic / physiology*
  • RNA, Messenger / analysis
  • Receptors, Interleukin-1 / analysis


  • Endotoxins
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • RNA, Messenger
  • Receptors, Interleukin-1