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Study: Inflammation may be protective against long-term CVD risk
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Inflammation may have a protective effect on cardiovascular health, according to results of a large study by the Interleukin-1 Genetics consortium that examined the effects of a gene found in anakinra, a drug previously studied in patients with rheumatoid arthritis and other inflammatory diseases.
Researchers created a genetic score that combined the effects of the alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the interleukin-1 (IL-1) receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta). Both alleles increase soluble IL-1Ra protein concentration, according to the researchers.
Daniel Freitag
The effects on inflammation biomarkers of this genetic score were compared with the effects of anakinra, a recombinant form of IL-1Ra.
“Drugs such as anakinra are licensed for the treatment of inflammatory conditions, including rheumatoid arthritis (RA), but we know little about the long-term health consequences of blocking IL-1,” John Danesh, FRCP, of the Department of Public Health and Primary Care at the University of Cambridge and leader of the study consortium, said in a press release.
Data were collected from 63,442 participants from a number of large cardiovascular (CVD) and population health studies, and the effects of the genetic score were quantified by studying mRNA concentrations of rs6743376 and rs1542176 in the participants.
Additional data from 1,125 patients with rheumatoid arthritis (RA) enrolled in clinical trials with anakinra were used to quantify the concentrations of inflammation biomarkers; results were then pooled and weighted.
Next, the researchers used the genetic score based on inflammation biomarkers and explored its relationship to RA, type 2 diabetes, coronary heart disease, ischemic stroke and abdominal aortic aneurysm in 453,411 participants.
“Our approach was to use ‘nature’s randomized trial’ to get answers currently beyond the resolution of drug trials,” Danesh said. “Our genetic analysis suggests, surprisingly, that blocking IL-1 over the long-term could increase the risk of cardiovascular diseases.”
Another arm of the study explored the genetic score, its relevance to IL-1 signaling and 24 additional disorders, including autoimmune, degenerative, neoplastic and other diseases in 205,329 patients and 423,905 healthy control participants.
After complex statistical analysis, an association was seen with the genetic score and subcutaneous adipose tissue, higher total cholesterol, higher low-density lipoprotein and increased triglyceride concentrations, according to the researchers. A log-linear, dose-dependent association was seen with coronary heart disease risk and with C-reactive protein concentrations. However, no associations were seen with the 24 other diseases studied.
“The common view is that inflammation promotes the development of heart disease — we’ve shown that the truth is clearly more complicated,” study author Daniel Freitag, PhD, from the University of Cambridge, said in the release. “We need to be careful that drugs like anakinra that aim to tackle [RA] by inhibiting IL-1 do not have unintended consequences on an individual's risk of heart disease.”
The study has limitations in applying the results to other populations.
“It is important to remember that this is not a study of an anti-arthritis drug but a gene that can mimic its effects,” Peter Weissberg, MD, FRCP, FMedSci, medical director at the British Heart Foundation, which helped fund the study, said in the release. “The effects of a gene are lifelong, whereas a drug only affects a person while it is being taken.” – by Shirley Pulawski
Reference: www.thelancet.com/cms/attachment/2025943597/2045187225/mmc1.pdf.
Disclosure: The work was funded by public grants and Merck, Novartis, GlaxoSmithKline and Pfizer. Please see the full study for a list of all authors’ relevant financial disclosures.
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