Cambridge University. UK: Inflammation, the body’s response to damaging stimuli, may have a protective effect against cardiovascular disease, according to a study published today in the journal Lancet Diabetes and Endocrinology.
The
finding is one of the outcomes of research using a powerful new genetic
tool that mimics the behaviour of certain anti-inflammatory drugs. The
technique allows researchers to study the effects of inhibiting
interleukin-1, a master regulator of inflammation, on a range of
different outcomes not yet investigated in clinical trials.
Interleukin-1 plays a central role in regulating the body’s
inflammatory response, setting off a cascade of signals within the body
against infection and other damage. Certain drugs, such as anakinra,
reduce inflammation by blocking interleukin-1. This action also occurs
naturally in individuals who carry particular genetic variants.
Although inflammation is meant to be protective, a disproportionate
response can be damaging to the body – for example, causing potentially
life-threatening symptoms seen in severe cases of influenza infection.
It also plays a crucial role in a number of autoimmune diseases such as
rheumatoid arthritis. Although scientists suspected that it would also
be likely to increase risk of cardiovascular disease, until now little
evidence existed to confirm or disprove this suggestion.
To examine the long-term implications of blocking this pathway,
researchers from the Interleukin-1 Genetics Consortium developed a
‘genetic score’ to combine the effects of two of these natural genetic
variants. They looked at the effect of this score on key biological
indicators of inflammation, comparing it to the effect of anakinra. They
investigated this score in relation to several medical conditions
including rheumatoid arthritis and coronary heart disease by analysing
data from over a million individuals.
The researchers found that individuals who carried the genetic variants
– in other words, had naturally-occurring interleukin-1 inhibition –
showed a decreased risk of developing rheumatoid arthritis. This was as
anticipated: anakinra is one of the drugs used to treat the condition.
The variants had no impact on the risks of developing type 2 diabetes or
ischaemic stroke.
Surprisingly, however, blocking interleukin-1 increased an individual’s
risk of developing coronary heart disease: the risk of a heart attack
was 15% higher in people who inherited a greater tendency to block
interleukin-1. The researchers also observed raised levels of
LDL-cholesterol – so-called ‘bad cholesterol’ – in these individuals,
which may explain some of this increased risk.
Blocking interleukin-1 also increased an individual’s risk of
developing abdominal aortic aneurysm, a swelling of the main blood
vessel that leads away from the heart, down through the abdomen to the
rest of the body; one in 50 deaths amongst men over 65 years of age is
due to such an aneurysm rupturing.
Although anakinra has been tested in clinical trials and shown to be
effective in treating symptoms of rheumatoid arthritis, there has been
little research into its effect on coronary heart disease. This is, in
part, because of the complexity of studying heart disease and the number
of individuals and length of study required in order for an effect to
become apparent. By studying naturally-occurring interleukin-1
inhibition, the researchers have been able to infer that the drug could
potentially elevate the risk of coronary heart disease and abdominal
aortic aneurysms.
Professor John Danesh from the Department of Public Health and Primary
Care at the University of Cambridge, who leads the consortium, says:
“Drugs such as anakinra are licensed for the treatment of inflammatory
conditions including rheumatoid arthritis, but we know little about the
long-term health consequences of blocking interleukin-1.
“Our approach was to use ‘nature’s randomised trial’ to get answers
currently beyond the resolution of drug trials. Our genetic analysis
suggests, surprisingly, that blocking interleukin-1 over the long-term
could increase the risk of cardiovascular diseases.”
Dr Daniel Freitag, lead author of the study, also at the University of
Cambridge, adds: “The common view is that inflammation promotes the
development of heart disease – we’ve shown that the truth is clearly
more complicated. We need to be careful that drugs like anakinra that
aim to tackle rheumatoid arthritis by inhibiting interleukin-1 do not
have unintended consequences on an individual’s risk of heart disease.”
Professor Peter Weissberg, Medical Director at the British Heart
Foundation, which helped fund the study, said: “It is important to
remember that this is not a study of an anti-arthritis drug but a gene
that can mimic its effects. The effects of a gene are lifelong, whereas a
drug only affects a person while it is being taken.
“Nevertheless the study suggests that patients who are prescribed
anakinra should have their cardiovascular risk factors carefully managed
by their doctor.”
The research was funded by the Medical Research Council, the British
Heart Foundation, the National Institute of Health Research (NIHR), the
NIHR Cambridge Biomedical Research Centre, the European Research Council
and the European Commission Framework Programme.
Reference
The Interleukin-1 Genetics
Consortium. Cardiometabolic consequences of genetic up-regulation of
the interleukin-1 receptor antagonist: Mendelian randomisation analysis.
Lancet Diabetes and Endocrinology. 26 February, 2015.
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