Sunday, 1 April 2012

Scientists investigate a new strategy to prevent heart disease


Scientists investigate a new strategy to prevent heart disease
Toni Kinneally 42903017
Coronary heart disease (CHD) kills more Australians than any other single disease1. Recent advances in genetics suggest that the interleukin-6 receptor (IL6R) genotype should be a target for the prevention of coronary heart disease.

A meta-analysis,“The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomization analysis”, conducted by the IL6R Mendelian Randomization Analysis Consortium used single nucleotide polymorphisms to review the potential effectiveness of inhibiting IL6 receptors in preventing CHD.

A single nucleotide polymorphism (SNP) is a difference in a single nucleotide in a sequence of DNA6. For example, a single cytosine (C) nucleotide may be replaced with either thymine (T), adenine (A) or guanine (G). Only three to five percent of human DNA codes for protein production6; however, regardless of whether a SNP is within a coding sequence it can act as a marker for a gene or gene variant. This is because whenever a SNP is very close to a gene, the SNP and the gene will almost always be inherited together10.
Figure 1: An SNP as marker for a disease-causing allele (gene). Source: Cain et al. 2012, p.418

In this study the team of researchers used an IBC Human CVD BeadChip or Cardiochip, a type of DNA microarray, to detect polymorphisms. The Cardiochip contains markers for 2000 gene variants implicated in cardiovascular disease8. In this particular study the chip was used to detect the IL6R SNP rs7529229, a marker for the IL6R variant rs8192284.

CHD describes the narrowing of arteries as a result of an inflammatory response, atherosclerosis, to the accumulation of fatty deposits on artery walls5. Currently prevention of CHD includes drugs which lower blood pressure and lower cholesterol2. Prior to this study it was known that increased concentrations of interleukin-6 (IL6) and C-reactive protein (CRP) are associated with increased risk of CHD and that the blocking of IL6 receptors by tocilizumab, a drug used for treating rheumatoid arthritis, reduces inflammation throughout the human body8. It was also known that CRP and IL6 are indicators of inflammation3. This suggested that a relationship between inflammation and risk of CHD may exist and that by managing inflammation, risk of CHD may also be managed, prompting further investigation8.

Figure 2: Summary of background information.
Interleukin-6 concentration
Risk of CHD

Tocilizumab blockade of IL6R
Inflammation

C-reactive protein concentration
Inflammation

C-reactive protein concentration
Risk of CHD


The meta-analysis statistically combined the results of forty studies4, comparing genetic findings with the effect of blocking IL6 receptors with an infusion of 4mg/kg every 4 weeks tocilizumab. The IL6R SNP rs7529229 which marked the IL6R gene variant rs8192284 was associated with increased IL6 concentration. Tocilizumab and consequent blocking of IL6 receptors produced the same result. However, this IL6R SNP was also associated with decreased CRP concentrations. Although the results of IL6 and CRP seem to be contradictory, this study did not investigate the relationship between CRP and IL6 concentrations. However, this study did find that in 25 458 CHD cases and 100 750 controls, the IL6R SNP rs7529229and therefore the IL6R variant rs8192284 was associated with reduced risk of CHD. 

Figure 3: Summary of results.
IL6R variant rs8192284
Interleukin-6 concentration

Tocilizumab blockade of IL6R
Interleukin-6 concentration

IL6R variant rs8192284

C-reactive protein concentration
Tocilizumab blockade of IL6R

C-reactive protein concentration
IL6R variant rs8192284
Risk of CHD


The authors concluded that, IL6R signaling seems to have a role in the development of CHD. The effects of tocilizumab blockade of IL6R were found to be the same as the effect of the gene variant rs8192284. This gene variant was found to be associated with reduced risk of CHD. Therefore, this association may also apply to tocilizumab. These results provide encouragement for further investigation, including clinical trials, into the use of tocilizumab or a similar drug in the prevention of coronary heart disease, to “repurpose” an existing drug for a new use.

References
1) Australian Institute of Health and Welfare 2011, Coronary Heart Disease, Australian Institute of Health and Welfare, viewed 17 March 2012, http://www.aihw.gov.au/coronary-heart-disease/.
2) NHS Choices 2010, Coronary heart disease – Prevention, NHS Choices, viewed 17 March 2012, http://www.nhs.uk/Conditions/Coronary-heart-disease/Pages/Prevention.aspx
3) Koenig, W. 2001, Inflammation and Coronary Heart Disease: An Overview, Cardiology in Review, viewed 17 March 2012, http://serpins.med.unc.edu/~fcc/Biology134_Folder/Pathology_213/CV_inflammation.pdf
4) The Cochrane Collaboration 2002, Combining studies: what is Meta-Analysis?, The Cochrane Collaboration, viewed 17 March 2012, http://www.cochrane-net.org/openlearning/html/mod12-2.htm
5) National Heart Lung and Blood Institute 2011, What is atherosclerosis?, National Heart Lung and Blood Institute, viewed 17 March 2012, http://www.nhlbi.nih.gov/health/health-topics/topics/atherosclerosis/
6) National Center for Biotechnology Information 2007, SNPs: Variations on a theme, National Center for Biotechnology Information, viewed 17 March 2012, http://www.ncbi.nlm.nih.gov/About/primer/snps.html  
7) Bio Array News 2012, Team Uses Cardiochip to ID SNP Associated with Inflammation in Coronary Heart Disease, Bio Array News, viewed 17 March 2012,  http://www.genomeweb.com/arrays/team-uses-cardiochip-id-snp-associated-inflammation-coronary-heart-disease?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+genomeweb+(GenomeWeb+%C3%9Cberfeed)
8) IL6R Mendelian Randomization Analysis Consortium 2012, Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies, The Lancet, viewed 17 March 2012, http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61931-4/fulltext
9) The Children’s Hospital of Philadelphia 2012, Gene Chip, Invented by Children’s Hospital of Philadelphia Scientist, Pinpoints New Target to Prevent Heart Disease, The Children’s Hospital of Philadelphia, viewed 15 March 2012, http://www.sacbee.com/2012/03/14/4336514/gene-chip-invented-by-childrens.html
10) Cain, M. Cooke, B. Jackson, R. Meyers, N. Minorsky, P. Reece, J. Urry, L. Wasserman, S. 2012, Campbell Biology 9th Edition Australian Version, Pearson, Australia.

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