A large international study indicates that anti-inflammatory drugs may become a new tool for preventing and treating coronary heart disease (CHD), the leading global cause of death. In investigating a specific gene variant linked to inflammation and heart disease, the researchers used the Cardiochip, a gene analysis tool designed by Brendan J. Keating, Ph.D., a researcher in the Center for Applied Genomics at The Children's Hospital of Philadelphia, and co-author of the study.
Scientists already knew that inflammation is associated with atherosclerosis, the buildup of fatty deposits on artery walls that causes CHD, but until now, no one had identified an inflammatory agent causing the disease. Likewise, it was unknown whether a drug targeted at reducing inflammation might treat CHD.
The current study focused on the interleukin-6 receptor (IL6R), a signaling protein found in the blood that increases inflammatory responses. "This study provides robust evidence that IL6R is implicated in coronary heart disease," said Keating. "Furthermore, our analysis showed that an existing anti-inflammatory drug, acting on this receptor, may offer a new potential approach for preventing CHD."
The study, which appeared online today in The Lancet, was performed by the IL6R Mendelian Randomisation Analysis Consortium, an international research team led by Dr. Juan Pablo Casas, Professor Aroon D. Hingorani, and Dr. Daniel I. Swerdlow, all of University College London in the U.K. The study was a meta-analysis of data from 40 existing studies that included nearly 133, 500 participants from the U.S. and Europe. Mendelian randomization is a research method that uses knowledge of genes and biological mechanisms to predict likely effects of a new drug before conducting a clinical trial, with its high cost and potential risk of side effects.
A companion study in the same issue of The Lancet, by the IL6R Genetics Consortium and Emerging Risk Factors Collaboration, found that a genetic variant in the IL6R gene, which carries the code for the IL6R protein, dials down inflammation and thus lowers the risk of heart disease.
The study in which Keating participated focused on SNPs (single nucleotide polymorphisms) single-base changes in the IL6R gene that codes for the IL6R protein.
Among the research team's tools was a DNA array, the IBC Human CVD BeadChip, also called the Cardiochip, created by Keating in 2006 and since used in many large gene studies. That chip contains DNA markers for 2000 gene variants implicated in cardiovascular disease. When brought into contact with test samples of DNA from research participants, the chip detects specific SNPs in the sample --gene variants that may affect biological functions and risks of heart disease among the participants.
They found that one SNP, the gene variant rs8192284, altered several biological markers associated with inflammation. Those results were similar to those found in trials of tocilizumab, an anti-inflammatory drug currently used to treat rheumatoid arthritis. By inhibiting the action of IL6R, this drug reduces the painful inflammation common in rheumatoid arthritis.
Further analysis of data from CHD patients and controls showed that subjects carrying the gene variant had a lower risk of CHD. "What this tells us is that IL6R blockers such as tocilizumab mimic the benefits of having this gene variant," said Keating. "A next step will be for cardiology researchers to design and carry out clinical trials to determine whether tocilizumab or similar anti-inflammatory drugs will prevent heart disease."
More than 30 organizations and agencies funded this study, including the U.K. Medical Research Council, the British Heart Foundation, the National Institutes of Health and the Wellcome Trust. A senior investigator from The Children's Hospital of Philadelphia, Hakon Hakonarson, M.D., Ph.D., director of the Hospital's Center for Applied Genomics, was among the co-authors who interpreted findings and wrote the report.
"The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomization analysis," The Lancet, published online March 14, 2012, doi:10.1016/S0140-6736(12)60110-X
About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 516-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.