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Team Uses Cardiochip to ID SNP Associated with Inflammation in Coronary Heart Disease

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This article was originally posted on March 16.

By Justin Petrone

A study published last week demonstrates that an anti-inflammatory drug recommended for managing rheumatoid arthritis could potentially be used to prevent and treat coronary heart disease.

The study partially relied on a custom Illumina array called the Cardiochip to show that a SNP in the IL6R gene was associated with lower risk of coronary heart disease and also altered inflammation-associated biomarkers in a way similar to the anti-inflammatory drug. The drug, called tocilizumab, is designed to inhibit the IL6R protein, an inflammatory cytokine, and is marketed by Chugai and Roche under the names Actemra and RoActemra.

Coauthor Brendan Keating said that the study provides "evidence that IL6R is implicated in coronary heart disease" and that tocilizumab "may offer a new potential approach for preventing CHD." Keating, a researcher at the Center for Applied Genomics at the Children's Hospital of Philadelphia who designed the Cardiochip, spoke with BioArray News last week.

The study, which appeared in The Lancet online, is the work of the IL6R Mendelian Randomization Analysis Consortium. Headed by researchers at University College London, the group conducted a meta-analysis of data from 40 existing studies that included nearly 133,500 participants from the US and Europe.

The meta-analysis led the group to conclude that IL6R signaling has a "causal role" in development of coronary heart disease and that IL6R blockers could provide a therapeutic approach to prevention of the disease.

In addition to that meta-analysis, the same group found that the IL6R SNP studied in the IL6R Mendelian Randomization Analysis Consortium is associated with reduced inflammation and lowers the risk of heart disease.

"The overall inference from our findings was that signaling at the IL-6 receptor plays a causal role in CHD and that the receptor is a potentially novel target for pharmacological prevention of CHD in the general population," lead author Daniel Swerdlow told BioArray News last week. "Further exploration of this approach is warranted in appropriately powered randomized trials," said Swerdlow, a researcher at University College London.

To identify the SNP, Keating and colleagues genotyped 4,489 individuals of European ancestry in the Whitehall II study, a longitudinal, prospective cohort study of 10,308 women and men who were employed in the London offices of the British Civil Service at the time they were recruited to the study in 1985. The eleventh wave of the study started in January.

From the 42 SNPs located within 55 kilobases of IL6R that are present on the Cardiochip, Keating and colleagues selected a subset of SNPs for further analysis in other datasets based on a number of criteria including the statistical strength of association with interleukin-6 concentration; linkage disequilibrium between SNPs in populations of European ancestry using Human HapMap data, to reduce redundancy; and previous disease and biomarker associations of SNPs in the region, according to the paper.

The variant identified was ultimately determined to be associated with differences in circulating concentrations of soluble IL6R, interleukin 6, C-reactive protein, and fibrinogen that were directionally concordant with those reported in trials of IL6R blockade with tocilizumab. At the same time, analysis of coronary heart disease cases
suggested the same variant was associated with reduced odds of coronary heart disease events. The authors suggested, in conclusion, that targeting IL6R could provide a new means to prevent coronary heart disease.

CHOP's Chip

Keating said that he conceived of the Cardiochip when he was a PhD student at the University of Oxford. The custom array contains 50,000 SNPs and was formally developed in 2007 with Illumina and investigators at the University of Pennsylvania, the University of Oxford, the University of Washington, and the US National Heart, Lung, and Blood Institute' Candidate-gene Association Resource Consortium. Keating is a faculty member at UPenn, but based within CHOP.

Keating and colleagues described the chip in a 2008 paper in PLoS One. According to that paper, the chip was developed to assess potentially relevant loci across a range of cardiovascular, metabolic, and inflammatory syndromes. It uses a so-called cosmopolitan tagging approach to capture the genetic diversity across about 2,000 loci in populations represented in the HapMap and SeattleSNPs projects.

The array content is informed by association studies of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway-based approaches, and literature searching.

Since it was developed, more than 210,000 individuals have been genotyped on the array in 60 different studies. The array has also been used to validate known loci in additional populations, to discover new loci associated with a spectrum of cardiovascular diseases and other traits, and to fine map a priori loci, Keating said.

Keating said that the chip was selected for use in this study as "a lot of the Cardiochip genotype and respective phenotype data that was needed for the paper had been collated and was much easier to analyze." The data could inform future studies as well, he noted. "As we essentially only looked at one SNP here there is obviously a lot of potential to expand this into other targets of interest," he added.

"The data obtained using the array was key to the success of the project, and a number of investigators in the consortium were in contact with one another because of links through use of the array," noted UCL's Swerdlow.

When asked why the group eschewed next-generation sequencing in this most recent study, Keating said that sequencing will eventually be "king" in terms of capturing rare and common variants, but said that focused arrays like the Cardiochip are "highly valuable" as the "cumulative numbers of individuals [genotyped with them] are very large."

"NGS will obviously get there at some point soon but it is still expensive at such scales," said Keating. "For me the main value is in bringing a lot of these studies together, albeit on such few SNPs. and getting the different group working together on appropriately harmonized phenotypes," he said.

Keating added that most of the studies that used the Cardiochip have eventually progressed into using whole-genome genotyping arrays in GWAS and added that many have "already embarked on whole-exome or whole-genome sequencing through various funding mechanisms."

Keating's efforts have also encouraged Illumina to develop its own set of focused arrays.

"Illumina liked the focused approach of the array and saw it as complementary to GWAS and they have developed a number of additional disease-focused arrays in immunology and metabolism which are even cheaper and have more updated content," said Keating.

Illumina sold the HumanCVD BeadChip from 2007 until last year. The chip included nearly 50,000 markers for 2,100 genes associated with disease processes such as blood pressure changes, insulin resistance, metabolic disorders, dyslipidemia, and inflammation, according to the firm's website.

A company spokesperson told BioArray News this week that Illumina stopped producing the HumanCVD when the "studies on the array were completed and the beadpool was fully utilized."

Illumina has other options for researchers studying cardiovascular diseases. It launched the Infinium Human Cardio-Metabo BeadChip in 2009 and the array is still available, according to the spokesperson. The array has nearly four times as much content as the HumanCVD and targets a "broader spectrum" of cardiovascular and metabolic disease, she said. The array was designed to test about 200,000 SNPs and allows users to add up to 25,000 custom markers more.


Have topics you'd like to see covered inBioArray News? Contact the editor at jpetrone [at] genomeweb [.]com

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