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Researchers Report on Epigenome-wide Association Study of Rheumatoid Arthritis

NEW YORK (GenomeWeb News) – An epigenome-wide association study conducted by investigators in the US and Sweden has uncovered methylation patterns that appear to modulate individuals' genetic risk of developing rheumatoid arthritis.

As they reported online this weekend in Nature Biotechnology, the researchers used arrays to profile cytosine methylation marks across the genome using blood samples from 354 rheumatoid arthritis cases and nearly as many controls, focusing on sites where cytosine and guanine nucleotides frequently fall next to one another.

Through comparisons of methylation profiles at these CpG sites in cases and controls, coupled with careful analyses, the team uncovered 10 differentially methylated regions that appear to influence genetic risk of rheumatoid arthritis.

Nine of the 10 top CpG sites clumped together in parts of the genome containing immune-related major histocompatibility, or MHC, genes, suggesting that some of the same sites linked to arthritis through genetic studies may have additional epigenetic ties to the disease. At four suspicious CpG sites, the team unearthed genetic variants linked to the presence of arthritis-related methylation profiles.

"This could explain why risk genes assert themselves and cause disease," co-senior author Tomas Ekstrom, a molecular cell biology researcher with the Karolinska Institute, said in a statement, "and why some people are affected more easily than others."

Past studies have implicated dozens of variants in rheumatoid arthritis risk. But beyond researchers' genetic understanding of the rheumatoid arthritis — which itself remains incomplete — some have speculated that epigenetic features also influence individuals' propensity for the disease.

Epigenetic marks such as cytosine methylation may also help mediate interactions between genetic and environmental risk factors for rheumatoid arthritis, authors of the new study said.

If so, they added, epigenetic associations with the disease could be an avenue into a more complete picture of rheumatoid arthritis, both in terms of the marks themselves and what they reveal about broader rheumatoid arthritis biology and genetics.

"We and others have suggested that genetic and epigenetic modifications could interact biologically," they wrote, "and that methylation analysis might uncover heritable variants contributing to disease that are invisible to conventional genome-wide association studies."

To explore such questions, the researchers started with blood samples from 354 Swedish individuals with rheumatoid arthritis who were enrolled in a population study in that country, profiling genome-wide methylation patterns in the samples with Illumina's HumanMethylation450 array.

From there, the team looked for sites showing distinctly different methylation levels in the rheumatoid arthritis cases relative to their methylation status in blood samples from 335 unaffected control individuals tested using the same array.

Before they jumped into potential associations between methylation and disease, though, the investigators took a step back to consider possible confounders that might interfere with their ability to find informative epigenetic contributors to rheumatoid arthritis. To dial back potentially confusing methylation patterns due to the range of blood cell types present in each sample, for instance, the researchers adjusted their results based on the estimated proportion of specific cell types in the blood.

Similarly, the team used analytical methods designed to focus in on methylation marks related to genetic risk of rheumatoid arthritis and to weed out signals that might stem from methylation changes caused by the disease itself.

Of the top 10 most promising sites — those that most often showed differential methylation in the rheumatoid arthritis cases compared to the controls — the team saw nine sites clustering in an MHC region on chromosome 6. The remaining differentially methylated site was also on chromosome 6, but fell outside of the MHC area.

When they took a closer look at the methylation marks relative to gene sequence information, meanwhile, investigators found four regions where disease-related differential methylation was genotype-dependent, hinging on the presence or absence of a particular variant.

"We think that certain genetic sequences may be biologically beneficial and conserved over time because they increase the amount of variation found in tagging patterns," Feinberg noted, "giving individuals a greater chance of adapting to environmental changes."

Study authors noted that future work may also help find epigenetic profiles with ties to environmental rather than genetic risk factors for rheumatoid arthritis.