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Rheumatoid arthritis is a disease where immune cells attack healthy cells, resulting in swelling, pain, and stiffness, mainly in the joints. While there is no cure for rheumatoid arthritis, sufferers can use medications to manage their symptoms. Not everyone responds well to this type of treatment, so researchers want to develop new ways to fight this disease.
Scientists have shown that a combination of genetic and environmental factors contribute to the onset of rheumatoid arthritis. The underlying genetic causes are complicated. Just like a car could break down for many reasons, multiple genetic risk factors can underlie rheumatoid arthritis. If scientists can understand the genetics of rheumatoid arthritis better, they can design improved therapies to treat it. They could also use genetics to predict if someone is at risk of developing it.
To study our genetics, scientists look at DNA, which serves as an instruction manual for building our bodies. Changes in DNA can cause disruption and disease. By comparing DNA from rheumatoid arthritis patients with that of healthy volunteers, scientists hope to identify changes in their DNA that could be causing the disease. This type of DNA comparison is called a genome-wide association study, or GWAS for short.
A previous GWAS found genetic changes in over 100 regions of DNA that were more common in people with rheumatoid arthritis than in people without it. Many of these changes, referred to as genetic markers, were related to genes involved in the immune system. This previous work only included people of European and East Asian ancestry. So researchers in the USA and Japan recently performed GWAS across a wider range of patients with rheumatoid arthritis to look for genetic markers across different ancestral backgrounds.
The authors analyzed DNA from 35,871 patients with rheumatoid arthritis and 240,149 healthy volunteers. These patients spanned 5 different ancestries, including 22,350 Europeans, 11,025 East Asians, 999 Africans, 986 South Asians, and 511 Arabs.
Using specialized computer programs designed to analyze GWAS data, the authors searched the DNA for any genetic changes that occurred more often in the patients with rheumatoid arthritis than in the healthy volunteers. They found 124 regions of DNA with genetic changes associated with rheumatoid arthritis, 34 of which had not been found before.
Although GWAS can help scientists find regions of DNA that contain genetic markers, it can’t tell them exactly which change within the region is causing the disease. Direct identification is difficult because the culprit changes are often hidden amongst a big block of other, unrelated changes. Imagine trying to pick out who is playing your favorite tune in a room of musicians playing different songs – their identity would be hidden by the background noise.
The authors tackled this problem by zooming into each region of DNA using a statistical technique that calculates the probability that each individual change is driving the disease, called fine-mapping. They investigated both the known and new regions of DNA changes with this technique. In 7 of these regions they found individual changes with a nearly 100% likelihood of contributing to rheumatoid arthritis.
They also narrowed down the number of individual changes they suspected could contribute to rheumatoid arthritis to less than 10 changes in 43 regions. This is analogous to narrowing down the group of musicians in the room to a handful who could be playing your favorite song. Many of the changes they found to be related to rheumatoid arthritis with fine-mapping were linked to genes involved in the immune system, including changes to a gene that usually works to reduce inflammation.
This team discovered new genetic markers for rheumatoid arthritis that occurred across all ancestries, but questions remain. For example, they were only able to identify genetic markers that were specific to people of European and East Asian descent. They had too few samples to identify genetic markers that might be specific to people of African, South Asian, or Arab descent.
This limitation meant that they could only predict the risk of a European or East Asian person developing rheumatoid arthritis from their DNA. They highlighted that future research is needed to examine genetic markers in rheumatoid arthritis patients from poorly represented ancestral backgrounds.
Original study: Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
Study was published on: November 4, 2022
Study author(s): Kazuyoshi Ishigaki, Saori Sakaue, Chikashi Terao, Yang Luo, Kyuto Sonehara, Kensuke Yamaguchi, Tiffany Amariuta, Chun Lai Too, Vincent A. Laufer, Ian C. Scott, Sebastien Viatte, Meiko Takahashi, Koichiro Ohmura, Akira Murasawa, Motomu Hashimoto, Hiromu Ito, Mohammed Hammoudeh, Samar Al Emadi, Basel K. Masri, Hussein Halabi, Humeira Badsha, Imad W. Uthman, Xin Wu, Li Lin, Ting Li, Darren Plant, Anne Barton, Gisela Orozco, Suzanne M. M. Verstappen, John Bowes, Alexander J. MacGregor, Suguru Honda, Masaru Koido, Kohei Tomizuka, Yoichiro Kamatani, Hiroaki Tanaka, Eiichi Tanaka, Akari Suzuki, Yuichi Maeda, Kenichi Yamamoto, Satoru Miyawaki, Gang Xie, Jinyi Zhang, Christopher I. Amos, Edward Keystone, Gertjan Wolbink, Irene van der Horst-Bruinsma, Jing Cui, Katherine P. Liao, Robert J. Carroll, Hye-Soon Lee, So-Young Bang, Katherine A. Siminovitch, Niek de Vries, Lars Alfredsson, Solbritt Rantapää-Dahlqvist, Elizabeth W. Karlson, Sang-Cheol Bae, Robert P. Kimberly, Jeffrey C. Edberg, Xavier Mariette, Tom Huizinga, Philippe Dieudé, Matthias Schneider, Martin Kerick, Joshua C. Denny, The BioBank Japan Project, Koichi Matsuda, Keitaro Matsuo, Tsuneyo Mimori, Fumihiko Matsuda, Keishi Fujio, Yoshiya Tanaka, Atsushi Kumanogoh, Matthew Traylor, Cathryn M. Lewis, Stephen Eyre, Huji Xu, Richa Saxena, Thurayya Arayssi, Yuta Kochi, Katsunori Ikari, Masayoshi Harigai, Peter K. Gregersen, Kazuhiko Yamamoto, S. Louis Bridges Jr, Leonid Padyukov, Javier Martin, Lars Klareskog, Yukinori Okada, Soumya Raychaudhuri
The study was done at: RIKEN Center for Integrative Medical Sciences (Japan), Broad Institute of MIT and Harvard (USA)
The study was funded by: Ministry of Health Malaysia, Swedish National Research Council, Versus Arthritis, National Institutes of Health, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Kanae Foundation for the Promotion of Medical Science, Astellas Foundation for Research on Metabolic Disorders, Canadian Institutes for Health Research Foundation, National Institute for Health and Care Research, Canadian Foundation for Innovation, National Research Foundation, Qatar Foundation, Spanish Ministry of Science and Innovation, Takeda Science Foundation
Raw data availability: Raw data can be found here and on GitHub.
Featured image credit: Photo by Towfiqu barbhuiya on Unsplash
This summary was edited by: Aubrey Zerkle