GENE-ius: Irish research leads to naming of human gene linked to rheumatoid arthritis

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MACIR team at UCD

Dr Kevin Sheridan, Dr David O'Connell, Prof. Gerry Wilson and Dr Emma Dorris marking the naming of the MACIR gene. Absent is Prof. Denis Shields.


A team of doctors and scientists at the UCD Centre for Arthritis Research has been investigating the previously unnamed, mystery gene since a difference in its DNA code was linked with rheumatoid arthritis.

The gene, now called MACIR – for macrophage immunometabolism regulator – was shown this year to be important for our immune system.

Dr Emma Dorris, senior researcher on the work, said: “The immune system is crucial for the normal functioning of the body. We looked at a type of immune cell, called a macrophage that has a role in inflammation, but also in growth and healing. These cells are like conductors of an orchestra; they tell the other immune cells when to turn on inflammation or fight infection, but also when to turn off ‘fight’ mode and to turn on ‘healing’ mode.

“Therefore, when they stop working properly, the whole immune system can go out of tune. When we reduce MACIR protein, the macrophages went very out of tune. They were no longer able to properly switch from ‘fight’ mode to ‘healing’ mode.

“People with rheumatoid arthritis have less MACIR compared to people that don’t have an autoimmune condition,” Dr Dorris said.

Prof. Gerry Wilson, director of the UCD Centre for Arthritis Research and lead author of the research, has been investigating this gene for nearly 10 years. He was involved in the large genetics study in 2010 that first identified it was linked to rheumatoid arthritis.

“Autoimmune disorders like rheumatoid arthritis are what we call complex diseases. There is no single gene that will ‘give you’ RA, but there can be variations in your DNA that make you more or less likely to develop it,” he said.

He outlined how MACIR affected people with rheumatoid arthritis. “Working with our colleagues in Queen Mary, University of London, we found that when people newly diagnosed with rheumatoid arthritis had more inflammation, they produced less MACIR,” he said.

The naming of human genes is now tightly regulated with oversight from the international Human Gene Nomenclature Committee, a part of the Human Genome Organisation (HUGO). Human gene symbols can no longer form known words and must be named after the gene function.

Previously, however, gene names included SONIC Hedgehog, SMURF1 and SMURF2. In addition to being beloved cartoons from the 1980s and nineties, these are all also human genes.

According to Dr Dorris: “Many genes were first found in flies and fly scientists have, well, a particular sense of humour. Whereas a gene may be amusing and linked to the culture at the time of its discovery, trouble arises when the human versions of these genes become linked to serious and life-threatening illnesses. The comedy quickly drains out of quirky names when a doctor has to counsel patients about genetic defects with names like ‘NEMO’ and ‘Lunatic Fringe’. Both names have since been changed in humans,” she added.

When the function of a gene is unknown, it is given a temporary symbol, based on where in the DNA it is located. The gene the Irish researchers were interested in was called C5orf30, which it means it was the thirtieth sequence of DNA code that looked like a gene on chromosome 5, the fifth biggest chromosome in our cells.

Dr Dorris from UCD School of Medicine explained how scientists figure out what a gene does.

“Usually, you ask: does it look like a duck, walk like a duck and quack like a duck? If the answer is yes, you hypothesize it’s a duck and carry out experiments to confirm.

“C5orf30 did not look like a duck. In fact, it looked like nothing else in the genome (the term for all our DNA code). So, it was a long process to discover what C5orf30 actually did.”

The research leading to the new name change has been supported by the Health Research Board (HRB), Arthritis Ireland and the Irish Research Council.

Dr Darrin Morrissey, Chief Executive of the HRB, said: “Important findings like this demonstrate the importance of research and collaboration. We are delighted that through the HRB and the Health Research Charities Ireland awards scheme we can play a part in supporting research that helps to better understand the causes and mechanisms of disease and brings the hope of finding new treatments to people.”

Gráinne O’Leary, Chief Executive of Arthritis Ireland, emphasised the importance of this type of research to people in Ireland living with arthritis. “Rheumatoid arthritis affects 45,000 people in Ireland, 70 per cent of them women. This is a chronic disease that can impact on every aspect of life: physical and mental well-being, relationships, career, social life. Through investing in research such as this, Arthritis Ireland is helping us draw closer to the day when people will be free from the pain of arthritis.”

 

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