From population-level genomic studies down to single-cell sequencing, a new research program is setting its sights on understanding acquired genetic mutations in autoimmune and inflammatory diseases.
From population-level genomic studies down to single-cell sequencing, a new research program is setting its sights on understanding acquired genetic mutations in autoimmune and inflammatory diseases.
Clinician-scientist Dr Owen Siggs has been awarded an eight-year multimillion-dollar fellowship, starting in 2021, at the Garvan Institute of Medical Research in Sydney, where he will examine how genetic mutations acquired during someone’s lifetime influence their risk of developing an inflammatory or autoimmune disease.
It’s the first time researchers have been in a position to interrogate inflammatory and autoimmune conditions in such detail, Dr Siggs told Rheumatology Republic. “It’ll let us tackle big questions with an ambitious research program,” he said.
Collectively, inflammatory and autoimmune conditions affect nearly 10% of the population; however, genomic sequencing studies have typically focused on inherited genetic mutations in a few common conditions, like rheumatoid arthritis or lupus.
Dr Siggs, aided by new sequencing tools and methods, plans to explore acquired genetic changes present in more than 40 inflammatory and autoimmune conditions.
Before his medical training, Dr Siggs studied immunology and genetics under Nobel Laureate Bruce Beutler,who co-developed etanercept, one of the early TNF inhibitors now used widely in rheumatology.
Dr Siggs’ previous research has focused on inherited genetic mutations in inflammatory and other diseases but from next year, he will be venturing into a new frontier of research where immunology and ageing have recently converged.
Researchers have found acquired gene mutations that accumulate over many years in white blood cells and appear to promote inflammation in blood vessels. First identified as a risk factor for heart disease – on par with high blood pressure and high cholesterol – the mutations are common, found in as many as one-fifth of people aged 70 and over.
“That’s what got me hooked. This is a really common phenomenon that appears to influence inflammation,” Dr Siggs explained.
“Ultimately, we want to know which autoimmune and inflammatory diseases might be influenced by these kinds of acquired genetic changes.”
This will involve population-wide studies, starting with data on 500,000 individuals in the UK Biobank.
At the other end of the resolution spectrum, single-cell sequencing will allow Dr Siggs and his team to look “in exquisite detail” at immune cells, isolated from individual patients, which they suspect are driving these diseases.
Lab-based studies will also be part of the program to establish exactly how acquired genetic changes – which might only be present in a tiny fraction of a patient’s immune cells – contribute to disease, in the hope of finding new pathways to target for treatment.
Working with the Garvan-led Clinical Immunogenomics Research Consortium Australasia (CIRCA), Dr Siggs knows first-hand how transformative genomic sequencing can be for some patients.
“We’re always on the lookout for interesting cases, and ways that genomics might be able to help,” he said.
