The potential to prevent and treat a common type of inflammatory arthritis has been advanced thanks to a University of Otago – Ōtākou Whakaihu Waka researcher's 'eureka moment'.
Dr Tony Merriman, of Otago's Department of Microbiology and Immunology and currently based at the University of Alabama at Birmingham, is lead investigator on a first-of-its-kind genome-wide association study into calcium pyrophosphate deposition (CPPD) disease.
By analysing the genes of 550,000 US veterans of African and European descent, researchers discovered two genes that cause the debilitating condition, caused by calcium pyrophosphate (CPP) crystal deposition in joints.
The study, published in the Annals of the Rheumatic Diseases, opens up promising new avenues for targeted prevention and treatment of CPPD disease, which are currently lacking.
"The most significant result of our research was the discovery of one of the genes, ENPP1.
"The protein encoded by this gene controls the production of chemicals – adenosine monophosphate and inorganic pyrophosphate – that, together with calcium ions, lead to the formation of the CPP crystals," Dr Merriman says.
A groundbreaking study has uncovered new genetic links to calcium pyrophosphate deposition (CPPD) disease, a common type of inflammatory arthritis. This image shows an X-ray revealing chondrocalcinosis (radiographic evidence of CPPD) in the cartilage of both knees. CREDIT: Sara Tedeschi
CPPD disease can cause acute or chronic joint symptoms and is one of the most common forms of inflammatory arthritis in people over 60 years of age.
Acute CPP crystal arthritis, historically called 'pseudogout', is the most widely recognized form of CPPD disease. Chondrocalcinosis, a radiographic finding that is most often due to CPPD, is common in older adults and doubles in prevalence with each decade beyond age 60.
The current research assessed genes for their association with CPPD disease. It was carried out using the Million Veterans Program, made up of more than 550,000 veterans (91 per cent male) of African and European genetic ancestry drawn from the US Veterans Health Administration.
The main finding was the identification of two genes, RNF144B and ENPP1, that cause CPPD disease in Americans. Importantly, the same genes were detected both in people of European ancestry and of African ancestry.
Co-investigator Dr Sara K. Tedeschi, of the Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, and Harvard Medical School, Boston, says the genome-wide association with ENPP1 is "particularly exciting" as a rheumatologist because "it makes sense".
"ENPP1 generates inorganic pyrophosphate, one of the components of CPP crystals. Patients with CPPD disease are desperate for an effective treatment, and trials testing ENPP1 inhibitors in CPPD disease would be of great interest."
Little is known about the other gene, RNF144B, aside from that it is possibly involved in inflammation.
More is known about ENPP1 and, of potential importance to people with CPPD disease, drugs targeting the protein have been developed in the treatment of infectious disease and cancer that could be evaluated for the treatment of CPPD disease.
Dr Josef Smolen, of the Medical University of Vienna, Austria, and Editor-in-Chief of the Annals of the Rheumatic Diseases, says there is a "considerable unmet need" for treatment of CPPD disease, which commonly focuses on the alleviation of inflammation, most often with non-steroidal anti-inflammatory drugs colchicine or prednisone.
"This first GWAS study in CPPD disease points to two targets for future treatment, which is crucial given the current lack of options for patients."
Dr Merriman says the researchers are "thrilled" about the potential impact of what they have uncovered, and the possibility of new drugs being developed for the treatment of CPPD disease.
"The findings of this study produced a 'eureka moment', which can be rare in a scientist's career."
