Breakthrough study finds genes behind calcium pyrophosphate deposition disease

In a first-of-its-kind genome-wide association study (GWAS) researchers have discovered two genes, RNF144B and ENPP1, that cause calcium pyrophosphate deposition (CPPD) disease in Americans of European and African descent. This crystalline arthritis is caused by calcium pyrophosphate (CPP) crystal deposition in joints. The findings of this novel study in the Annals of the Rheumatic Diseases, published by Elsevier, open up promising new avenues for targeted prevention and treatment of CPPD disease, which are currently lacking.

Characterized by the deposition of CPP crystals in articular tissues, CPPD disease is a heterogeneous crystalline arthritis that can cause acute or chronic joint symptoms and is one of the most common forms of inflammatory arthritis in individuals over 60 years of age. In Europe and North America, the prevalence of imaging evidence of CPPD disease is estimated to be about 10% in middle-aged adults, depending on articular location, with prevalence increasing to approximately 30% in adults over 80 years of age. CPPD disease is also associated with cartilage degradation and osteoarthritis, although it remains unclear whether CPPD disease is a cause or consequence of these conditions.

Acute CPP crystal arthritis, historically called "pseudogout," is the most widely recognized form of CPPD disease. It results from CPP crystals in the joint activating pro-inflammatory pathways, leading to IL-1b secretion and causing acute inflammatory arthritis. 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 entailed a GWAS in which all genes in the human genome were simultaneously assessed for association with CPPD disease. The study was carried out in the Million Veterans Program, comprising more than 550,000 Veterans (91% 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 in both people of European ancestry and African ancestry.

Lead investigator Tony R. Merriman, PhD, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham; Birmingham Department of Veterans Affairs Health Care System; and Department of Microbiology and Immunology, University of Otago (Dunedin, New Zealand), says, "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."

Co-investigator Sara K. Tedeschi, MD, MPH, Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, and Harvard Medical School, Boston, adds, "The genome-wide association with ENPP1 is particularly exciting to me 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.

Josef Smolen, MD, Medical University of Vienna (Austria), and Editor-in-Chief of the Annals of the Rheumatic Diseases, comments, "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 concludes, "We are thrilled about the potential impact of what we have uncovered in our research 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."