Calcium pyrophosphate deposition disease (CPPD), or pseudogout, is one of the most common forms of inflammatory arthritis in individuals over 60 years of age and is characterized by the deposition of CPP crystals in articular tissues, leading to recurrent painful attacks and chronic joint inflammation, potentially causing cartilage breakdown if left untreated.
CPPD faces a high unmet need, as treatment options commonly focus on the alleviation of inflammation, most often with non-steroidal anti-inflammatory drugs. The genetic basis of CPPD is unknown, which limits the development of new therapeutic strategies.
This image shows an X-ray revealing chondrocalcinosis (radiographic evidence of CPPD) in the lateral menisci and hyaline cartilage of both knees. [Sara Tedeschi, MD]
In a new study published in the Annals of the Rheumatic Diseases titled, “Genome-wide association study in chondrocalcinosis reveals ENPP1 as a candidate therapeutic target in calcium pyrophosphate deposition disease,” researchers have undergone the first systematic genome-wide association study (GWAS) for CPPD to identify two genes, RNF144B and ENPP1, that are strongly associated with CPPD development in Americans of European and African descent. The results open new avenues for targeted prevention and treatment for pseudogout.
“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,” emphasized Josef Smolen, MD, editor-in-chief of the Annals of the Rheumatic Diseases.
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.
Traditionally, CPDD has not been explicitly included or codified in large biobanks, thereby limiting genetic studies. Additionally, studies of common genetic chondrocalcinosis and CPPD disease have been restricted to small cohorts.
Led by Tony Merriman, PhD, professor in the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham, the study carried out GWAS in the Million Veterans Program, which comprises more than 550,000 Veterans of African and European genetic ancestry drawn from the U.S. Veterans Health Administration. Colocalization analysis of CPPD genetic association signals with genetic control of gene expression and alternative splicing supported ENPP1 and RNF114B as candidate causal genes.
According to Sara K. Tedeschi, MD, assistant professor, Harvard Medical School, rheumatology director at Brigham and Women’s Hospital, and co-author of the study, the genome-wide association with ENPP1 is particularly exciting for a rheumatologist because it “makes sense.” 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.
“Patients with CPPD disease are desperate for an effective treatment, and trials testing ENPP1 inhibitors in CPPD disease would be of great interest,” said Tedeschi.
RNF144B is identified to negatively regulate apoptosis and is inducible to promote the expression of pro-inflammatory cytokine, IL-1β, in primary human macrophages. The authors state that how RNF144B could contribute to the pathogenesis of CPPD remains unclear.
Drugs targeting the ENPP1 protein have been developed to address infectious disease and cancer. Future work will evaluate these existing drugs for the treatment of CPPD disease.
The post Genetic Links for Common Inflammatory Arthritis Open Treatment Options appeared first on GEN - Genetic Engineering and Biotechnology News.
CPPD faces a high unmet need, as treatment options commonly focus on the alleviation of inflammation, most often with non-steroidal anti-inflammatory drugs. The genetic basis of CPPD is unknown, which limits the development of new therapeutic strategies.
This image shows an X-ray revealing chondrocalcinosis (radiographic evidence of CPPD) in the lateral menisci and hyaline cartilage of both knees. [Sara Tedeschi, MD]
In a new study published in the Annals of the Rheumatic Diseases titled, “Genome-wide association study in chondrocalcinosis reveals ENPP1 as a candidate therapeutic target in calcium pyrophosphate deposition disease,” researchers have undergone the first systematic genome-wide association study (GWAS) for CPPD to identify two genes, RNF144B and ENPP1, that are strongly associated with CPPD development in Americans of European and African descent. The results open new avenues for targeted prevention and treatment for pseudogout.
“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,” emphasized Josef Smolen, MD, editor-in-chief of the Annals of the Rheumatic Diseases.
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.
Traditionally, CPDD has not been explicitly included or codified in large biobanks, thereby limiting genetic studies. Additionally, studies of common genetic chondrocalcinosis and CPPD disease have been restricted to small cohorts.
Led by Tony Merriman, PhD, professor in the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham, the study carried out GWAS in the Million Veterans Program, which comprises more than 550,000 Veterans of African and European genetic ancestry drawn from the U.S. Veterans Health Administration. Colocalization analysis of CPPD genetic association signals with genetic control of gene expression and alternative splicing supported ENPP1 and RNF114B as candidate causal genes.
According to Sara K. Tedeschi, MD, assistant professor, Harvard Medical School, rheumatology director at Brigham and Women’s Hospital, and co-author of the study, the genome-wide association with ENPP1 is particularly exciting for a rheumatologist because it “makes sense.” 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.
“Patients with CPPD disease are desperate for an effective treatment, and trials testing ENPP1 inhibitors in CPPD disease would be of great interest,” said Tedeschi.
RNF144B is identified to negatively regulate apoptosis and is inducible to promote the expression of pro-inflammatory cytokine, IL-1β, in primary human macrophages. The authors state that how RNF144B could contribute to the pathogenesis of CPPD remains unclear.
Drugs targeting the ENPP1 protein have been developed to address infectious disease and cancer. Future work will evaluate these existing drugs for the treatment of CPPD disease.
The post Genetic Links for Common Inflammatory Arthritis Open Treatment Options appeared first on GEN - Genetic Engineering and Biotechnology News.