Objective:

To identify genetic variants associated with calcium pyrophosphate deposition disease (CPPD) through a genome-wide association study.

Approach:

• Study Design: A genome-wide association study analyzed over 26 million genetic variants in participants from the Million Veteran Program, focusing on chondrocalcinosis.
• Population: The study involved over 635,000 U.S. veterans of African and European ancestry.

Key Findings:

• Two significant loci on chromosome 6 within ENPP1 and RNF144B were associated with chondrocalcinosis, confirmed in a secondary analysis of crystal arthropathy.
• ENPP1 variant rs6939185 was linked to a 32% increased risk in individuals of European ancestry.
• ENPP1 variant rs11963689 was associated with a 78% increased risk in individuals of African ancestry.
• The associated variants were specific to CPPD-related phenotypes and not linked to other mineralization-related conditions.

Interpretation:

The findings suggest that genetic variations in ENPP1 and RNF144B contribute to the risk of CPPD, enhancing understanding of its genetic architecture.

Limitations:

• The MVP cohort was predominantly male (91.2%) with a mean age of 62, limiting generalizability.
• Estimated heritability of chondrocalcinosis was modest at ~15% in African ancestry and ~9% in European ancestry.
• Study limitations include reliance on administrative coding, potential underascertainment of disease, absence of tissue-specific expression data from cartilage.
• There was a lack of female representation in the study.

Conclusion:

The study identified genetic variations in ENPP1 and RNF144B associated with chondrocalcinosis.

Sources:

• Annals of the Rheumatic Diseases