A genome-wide association study has identified two genes—ENPP1 and RNF144B—as being associated with risk of calcium pyrophosphate deposition disease, a form of crystal arthritis that primarily affects older adults.

The study analyzed more than 26 million genetic variants in participants from the Million Veteran Program (MVP), a cohort of over 635,000 U.S. veterans of African and European ancestry. It represents the first genome-wide association study (GWAS) focused on chondrocalcinosis, the radiographic finding typically attributed to calcium pyrophosphate deposition (CPPD).

CPPD, sometimes referred to as pseudogout, results from deposition of calcium pyrophosphate crystals in joint cartilage, leading to inflammation and joint damage. Although it shares some clinical features with gout, CPPD is caused by distinct crystal types and has lacked comprehensive genetic characterization.

The investigators identified two genome-wide significant loci on chromosome 6, located within ENPP1 and RNF144B, associated with chondrocalcinosis:

• Among individuals of European ancestry, ENPP1 variant rs6939185 was associated with a 32% increased risk of chondrocalcinosis.

• Among individuals of African ancestry, variant rs11963689 was associated with a 78% increased risk.

A secondary analysis of crystal arthropathy—operationally defined to include calcium crystal deposition disorders excluding gout—confirmed these associations in both ancestry groups.

ENPP1 encodes an enzyme responsible for generating inorganic pyrophosphate (PPi), which combines with calcium to form calcium pyrophosphate crystals. The identified variants were associated with increased ENPP1 expression in multiple tissues, including brain and skeletal muscle, based on colocalization with expression data from the GTEx project.

At the same locus, the variant also influenced expression of RP1-131F15.2, a long noncoding RNA, in the thyroid and pituitary glands.

The RNF144B locus was associated with alternative RNA splicing across 25 tissues. While the function of RNF144B in CPPD pathogenesis remains unclear, the gene has been implicated in immune signaling and inflammatory pathways.

The associated variants were not significantly linked to other mineralization-related conditions, including osteoarthritis, osteoporosis, fractures, or aortic valve disease, indicating specificity to CPPD-related phenotypes.

The findings suggest that ENPP1 may represent a potential therapeutic target. Selective NPP1 inhibitors, originally developed for other indications, could be evaluated for CPPD treatment. However, given ENPP1’s widespread expression, the investigators noted that systemic inhibition may lead to off-target effects and should be assessed cautiously.

The MVP cohort was 91.2% male, with a mean age of 62 years, potentially limiting generalizability to broader populations. The estimated heritability of chondrocalcinosis was ~15% in African ancestry and ~9% in European ancestry, indicating a modest genetic contribution.

Limitations of the study include reliance on administrative coding (Phecodes), potential underascertainment of disease in controls, absence of tissue-specific expression data from cartilage, and a lack of female representation.

The study identified genetic variation in ENPP1 and RNF144B as being associated with chondrocalcinosis and calcium crystal arthropathy in individuals of both African and European ancestry. These results contribute to understanding the genetic architecture of CPPD and may inform future investigations of disease mechanisms and potential therapeutic approaches.

Some authors reported consulting fees unrelated to the content of this study. See the full publication for detailed disclosures.

Source: Annals of the Rheumatic Diseases