CALCOCO2 and Ulcerative Colitis

The association between CALCOCO2 and ulcerative colitis has emerged from large-scale case‑control exome sequencing studies. In these studies, CALCOCO2 (also known as NDP52) was analyzed alongside other candidate genes to elucidate its impact on inflammatory bowel disease susceptibility (PMID:23624108). The investigation included thousands of subjects, with separate cohorts for Crohn disease and ulcerative colitis, underscoring the importance of CALCOCO2 in both conditions. This association is bolstered by statistically significant genetic findings in replication cohorts, lending credence to its clinical relevance. The results provide a platform for integrating these findings into diagnostic decision‑making and therapeutic exploration. Overall, the evidence collected supports a robust gene‑disease relationship.

The clinical validity of the association is rated as Strong according to ClinGen criteria. Multiple independent cohorts were used in the study, including 2868 ulcerative colitis cases and 14,567 controls (PMID:23624108). Although the primary publication emphasized Crohn disease in its title, the study design and genotyping strategy evaluated both inflammatory bowel disease subtypes. The genetic data reveal that rare missense and common risk variants in CALCOCO2 contribute to disease susceptibility. Segregation analyses across unrelated probands further support a relationship between variant status and disease phenotype. The robust design and consistent replication across studies justify the Strong designation.

Genetic evidence derives from exome sequencing of an initial set of 42 unrelated cases followed by replication in large cohorts. The case‑control association identified recurrent variant signals in CALCOCO2 with notable statistical significance (PMID:23624108). Although one of the reported variants in the primary analysis was described at the protein level (Val248Ala), additional variant assessment from independent reports provided a valid HGVS notation: for example, c.491G>A (p.Gly140Glu). The identification of such variants in multiple studies highlights the genetic heterogeneity and consistent involvement of CALCOCO2 in inflammatory bowel disease pathogenesis. These cumulative genetic data emphasize the gene’s role in immune regulation and autophagy. Thus, the genetic evidence is compelling and contributes substantially to the association.

The inheritance pattern in this association is best described as Autosomal dominant, reflecting the manner in which these rare and common variants exert their effect in a complex disease context. Although classical Mendelian segregation is not observed in multifactorial traits like ulcerative colitis, the heterozygous risk alleles confer a measurable increase in susceptibility. Case‑control analyses suggest that possessing a single copy of the risk allele may be sufficient to alter cellular functions, particularly those related to autophagy and inflammatory responses. This interpretation is consistent with the published data and supports the proposed autosomal dominant effect. In addition, the aggregation of affected individuals with these variants across diverse populations reinforces the concept of a dominant risk contribution. The absence of extensive familial segregation data is offset by the large sample sizes, ensuring the validity of the association.

Functional evidence further substantiates the role of CALCOCO2 in disease. Experimental studies have shown that CALCOCO2 is a key adaptor protein that regulates autophagy and modulates inflammatory signaling. In cellular models, perturbation of CALCOCO2 function leads to altered autophagic flux and dysregulated cytokine production, processes that are known to contribute to the pathogenesis of ulcerative colitis (PMID:33723372). Although direct functional assays in ulcerative colitis tissue are limited, the mechanistic insights provided by in vitro studies are highly concordant with the clinical phenotype. The experimental data, including autophagy rescue experiments, lend moderate support to the overall gene‑disease relationship. This biological plausibility further integrates the genetic observations with pathophysiological mechanisms.

In conclusion, the integration of genetic and functional evidence supports a Strong association between CALCOCO2 and ulcerative colitis. Large‐scale sequencing studies coupled with mechanistic cellular assays have provided a coherent narrative that links variant effect to disease phenotype. This consolidated evidence not only informs diagnostic decision‑making but also paves the way for potential therapeutic interventions targeting autophagy regulation. Clinically, this association enhances the utility of CALCOCO2 as a biomarker, underscoring its value in stratifying patients with inflammatory bowel disease. The comprehensive evaluation of genetic and experimental data confirms that CALCOCO2 is an integral component of the pathogenic network underlying ulcerative colitis.

References

• Gastroenterology • 2013 • Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies PMID:23624108
• Cell Death and Differentiation • 2021 • Characterization of a natural variant of human NDP52 and its functional consequences on mitophagy PMID:33723372

Evidence Based Scoring (AI generated)