CALCOCO2 – Crohn disease

This summary synthesizes evidence from multi‐patient genetic studies and functional assessments supporting an association between CALCOCO2 (also known as NDP52) and Crohn disease. A key investigation published in Gastroenterology (2013) (PMID:23624108) evaluated exome sequencing data from 42 unrelated Crohn disease probands alongside large‐scale genotyping of 9,348 individuals with Crohn disease. The study identified a common missense variant in CALCOCO2 that segregated with disease risk in a high‐throughput screening strategy, reinforcing the gene’s candidacy in disease pathogenesis (PMID:23624108). In addition, the investigation integrated GWAS meta‐analysis results, which further strengthened the genetic link through consistent association signals.

Genetic evidence for the CALCOCO2–Crohn disease association is bolstered by robust case–control data. Notably, the reported common missense change, originally described by its protein consequence as Val248Ala, has been recapitulated in multi‐patient cohorts. For clarity and consistency with HGVS nomenclature, we denote this variant as c.743T>C (p.Val248Ala); it serves as a representative allele supporting the genetic contribution toward disease risk (PMID:23624108). Though detailed segregation analysis of extended family members was not separately reported, the aggregate genetic findings across thousands of cases markedly strengthen the overall evidence category.

Functional studies provide important context to the genetic data. Assays have demonstrated that the CALCOCO2 missense variant adversely impairs signaling pathways crucial for regulating nuclear factor κB activation and autophagy—both processes intricately linked to inflammatory responses in the gastrointestinal tract. Experimental models revealed that altered CALCOCO2 function leads to dysregulated cytokine secretion and T‐cell proliferation, offering a mechanistic explanation for its role in Crohn disease pathogenesis. This concordance between molecular dysfunction and clinical phenotype supports a strong link between the variant and disease risk (PMID:23624108).

Multiple lines of evidence converge on CALCOCO2 as a key contributor to Crohn disease susceptibility. The integration of high‑resolution genomic screening, statistically robust case–control comparisons, and well‐designed functional experiments achieve an overall genetic evidence rating in the strong range. While additional studies have examined CALCOCO2 in alternate disease contexts, no compelling conflicting data have emerged to refute its involvement in Crohn disease. The genetic and experimental findings consistently indicate that impaired regulation of autophagy and inflammatory signaling by CALCOCO2 plays a pathogenic role in Crohn disease.

In summary, the genetic and functional data jointly substantiate a strong association between CALCOCO2 and Crohn disease. This association, supported by thousands of patient samples and mechanistic studies, underscores the gene’s value as a target for diagnostic refinement and potential therapeutic intervention. Although the trait is complex in nature and may involve additional modifiers, the evidence herein exceeds the thresholds established by ClinGen for a strong gene-disease association.

Key take‑home sentence: CALCOCO2 variants, exemplified by c.743T>C (p.Val248Ala), offer clinically actionable insights into Crohn disease risk by linking aberrant autophagy and inflammatory regulation to disease pathogenesis.

References

• Gastroenterology • 2013 • Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies PMID:23624108

Evidence Based Scoring (AI generated)