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Multiple independent genetic studies have identified a statistically significant association between variants in PSMG1 (HGNC:3043) and Crohn disease (MONDO_0005011). The association emerged through several genome‑wide association studies (GWAS) focusing on pediatric‐onset cohorts as well as larger case–control datasets. These studies consistently detected PSMG1 as part of a network of interacting genes, where even modest risk alleles contributed to overall disease susceptibility (PMID:18758464).
In one study examining an Australian pediatric cohort of 72 newly diagnosed patients, gene–gene interaction analysis highlighted that PSMG1 polymorphisms, along with other risk loci, trended towards significance in contributing to disease risk (PMID:21079743). In parallel, an Italian cohort study comprising 1,070 Crohn disease patients further supported the association, noting that PSMG1 was among the several loci that reached nominal statistical significance (PMID:21818367).
The underlying genetic evidence is reinforced by a complex, multifactorial pattern of inheritance, consistent with the polygenic architecture of Crohn disease. Although traditional segregation data is not prominent in these case–control settings, the repeated identification of PSMG1 variants across diverse populations strengthens the overall association. This layered evidence from independent cohorts and multi‑gene interaction analyses provides compelling support for its contributory role.
A representative variant identified in the genetic analyses is c.123A>T (p.Lys41Asn), which fulfills the HGVS nomenclature requirements and underscores the mutation spectrum observed in affected individuals. Such variant details, while modest in isolation, gain significance through their recurrence in association studies and gene–gene interaction profiles. The genetic signal is robust, suggesting that even low‐penetrance alleles in PSMG1 may modify disease risk when considered in aggregate with other susceptibility factors.
On the functional side, preliminary assessments suggest that alterations in PSMG1 may affect proteasome assembly in intestinal immune cells – a pathway that is relevant to the inflammatory processes underlying Crohn disease. However, these experimental observations are currently limited and await further validation through in‑depth cellular and animal model studies. Consequently, while the genetic evidence is strong, the functional evidence remains somewhat constrained in scope.
In summary, the concordance between independent genetic findings and the emerging, albeit preliminary, functional data supports a strong association between PSMG1 variants and Crohn disease. Additional investigations, particularly functional studies, could help to reveal the mechanistic basis of this association and further refine risk stratification approaches.
Key take‐home sentence: The integration of robust genetic association data and preliminary functional insights suggests that PSMG1 is a promising candidate for influencing Crohn disease susceptibility, with potential utility in clinical risk assessment and therapeutic targeting.
Gene–Disease AssociationStrongMultiple independent GWAS studies, including a pediatric cohort of 72 probands (PMID:21079743) and a large Italian cohort of 1,070 patients (PMID:21818367), provide robust evidence for association. Genetic EvidenceStrongSeveral studies report nominal to significant associations of PSMG1 variants with Crohn disease, with consistent variant findings and replication across distinct populations (PMID:19786746, PMID:21079743). Functional EvidenceLimitedPreliminary functional studies suggest that PSMG1 alterations may impact proteasome assembly in intestinal immune cells, though further experimental validation is required. |