ARPC2 and Ulcerative Colitis

ARPC2, a critical component of the actin‐related protein 2/3 complex, has been implicated in the pathogenesis of ulcerative colitis, a common form of inflammatory bowel disease. Multiple multi-patient studies have identified ARPC2 among several loci associated with increased UC susceptibility, supporting its role as a modest risk factor (PMID:18836448). The association emerges from genome-wide analyses that compared affected individuals to controls, thereby highlighting reproducible genetic signals across independent cohorts.

In the initial large‐scale study, 1,167 UC cases and 777 healthy controls were examined, and ARPC2 was reported among loci showing significant association with disease (PMID:18836448). A subsequent Dutch study involving 561 UC cases in the replication phase and an overall analysis of 1,455 cases with 1,902 controls further demonstrated an additive effect of various risk alleles, with ARPC2 contributing to the polygenic susceptibility for UC (PMID:19861958). Additionally, data from a South Asian cohort, despite ethnic heterogeneity, reinforced the identification of ARPC2 as one of several modest loci in inflammatory bowel disease (PMID:30568945).

The genetic evidence for ARPC2 is characterized by a consistent, albeit modest, signal across multiple studies. While no distinct, high-penetrance coding variants for ARPC2 have been identified, the recurrent association across diverse populations points to a regulatory rather than structural mechanism of disease causation. The absence of an unambiguous HGVS-coded variant indicates that ARPC2 likely influences disease risk through subtle alterations in gene expression or RNA processing.

Notably, functional assessments of ARPC2 have provided insight into its regulatory potential. Research has demonstrated that the ARPC2 mRNA exists in two alternatively spliced 5'-UTR forms, with the longer variant harboring an internal ribosome entry site (IRES) and a guanine-quadruplex motif. This structural configuration supports cap-independent translation, particularly under conditions of cellular stress, thereby offering a plausible biological mechanism for the gene’s contribution to inflammatory responses (PMID:31387452).

Integrating the genetic and functional evidence, the data support a moderate association between ARPC2 and ulcerative colitis. Although the effect sizes are modest and no single pathogenic variant is uniquely compelling, the consistent replication across populations and the biologically plausible mechanism of translational regulation lend credence to the clinical relevance of ARPC2 in UC. These findings augment the polygenic risk model for ulcerative colitis and may eventually inform diagnostic decision-making and personalized treatment strategies.

Key take‑home sentence: ARPC2 represents a risk-modifying factor in ulcerative colitis, with integrated genetic and functional evidence supporting its utility in refining the molecular diagnosis and risk stratification of this complex disease.

References

• Nature Genetics • 2008 • Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility PMID:18836448
• The American Journal of Gastroenterology • 2010 • Genetic analysis in a Dutch study sample identifies more ulcerative colitis susceptibility loci and shows their additive role in disease risk PMID:19861958
• World Journal of Clinical Cases • 2018 • Genetic associations of inflammatory bowel disease in a South Asian population PMID:30568945
• RNA Biology • 2019 • Alternatively spliced variants of the 5'-UTR of the ARPC2 mRNA regulate translation by an internal ribosome entry site (IRES) harboring a guanine-quadruplex motif PMID:31387452

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