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The association between LCE3D and psoriasis is supported by robust findings from large-scale case‑control studies. One discovery study screened 781 psoriasis cases and 676 controls, with subsequent replication in nearly 10,000 cases and an equivalent number of controls (PMID:24212883). This high-powered analysis achieved genome‑wide significance for multiple coding variants in LCE3D. The consistency of the association across independent cohorts underlines its clinical relevance. Such evidence lends the association a ClinGen category of Strong and highlights its potential contribution to diagnostic decision‑making in psoriasis. The study design and statistical strength support the commercial and translational value of incorporating LCE3D in genetic panels.
The genetic evidence is derived from common missense single‑nucleotide variants that predispose to psoriasis. Notably, one recurrent variant, c.411A>G (p.Lys137Arg), has been identified as a significant contributor, reflecting its impact on protein function. Although detailed familial segregation data are absent, the large case numbers (781 cases in the discovery phase and 9,946 in replication (PMID:24212883)) underscore the variant’s importance. In addition, secondary studies reporting genotype–phenotype correlations further substantiate the genetic association. These observations confirm that alterations in LCE3D meaningfully elevate the risk of developing psoriasis, even if the precise mode of inheritance is complex.
Despite the robust genetic findings, functional or experimental data remain limited. Currently, no direct functional assays, expression studies, or animal models have been reported that delineate the pathogenic mechanism of LCE3D variants in psoriasis. However, the well‐established role of LCE3D in skin barrier integrity and epithelial differentiation offers a plausible biological basis for its involvement. Inferences from pathway analyses suggest that dysfunction in this gene may compromise epidermal homeostasis, predisposing individuals to inflammatory processes seen in psoriasis. Further functional validation is required to elucidate the exact molecular consequences of the identified variants. This gap highlights an important area for future research to better inform therapeutic strategies.
The evidence has been carefully scrutinized for any conflicting reports. No studies have convincingly refuted the association; rather, data from both the discovery and treatment‐response studies converge on a consistent link between LCE3D and psoriasis. Although some candidate genes were also analyzed in the respective studies, the association signal for LCE3D remained robust. This uniformity reinforces clinical confidence in the genetic association. The absence of contradicting evidence from independent cohorts or experimental platforms enhances the credibility of the data. This clarity is crucial for integrating genetic findings into clinical workflows and commercial diagnostic tools.
Integrating the findings, the strong genetic association combined with the biological plausibility of LCE3D’s role in skin barrier function supports its clinical utility in psoriasis. While the experimental follow‑up is currently limited, the convergence of large‐scale association data is compelling. There remains the potential for additional evidence to extend beyond the current analyses, which may further solidify the gene’s role. These data collectively inform diagnostic decision‑making and offer a framework for personalized treatment in psoriasis. The commercial implications include the integration of LCE3D into genetic testing platforms. Overall, the evidence advocates for considering LCE3D variants in both clinical and research settings.
Key take‑home sentence: Robust genetic evidence firmly supports LCE3D as a valuable diagnostic marker in psoriasis, warranting its incorporation into clinical and commercial genetic testing strategies.
Gene–Disease AssociationStrongLarge‑scale case‑control studies, including over 9,700 individuals across discovery and replication phases (PMID:24212883), underline a robust association between LCE3D and psoriasis. Genetic EvidenceStrongThe identification of common missense variants, notably c.411A>G (p.Lys137Arg), in multiple cohorts reinforces the genetic contribution of LCE3D to psoriasis susceptibility. Functional EvidenceLimitedNo direct functional assays or model organism studies have yet been reported; however, the known role of LCE3D in skin barrier function supports its potential biological impact. |