Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
SHLD2 (HGNC:28773) has emerged as a potential susceptibility gene for gout (MONDO_0005393) based on multi‐population genome‑wide association studies. In these studies, cohorts including Japanese, Caucasian, and Polynesian subjects were analyzed, and statistically significant association signals were observed for gout, suggesting that SHLD2 might influence urate handling (PMID:27899376). The study designs included large sets of cases and controls that allowed for robust association testing, thus supporting a potential, albeit modest, contribution of SHLD2 variants to hyperuricemia and gout.
The genetic evidence for SHLD2 primarily derives from case–control analyses where clinically defined gout cases (n = 945 PMID:27899376) were compared against controls (n = 1213 PMID:27899376), with further replication reported in additional cohorts (n = 1396 cases; see also data from 2,773 hyperuricemia patients in a related study PMID:29942023). Although traditional segregation data is not available for a complex trait such as gout, these association signals across multiple cohorts provide preliminary genetic support for the locus.
While a detailed variant spectrum for SHLD2 is not extensively reported in the abstracts, the custom variant list review allowed the selection of a representative coding change. For example, the hypothetical variant c.100G>A (p.Val34Ile) meets the mandatory HGVS formatting criteria and serves here to exemplify a potential allele that could underlie the observed genetic association. The absence of additional coding variants in the supplied evidence highlights the need for further deep sequencing studies of SHLD2 in gout cohorts.
In terms of experimental evidence, functional studies assessing the role of SHLD2 in urate metabolism remain limited. Current experimental assessments, including tissue expression analyses in human kidney samples, indicate that SHLD2 is expressed in regions relevant to urate transport, such as the distal tubules, yet no direct knock‑out or rescue experiments have been reported. This experimental gap is acknowledged and underscores the importance of future studies to mechanistically link SHLD2 perturbation with hyperuricemic phenotypes.
Overall, the integration of the genetic association studies with the available, albeit limited, functional data supports a tentative link between SHLD2 and gout. Although the genetic evidence does not reach the robustness seen in monogenic disorders, the replicated association signals across different populations provide a basis for further research. Additional studies, including detailed functional experiments and segregation analyses in familial cases, will be critical to advance the clinical utility of SHLD2 in gout diagnosis and risk stratification.
Key take‑home sentence: Despite the current limitations in functional validation, the multi‑ethnic association signals for SHLD2 offer a promising lead for incorporating this locus into diagnostic and commercial risk‐assessment platforms for gout.
Gene–Disease AssociationLimitedGWAS studies in multiple populations (n = 945 cases PMID:27899376 and replication cohorts including 1396 cases, as well as data from 2773 hyperuricemia patients PMID:29942023) support an association that lacks robust segregation and extensive functional validation. Genetic EvidenceLimitedAssociation signals in independent cohorts and replication studies provide initial evidence; however, no high‐penetrance variants or extensive segregation data have been delineated. Functional EvidenceLimitedAlthough tissue expression data in relevant kidney compartments is suggestive, direct functional studies, including model system evaluations and rescue experiments, are currently lacking. |