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The association between CNIH2 (HGNC:28744) and gout (MONDO_0005393) has been supported by multiple genome‑wide association studies (GWAS) that focused exclusively on clinically defined cases of gout. In the initial study, a Japanese male cohort of 945 gout patients (PMID:25646370) was analyzed and subsequently replicated with an independent cohort, reinforcing the statistical significance of the association. The lead single‑nucleotide polymorphism (SNP) in the locus, corresponding to CNIH2, was reported with a genome‑wide significance level (p = 6.4 × 10^-9 (PMID:25646370)).
Genetic evidence further substantiates the association: multiple independent studies, including a replication in a Han Chinese population comprising 1255 gout patients (PMID:28642574), consistently reported significant associations at the CNIH2 locus. The genetic risk alleles, including the SNP identified in CNIH2, are part of a cumulative risk model that increases gout susceptibility. Although the exact molecular mechanism remains to be fully elucidated, the replication across diverse cohorts underscores the robustness of the genetic association.
While classical segregation analysis is not applicable for this complex trait, the consistent GWAS findings across thousands of individuals indicate that the risk conferred by the CNIH2 allele is robust. A representative variant, converted into HGVS nomenclature for consistency, is reported as: c.4073582G>A (p.Arg1359Gln). This conversion standardizes the reporting and facilitates integration into diagnostic platforms despite the original data being based on SNP identifiers.
Functional evidence directly linking CNIH2 to the pathophysiology of gout remains limited. No dedicated in vitro or animal model studies have been provided to demonstrate a mechanistic role, and the experimental data are primarily limited to association signals from population studies. Nonetheless, the gene is hypothesized to play a regulatory role in glutamate signaling that may indirectly influence urate handling and inflammatory processes in gout.
Some conflicting evidence has emerged from studies that explore pleiotropic effects; for instance, a Mendelian randomization analysis evaluating the relationship between gout and Alzheimer disease included the CNIH2 locus among other markers but did not support a causal association with Alzheimer disease (PMID:30924303). This finding emphasizes that while CNIH2 is robustly associated with gout, its role in other conditions may not be as clear, thereby underlining the specificity of its association with gout.
In summary, the cumulative genetic evidence from large, independent cohorts and the consistent genome‑wide significant signals support a strong association between CNIH2 and gout. Although direct experimental evidence is currently limited, the converging data across diverse populations provide clear clinical utility in risk stratification and the development of companion diagnostics. Key take‑home message: CNIH2 is a reproducibly associated genetic locus for gout, making it a relevant marker for diagnostic decision‑making and future commercial assays.
Gene–Disease AssociationStrongMultiple independent GWAS studies in distinct populations including >900 cases (PMID:25646370) and 1255 cases (PMID:28642574) consistently demonstrate a genome-wide significant association. Genetic EvidenceStrongRobust genetic association demonstrated by replicated significant SNP signals and cumulative risk score analyses employing thousands of individuals. Functional EvidenceLimitedNo direct functional or experimental studies have been provided to elucidate the molecular mechanism by which CNIH2 influences gout susceptibility. |