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TBKBP1 has emerged as a strong candidate gene associated with ankylosing spondylitis. Multiple independent case–control studies conducted in diverse populations have consistently demonstrated significant associations between TBKBP1 single-nucleotide polymorphisms and disease risk (PMID:21743469). These studies leveraged large cohorts of HLA-B27–positive individuals to underscore the genetic contribution of TBKBP1 to disease susceptibility. The cumulative evidence from these studies supports a robust gene–disease relationship that is clinically actionable for diagnostic decision‑making.
Genetic evidence for TBKBP1 in ankylosing spondylitis includes data from several large-scale studies. One study evaluated 396 HLA-B27–positive Chinese Han patients (PMID:25494292), and another replicated the findings in 572 Korean patients (PMID:28638311). In addition, a further investigation in Chinese Han cohorts provided additional statistical support from a case–control design (PMID:23637848). Although the variant spectrum has been evaluated in a GWAS context without a clearly defined HGVS coding change, the consistent association across cohorts contributes to the overall strong genetic evidence.
The genetic studies focused on common SNPs as markers, and while no specific coding variant in HGVS format could be identified for TBKBP1, the reproducible associations in multiple populations lend strong support to its role in disease. The analyses consistently demonstrated significant p‑values that meet or exceed conventional thresholds of association. The absence of a classic Mendelian inheritance pattern reflects the complex, polygenic nature of ankylosing spondylitis. As such, the genetic data are best explained by a multifactorial inheritance model where TBKBP1 contributes to the overall risk in conjunction with other susceptibility loci.
Functional evidence for TBKBP1 is more limited but biologically relevant. In vitro experiments have demonstrated that TBKBP1 interacts with TBK1, a critical mediator in immune signaling pathways that are implicated in the pathogenesis of ankylosing spondylitis (PMID:23286385). These protein–protein interaction studies provide a mechanistic hypothesis that TBKBP1 may influence antigen processing and inflammatory responses. However, direct functional assays in patient‑derived tissues remain sparse, underscoring the need for further experimental validation.
While no study has directly contradicted the association between TBKBP1 and ankylosing spondylitis, the functional evidence remains less robust compared to the genetic findings. The genetic association has been replicated across multiple cohorts and different ethnic groups, and statistical significance has been consistently observed. The absence of direct causal mutations in TBKBP1 does not detract from its role as a susceptibility gene; rather, it reflects the complexity of genetic contributions in polygenic disorders such as ankylosing spondylitis.
Integrating the genetic and functional data, TBKBP1 demonstrates a strong association with ankylosing spondylitis, supported by replicated case–control studies and complemented by plausible functional insights. Collectively, these findings suggest that TBKBP1 is an important component of the genetic risk architecture in ankylosing spondylitis and could inform future diagnostic and therapeutic strategies. Key take‑home sentence: TBKBP1 is a clinically relevant susceptibility gene for ankylosing spondylitis, underscoring its potential utility in precision diagnostics and risk stratification.
Gene–Disease AssociationStrongMultiple independent case–control studies across diverse populations, including analyses in 396 HLA-B27–positive Chinese Han patients (PMID:25494292) and 572 Korean patients (PMID:28638311), provide statistically significant support for the association. Genetic EvidenceStrongSeveral large-scale studies consistently demonstrated significant association signals from TBKBP1 SNPs with ankylosing spondylitis, exceeding conventional thresholds of significance and supporting a multifactorial inheritance model. Functional EvidenceLimitedIn vitro data indicate that TBKBP1 interacts with TBK1, suggesting a potential role in immune signaling; however, direct functional assays in disease‐relevant models are limited. |