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The association between FAM167A (HGNC:15549) and systemic lupus erythematosus (MONDO_0007915) has been evaluated in multiple large-scale case–control studies. A prominent North American study included 1,311 SLE cases and 1,783 controls (PMID:18204098), while additional controls (n = 1,557) were used to further validate the findings. The replicated evidence from these cohorts supports a significant genetic risk conferred by variants in this region. These analyses used strict quality‐control filters, thereby reducing technical artifacts and adjusting for population stratification. Overall, the cumulative data indicate a consistent association signal in the region encompassing FAM167A. This robust evidence underpins the clinical relevance of the gene in SLE diagnostic considerations.
In a subsequent replication study conducted in a Japanese population, the association was observed with 327 SLE patients and 322 controls, further corroborating the initial findings (PMID:19180478). The Japanese study reported that the risk allele demonstrated the strongest association under a recessive inheritance model, emphasizing the potential importance of gene dosage effects in disease risk. In addition, the observed odds ratios in both Caucasian and Japanese populations have underscored the significance of regulatory variation in this locus. Such independent replication across diverse ethnic groups considerably strengthens the association. The consistency between studies attests to the generalizability of the genetic signal. This multiethnic validation is pivotal for driving clinical translation and further genetic research.
The genetic evidence comprises aggregated association signals from genome‐wide analyses of SLE. Meta-analyses of these studies have identified non-coding variants near FAM167A that are statistically associated with disease risk. Although most of the reported variants originally mapped to nearby genes, FAM167A is consistently included in the associated risk locus. The cumulative replication data from different cohorts have contributed to a high score under ClinGen standards. In addition, the observed effect sizes across studies remain concordant, consolidating the genetic contribution of FAM167A to SLE. This alignment of evidence across independent investigations supports the strong genetic evidence for this association.
Despite the compelling genetic association, direct functional evidence specific to FAM167A in the pathogenesis of SLE remains limited. While studies have reported altered mRNA expression levels in related immune cell types and implicated regulatory regions, detailed experimental studies (e.g., cellular or animal models) are lacking. Functional assessments in the literature have largely focused on neighboring genes within the risk haplotype. Consequently, the mechanistic basis by which FAM167A influences SLE risk is still incompletely defined. Nonetheless, regulatory impact observed in gene expression analyses suggests a possible role in immune dysregulation. This gap emphasizes the need for future functional studies to elucidate the specific pathogenic mechanisms.
Integrating the genetic and available experimental findings, the overall weight of evidence supports a strong association for FAM167A with systemic lupus erythematosus. The replicated genetic associations across diverse cohorts and rigorous case–control analyses fulfill many of the criteria for a robust gene–disease link. Although additional experimental data are required to define the molecular mechanism, the current evidence is sufficient to influence diagnostic decision-making and inform risk predictions in clinical settings. The association exceeds the minimum evidence threshold for commercial and research applications. Ongoing studies may further augment the functional understanding and clinical actionability of this association.
Key Take‑home sentence: Robust multiethnic genetic evidence supports the clinical utility of assessing the FAM167A locus in systemic lupus erythematosus, underscoring its potential role as a reliable marker for risk stratification.
Gene–Disease AssociationStrongLarge-scale case–control studies with replication in North American and Japanese cohorts (PMID:18204098, PMID:19180478) support the association. Genetic EvidenceStrongGenome-wide association and meta-analysis studies consistently implicate the regulatory region encompassing FAM167A in SLE risk with concordant odds ratios across multiple populations. Functional EvidenceLimitedDirect functional studies addressing FAM167A’s mechanistic role in SLE are lacking, although altered regulatory activity has been suggested in expression analyses. |