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The association between CAND2 and atrial fibrillation has emerged from several large-scale, multi-ethnic studies. In a study comprising over 64,440 individuals (PMID:32822252), common and low‐frequency variants near CAND2 were identified among several loci that affect atrial conduction as measured by P‑wave duration. This large sample size and robust statistical significance support a strong gene‑disease relationship.
A second study using a combined genetic and transcriptional approach in European and Japanese cohorts (PMID:25124494) reported that the CAND2 locus, tagged by the variant rs4642101 (with a relative risk of 1.10 and p‑value in the order of 10^(-9)), was significantly associated with atrial fibrillation. However, a later analysis in a different Chinese cohort (PMID:29459676) did not observe a significant association for the same locus, suggesting that sample size or population-specific factors might underlie these differences.
Genetic evidence thus overwhelmingly supports the involvement of CAND2 in atrial fibrillation, with studies reporting associations across large, diverse cohorts. Although the detailed variant spectrum for CAND2 is not extensively reported in the literature and no explicit HGVS‐formatted variant has been provided, the recurrence of the locus in independent studies reinforces its role in modulating atrial electrophysiology.
While the genetic data point to a clear association, functional insights into the pathogenic mechanism of CAND2 in atrial arrhythmogenesis remain limited. No dedicated cellular or animal model has yet directly validated its role in atrial conduction, and functional assays have largely been restricted to broader candidate gene panels for atrial fibrillation (PMID:28549997). This represents a gap where further experimental work could complement the observed genetic associations.
Despite the noted conflicting evidence from one study, the totality of genetic findings—spanning large cohorts, significant meta‐analyses, and supportive cis‐eQTL data—supports a strong overall gene‑disease association. With additional evidence likely exceeding the formal ClinGen cap, clinicians and commercial entities can consider CAND2 as a potential marker in diagnostic evaluations and future therapeutic strategies for atrial fibrillation.
Key take‑home: The robust genetic association of CAND2 with atrial fibrillation, despite some conflicting replication, underscores its clinical utility in risk stratification and the need for additional functional validation to further delineate underlying pathogenic mechanisms.
Gene–Disease AssociationStrongLarge-scale studies (>64,440 individuals [PMID:32822252]) and significant association signals (e.g., rs4642101 with p≈10^-9 [PMID:25124494]) support a strong association, despite conflicting replication in one study ([PMID:29459676]). Genetic EvidenceStrongMultiple independent GWAS and meta-analyses consistently implicate the CAND2 locus across diverse populations, though the detailed variant spectrum remains sparse. Functional EvidenceLimitedDirect functional assays specifically assessing CAND2’s role in atrial conduction are lacking, with current evidence derived indirectly from broad candidate gene panels. |