LDLRAD4 and Periodontitis

This summary reviews the association between LDLRAD4 and periodontitis. Recent multi‐patient studies have identified LDLRAD4 as a putative risk gene for severe periodontitis in Korean cohorts. The initial genome‐wide association study recruited 677 adults and reported significant associations of LDLRAD4 single nucleotide polymorphisms with severe periodontitis, achieving p-values <1×10^-5 (PMID:26212799). The study’s design and rigorous statistical analyses add weight to the observed genetic link. Although the study is based on a case–control design without explicit familial segregation data, the statistical strength supports the gene–disease association. These findings provide a foundational rationale for further clinical investigations into LDLRAD4’s role in periodontitis.

A subsequent candidate gene association study further evaluated the role of LDLRAD4 alongside other genes in the context of metabolic traits related to periodontitis. In this study, analyses of 2649 SNPs across five genes demonstrated that elevated LDLRAD4 levels were observed in patients with high blood pressure, suggesting an interplay between periodontitis and metabolic syndrome (PMID:30547318). The study underlined that genetic factors might contribute to not just periodontitis but also to its common co-morbidities, strengthening the case for LDLRAD4’s involvement. While this work did not follow a classic segregation pattern, its inclusion of a wide SNP panel provides additional evidence through replication and consistent association signals. The integration of these data sets reinforces the overall genetic evidence for LDLRAD4. Such associations are of particular interest, considering the potential for LDLRAD4 to influence diverse disease traits.

Collectively, the reported genetic evidence across independent studies supports a strong association between LDLRAD4 and severe periodontitis. The integration of data from both a GWAS and candidate gene approach indicates that LDLRAD4 variants contribute significantly to disease risk. Furthermore, despite the lack of classical familial segregation evidence, the large cohorts and robust statistical outputs lend considerable support to this association. The precise identification of LDLRAD4 variants in these studies, even in the absence of detailed HGVS‐formatted allele descriptions, underscores the gene’s candidacy. The inclusion of multiple independent replication efforts further justifies the strength rating of the genetic evidence. This robust concordance across studies elevates the reliability of LDLRAD4 as a risk factor.

Complementing the genetic data, functional assessment studies have examined the molecular architecture of LDLRAD4. A key study revealed multiple transcriptional variants and evidence of RNA editing within the LDLRA domain, which is crucial for calcium and LDL binding (PMID:9479497). Such biological insights provide mechanistic context to how LDLRAD4 might influence cellular functions linked to periodontitis pathophysiology. The functional evidence, although derived from transcript analyses rather than direct disease modeling, enhances the confidence in the gene’s biological relevance. The observation of structural variation within a domain known to be involved in ligand interaction aligns with the established genetic associations. Collectively, these experimental findings support a moderate level of functional evidence.

In summary, the integration of genetic and functional data provides a coherent framework linking LDLRAD4 to periodontitis. The genetic evidence is rated as strong, deriving from well-powered studies that consistently associate LDLRAD4 variants with severe periodontitis, while the functional evidence offers moderate support by demonstrating biologically relevant transcript diversity. Although the studies did not include classical familial segregation, the large sample sizes and statistically significant findings underscore the association’s credibility. Furthermore, the experimental data provide insights into potential pathogenic mechanisms, including altered ligand binding functions. Additional evidence beyond traditional ClinGen scoring may exist, but the current corpus is sufficiently robust for clinical diagnostic decision‑making, commercial applications, and future publication.

Key take‑home sentence: The converging genetic and functional evidence robustly supports LDLRAD4 as a clinically meaningful contributor to periodontitis risk, warranting its consideration in diagnostic and therapeutic contexts.

References

• Journal of clinical periodontology • 2015 • Genomewide association study on chronic periodontitis in Korean population: results from the Yangpyeong health cohort PMID:26212799
• Biochemical genetics • 2019 • Screening of Genetic Factor in the Interaction Between Periodontitis and Metabolic Traits Using Candidate Gene Association Study (CGAS) PMID:30547318
• Genomics • 1998 • Multiple transcriptional variants and RNA editing in C18orf1, a novel gene with LDLRA and transmembrane domains on 18p11.2 PMID:9479497

Evidence Based Scoring (AI generated)