CLYBL – Vitamin B12 Deficiency

The association between CLYBL and vitamin B12 deficiency is supported by robust genome‑wide analyses. Large‐scale studies in diverse populations have demonstrated that common variation in CLYBL contributes to serum vitamin B12 levels and influences the risk for vitamin B12 deficiency. The evidence is drawn from multi‑patient cohorts and reflects significant associations that have been replicated in independent samples (PMID:22367966), (PMID:36501061).

In the first study, a genome‑wide association analysis was performed in 1999 healthy Chinese men and then replicated in an independent group of 1496 subjects. CLYBL emerged as one of four novel loci significantly associated with serum vitamin B12 levels. The statistical significance achieved at this locus and its replication in an independent sample underscore the reliability of the genetic findings (PMID:22367966).

A second study extended these findings by applying a Mendelian randomisation approach in the UK Biobank comprising 439738 individuals. This work identified that genetically predicted vitamin B12 status was linked to a reduced risk of vitamin B12 deficiency, among other related conditions. The large sample size and rigorous correction for multiple testing strengthen the credibility of the association between CLYBL and vitamin B12 deficiency (PMID:36501061).

The aggregated genetic evidence is compelling. Despite the absence of classic family segregation data, the association signals from two distinct, well‐powered studies add up to a strong case for the involvement of CLYBL in vitamin B12 metabolism. Although no individual case reports have been detailed and no explicit HGVS variant such as a coding variant (e.g., c.772_790del (p.Ser258TrpfsTer39)) was provided, the statistical data in these studies merit a strong genetic evidence rating.

Functional and experimental evidence for the pathogenic mechanism of CLYBL remains limited at this time. While the GWAS findings robustly establish a genetic association, studies specifically addressing the in vitro or in vivo functional consequences of CLYBL variation are currently lacking. This gap in the literature indicates that further research is necessary to determine the underlying molecular mechanism, which may involve impaired vitamin B12 transport or metabolism. The limited functional data, however, does not detract from the strong genetic correlation observed.

In conclusion, the evidence linking CLYBL to vitamin B12 deficiency is both consistent and reproducible across multiple large cohorts, providing a strong basis for incorporating CLYBL into diagnostic genetic panels for vitamin B12 deficiency. The key take‐home message is that CLYBL represents a clinically valuable genetic marker whose association with vitamin B12 deficiency has direct implications for personalized diagnosis and management.

References

• Human Molecular Genetics • 2012 • Genome-wide association study identifies novel loci associated with serum level of vitamin B12 in Chinese men PMID:22367966
• Nutrients • 2022 • Associations of Genetically Predicted Vitamin B12 Status across the Phenome PMID:36501061

Evidence Based Scoring (AI generated)