Expressive

rs114858855 (FIG4): TMAO Levels Genetic Variant

Key takeaways

  • A genome-wide association study identified this variant as significantly linked to circulating TMAO levels in 626 individuals of European descent.
  • Genetic factors explain roughly 27% of variation in TMAO levels, indicating a moderate but not dominant hereditary influence.
  • No significant epigenetic signals in immune cells were found to predict TMAO levels in the same population.
  • TMAO levels were not correlated with blood lipids or inflammatory markers in this study.
  • The ALT allele is associated with reduced expression of a nearby gene in skin tissue, based on GTEx v11 data.

Key takeaways

  • A genome-wide association study identified this variant as significantly linked to circulating TMAO (trimethylamine-N-oxide) levels in 626 individuals of European descent.
  • Genetic factors explain roughly 27% of variation in TMAO levels, indicating a moderate but not dominant hereditary influence.
  • No significant epigenetic signals in immune cells were found to predict TMAO levels in the same population.
  • TMAO levels were not correlated with blood lipids or inflammatory markers in this study.
  • The ALT allele is associated with reduced expression of a nearby gene (ENSG00000260273) in skin tissue, based on GTEx v11 data.

What the research says A genome-wide association study (GWAS) in the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) identified a genome-wide significant association at an intergenic region on chromosome 4 with plasma TMAO levels in 626 individuals of European descent. TMAO heritability was estimated at approximately 27% in this population, suggesting a moderate genetic component. An epigenome-wide study of DNA methylation in CD4+ T-cells from the same cohort (n=847) found no statistically significant associations with TMAO after correcting for multiple testing.

Reported associations

  • Circulating TMAO levels: A genome-wide significant hit was identified in the GOLDN family study (n=626 GWAS; n=847 epigenome-wide), with TMAO heritability estimated at approximately 27%; TMAO was not associated with plasma lipids or inflammatory cytokines in this population.

Evidence quality The reported TMAO association rests on a single study conducted in the GOLDN cohort (n=626 for GWAS), a family-based sample of European-descent individuals recruited at two clinical centers. The genome-wide significant hit is described as intergenic, meaning the causal mechanism remains unestablished. The study authors explicitly note that prior large-scale human studies have generally failed to replicate genetic associations with TMAO, and the GOLDN finding itself has not been confirmed in an independent replication cohort. The accompanying epigenome-wide analysis (n=847) found no methylation signals surviving multiple-testing correction. The sample is modest in size, ethnically homogeneous, and has not been externally validated. Overall, the evidence is preliminary.

Tissue-specific expression effects

  • ENSG00000260273: The ALT allele is associated with reduced expression in both non-sun-exposed skin (suprapubic region) and sun-exposed skin (lower leg), based on GTEx v11 cis-eQTL data (953 donors, FDR-corrected). GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is TMAO and why is rs114858855 linked to it?

TMAO (trimethylamine-N-oxide) is a metabolite produced in the liver from compounds found in foods like red meat and seafood, and has been studied as a potential cardiovascular risk marker. A genome-wide study of 626 European-descent individuals found rs114858855 to be significantly associated with circulating TMAO levels.

How strong is the evidence connecting rs114858855 to TMAO?

The evidence is preliminary. The association comes from a single family-based study of 626 people, and the study authors note that large-scale human studies have generally not replicated TMAO genetic associations. Independent replication has not been reported.

Does rs114858855 affect gene expression in the body?

Yes. GTEx v11 data from 953 donors shows that the ALT allele is associated with reduced expression of the nearby gene ENSG00000260273 in both sun-exposed and non-sun-exposed skin tissue.

Does this variant affect cholesterol or inflammation?

The reviewed study found that TMAO levels, which rs114858855 is associated with, were not significantly correlated with plasma lipids or inflammatory cytokines in the study population.

How heritable are TMAO levels?

A family-based study estimated TMAO heritability at approximately 27%, meaning genetic factors account for roughly one quarter of the variation in TMAO levels, with environmental and dietary factors accounting for the rest.