Expressive

rs10461139 (TET2): Metabolomics and expression variant

Key takeaways

  • This variant shows opposite effects on the nearby PPA2 gene depending on tissue: increased activity in testis and whole blood, but decreased activity in the heart.
  • The alternate allele reduces TET2 gene activity in skin cells and fibroblasts, based on expression data from 953 tissue donors.
  • This locus spans both TET2 and its antisense RNA partner TET2-AS1, placing it within a broader gene-regulatory context.
  • A genome-wide metabolomics study of approximately 450,000 UK Biobank participants included this locus in a screen of 249 blood metabolite measurements.
  • No disease outcomes or lifestyle associations have been documented for this variant in the provided sources; evidence is preliminary.

Key takeaways

  • This variant shows opposite effects on the nearby PPA2 gene depending on tissue: increased activity in testis and whole blood, but decreased activity in heart left ventricle.
  • The alternate allele reduces TET2 (Ten-eleven translocation methylcytosine dioxygenase 2) gene activity in skin cells and fibroblasts, based on expression data from 953 tissue donors.
  • This locus spans both TET2 and its antisense RNA partner TET2-AS1, placing it within a broader gene-regulatory context on chromosome 4.
  • A genome-wide metabolomics study of approximately 450,000 UK Biobank participants included this locus in a screen of 249 blood metabolite measurements, though variant-level effect sizes for rs10461139 are not detailed in the available study text.
  • No disease outcomes or lifestyle associations have been documented for this variant in the provided sources; evidence is preliminary and limited to gene expression and metabolomics data.

What the research says A trans-ancestral metabolomics genome-wide association study (mGWAS) of approximately 450,000 UK Biobank participants across three ancestry groups (British White European n=434,646; British African n=6,573; British Central/South Asian n=8,796) measured 249 circulating metabolic phenotypes using proton nuclear magnetic resonance (NMR) spectroscopy and identified 29,824 locus-metabolite associations across 753 genomic regions at a significance threshold of P < 2.0 x 10^-10, with rs10461139 falling within this dataset. Expression quantitative trait locus (eQTL) data from GTEx v11 (953 tissue donors, FDR < 0.05) links the alternate allele at this locus to reduced TET2 expression in cultured fibroblasts and sun-exposed lower leg skin, and to directionally opposite changes in expression of the neighboring PPA2 gene across testis, whole blood, and heart left ventricle GTEx Portal.

Reported associations

  • Circulating metabolites (broad metabolomics screen): This locus falls within a large mGWAS covering 249 metabolic traits - including lipoprotein subclasses, amino acids, and ketone bodies - measured in approximately 450,000 UK Biobank participants at a genome-wide significance threshold of P < 2.0 x 10^-10; specific metabolite-level associations for rs10461139 are not detailed in the available study excerpt.

Evidence quality The metabolomics study is large in scale, encompassing approximately 450,000 UK Biobank participants with trans-ancestral coverage across three ancestry groups and a stringent significance threshold of P < 2.0 x 10^-10. No PMID is available for the primary metabolomics study in the provided data, and variant-level metabolite associations for rs10461139 are not detailed in the available excerpt, preventing specific metabolic trait claims for this locus. GTEx eQTL evidence is based on 953 donors at FDR < 0.05 and represents well-characterized expression-level signals GTEx Portal; these reflect regulatory mechanisms rather than disease endpoints. No independent replication of rs10461139-specific findings is documented in the provided sources. Overall, evidence for this variant is preliminary.

Tissue-specific expression effects

  • TET2: The alternate allele is associated with reduced expression in cultured fibroblasts and in sun-exposed lower leg skin, indicating a regulatory role for this variant in connective tissue and epithelial cell types GTEx Portal.
  • PPA2: The alternate allele is associated with increased expression in testis and whole blood, but with reduced expression in heart left ventricle, representing opposite directional effects on this neighboring gene depending on tissue context GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What does the TET2 gene do?

TET2 encodes an enzyme that chemically modifies DNA methylation marks, which are tags on DNA that help control which genes are active in a cell. It plays a regulatory role in gene expression across many tissue types.

What is rs10461139 associated with?

rs10461139 has been examined in a large-scale metabolomics study of approximately 450,000 people and is linked by expression data to reduced TET2 gene activity in skin and fibroblasts, and to tissue-specific changes in the nearby PPA2 gene. No specific disease associations are documented in the available sources.

What is TET2-AS1?

TET2-AS1 is an antisense RNA gene located at the same chromosomal position as TET2. Antisense RNAs are transcribed from the opposite DNA strand relative to a protein-coding gene and may help regulate that gene's activity.

Why does this variant affect PPA2 differently in different tissues?

Genetic variants in regulatory regions can influence nearby genes through tissue-specific elements such as enhancers and promoters. Different tissues activate different sets of these elements, which is why the same variant can increase PPA2 activity in testis and blood while decreasing it in the heart.

Is rs10461139 linked to any diseases?

The available research does not report disease outcome associations for rs10461139. Current evidence consists of metabolomics and gene expression data, which describe molecular-level signals rather than confirmed disease risk.