rs10838681 (NR1H3): ACP2 and LRP4 Expression
Key takeaways
- rs10838681 reduces ACP2 gene activity across six distinct tissue types including skin, blood, brain, and esophagus
- The same variant has opposite effects on LRP4 in pancreas (reduced) versus tibial nerve (increased), illustrating tissue-specific regulation
- This variant sits near NR1H3, a gene studied in the context of circulating fatty acid and blood metabolite genetics
- GTEx v11 data from 953 donors confirm all expression effects with p-values far below genome-wide significance thresholds
- These are gene expression effects, not direct disease associations - downstream health consequences remain to be established
Key takeaways
- rs10838681 reduces ACP2 gene activity across six distinct tissue types including skin, blood, brain, and esophagus
- The same variant has opposite effects on LRP4 in pancreas (reduced) versus tibial nerve (increased), illustrating tissue-specific regulation
- This variant sits near NR1H3, a gene studied in the context of circulating fatty acid and blood metabolite genetics
- GTEx v11 data from 953 donors confirm all expression effects with p-values far below genome-wide significance thresholds
- These are gene expression effects, not direct disease associations - downstream health consequences remain to be established
What the research says GTEx v11 data from 953 donors identify rs10838681 as an expression quantitative trait locus (eQTL), meaning it influences how actively nearby genes are expressed, with documented effects on both ACP2 and LRP4 GTEx Portal. The alternate allele consistently reduces ACP2 expression across six tissues - sun-exposed lower leg skin, esophageal mucosa, spleen, brain cerebellum, non-sun-exposed suprapubic skin, and whole blood - with p-values ranging from 2.8e-18 to 5.3e-43 GTEx Portal. At LRP4, the same alternate allele reduces expression in the pancreas (p=4.0e-19) while increasing it in the tibial nerve (p=9.1e-20), a tissue-specific split in direction GTEx Portal.
Reported associations
- ACP2 expression - skin (sun-exposed lower leg): Reduced ACP2 expression; strongest signal at this locus (p=5.3e-43) GTEx Portal
- ACP2 expression - whole blood: Reduced ACP2 expression (p=2.9e-40) GTEx Portal
- ACP2 expression - esophagus mucosa: Reduced ACP2 expression (p=1.3e-32) GTEx Portal
- ACP2 expression - skin (non-sun-exposed, suprapubic): Reduced ACP2 expression (p=1.3e-28) GTEx Portal
- ACP2 expression - spleen: Reduced ACP2 expression (p=2.2e-19) GTEx Portal
- ACP2 expression - brain cerebellum: Reduced ACP2 expression (p=2.8e-18) GTEx Portal
- LRP4 expression - pancreas: Reduced LRP4 expression (p=4.0e-19) GTEx Portal
- LRP4 expression - tibial nerve: Increased LRP4 expression (p=9.1e-20) GTEx Portal
Evidence quality All documented associations derive from GTEx v11 eQTL analysis across 953 donors. P-values for ACP2 effects range from 2.8e-18 (brain cerebellum) to 5.3e-43 (skin, sun-exposed), and for LRP4 are 4.0e-19 (pancreas) and 9.1e-20 (tibial nerve), all well below conventional genome-wide significance thresholds. The consistent direction of reduced ACP2 expression across six anatomically distinct tissue types strengthens confidence in that signal. The opposing directions for LRP4 in pancreas versus tibial nerve do not constitute conflicting findings; tissue-specific eQTL directionality is a recognised phenomenon in eQTL research. The studies provided examine circulating fatty acids and blood metabolites in cohorts of up to 450,000 UK Biobank participants, establishing the broader genomic context for this region, though direct phenotypic associations for this specific variant are not detailed in the available evidence. Downstream health consequences of the observed expression changes remain to be established.
Tissue-specific expression effects
- ACP2: The alternate allele is associated with reduced ACP2 expression in all six reported tissues - sun-exposed lower leg skin, esophageal mucosa, spleen, brain cerebellum, non-sun-exposed suprapubic skin, and whole blood. The consistency of reduced expression across these anatomically diverse tissues is a notable feature of this locus GTEx Portal
- LRP4: The alternate allele is associated with reduced LRP4 expression in the pancreas but increased LRP4 expression in the tibial nerve. This opposing pattern across tissues suggests distinct local regulatory environments at the locus GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Lifestyle context
Concrete actions anchored to the cited research. We do not prescribe, we describe.
Screening
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clear cell renal cell carcinoma screening High
rs10838681 A allele is associated with increased risk of clear cell renal cell carcinoma in a large GWAS (n=759800, p=6e-9)
discuss screening options with physician
Frequently asked questions
What is rs10838681?
rs10838681 is a genetic variant located near the NR1H3 gene. GTEx v11 data show it influences the expression of two nearby genes, ACP2 and LRP4, across multiple tissue types with genome-wide-significant p-values.
What does rs10838681 do to gene expression?
Carrying the alternate allele at rs10838681 is associated with reduced expression of ACP2 in six tissue types including skin, esophagus, spleen, brain, and blood. For LRP4, the effect depends on tissue - reduced in the pancreas and increased in the tibial nerve.
Is rs10838681 linked to any diseases?
The available evidence for rs10838681 is limited to gene expression effects measured by GTEx, not direct disease associations. Whether these expression changes translate into health outcomes requires research beyond what is currently documented.
Why does this variant have opposite effects on LRP4 in different tissues?
The opposing effects on LRP4 in the pancreas versus the tibial nerve reflect tissue-specific regulatory environments. The same genetic variant can activate or suppress different regulatory elements depending on which molecular machinery is active in a given tissue.
What does NR1H3 have to do with this variant?
NR1H3 is the gene nearest to rs10838681. This genomic region has been studied in large-scale analyses of circulating fatty acids and blood metabolites involving hundreds of thousands of UK Biobank participants.