Expressive

rs10318 (GREM1): Colorectal Cancer Risk Variant

Key takeaways

  • rs10318 is a variant in the GREM1 (Gremlin-1) gene region, linked to colorectal cancer risk in multi-locus polygenic risk models
  • The alternate allele at this locus increases GREM1 and GREM1-AS1 expression in liver and pancreas tissue
  • GREM1-AS1 expression is reduced in brain anterior cingulate cortex and esophageal junction tissue for the alternate allele
  • A 183-locus colorectal cancer genetic risk model was validated across 350,013 prospective participants in two independent cohorts

Key takeaways

  • rs10318 is a variant in the GREM1 (Gremlin-1) gene region, linked to colorectal cancer risk in multi-locus polygenic risk models
  • The alternate allele at this locus increases GREM1 and GREM1-AS1 expression in liver and pancreas tissue
  • GREM1-AS1 expression is reduced in brain anterior cingulate cortex and esophageal junction tissue for the alternate allele
  • A 183-locus colorectal cancer genetic risk model was validated across 350,013 prospective participants in two independent cohorts

What the research says A 2024 Genome Medicine study developed trans-ancestry polygenic risk score (PRS) models for colorectal neoplasm screening in East Asian and European populations; PRS183, built from 183 CRC-associated loci, showed the best discriminatory ability in both populations, and a significant dose-response relationship between PRS score and incident colorectal neoplasms was confirmed in prospective cohorts totaling 350,013 participants across the PLCO and UK Biobank studies. Incorporating lifestyle factors alongside this genetic model improved risk stratification beyond either approach alone, with a best negative predictive value (NPV) of 0.93 and positive predictive value (PPV) of 0.32. GTEx v11 expression data from 953 donors shows that rs10318 is significantly associated with increased GREM1 and GREM1-AS1 (an antisense transcript at this locus) levels in liver and pancreas, and with reduced GREM1-AS1 levels in brain anterior cingulate cortex (Brodmann area 24) and esophageal gastroesophageal junction tissue GTEx Portal.

Reported associations

  • Colorectal neoplasm (polygenic risk): rs10318 falls within the GREM1 locus, a region included in multi-locus PRS models for CRC and precancerous adenoma; prospective validation in 350,013 participants (PLCO and UK Biobank) found a significant dose-response relationship between PRS score and incident colorectal neoplasm, with PRS183 outperforming the 148-locus model in both East Asian (ZJCRC) and European (PLCO) validation sets
  • GREM1 expression - liver: the alternate allele at this locus is associated with increased GREM1 expression in liver (beta +0.80, p=1.8e-15) GTEx Portal
  • GREM1 expression - pancreas: the alternate allele is associated with increased GREM1 expression in pancreas (beta +0.44, p=1.2e-10) GTEx Portal
  • GREM1-AS1 expression - pancreas and liver: the alternate allele increases the GREM1-AS1 antisense transcript in pancreas (beta +0.95, p=4.8e-28) and liver (beta +0.80, p=1.4e-20) GTEx Portal
  • GREM1-AS1 expression - brain and esophagus: the alternate allele reduces GREM1-AS1 transcript levels in brain anterior cingulate cortex BA24 (beta -0.46, p=6.1e-6) and esophageal gastroesophageal junction (beta -0.17, p=2.3e-5) GTEx Portal

Evidence quality The CRC screening study used large, multi-cohort validation sets: approximately 30,000 cross-sectional participants from the ZJCRC (East Asian) and PLCO (European) cohorts, plus 350,013 prospective participants from PLCO and UK Biobank, supporting cross-ancestry generalizability. However, the available study text does not explicitly name rs10318 as one of the 183 included loci, and no single-variant odds ratio for this specific variant was reported in the provided evidence. GTEx eQTL associations are statistically strong (p values ranging from 2.3e-5 to 4.8e-28 across four tissues), but eQTL data captures transcript-level changes rather than direct disease outcomes. No functional or mechanistic studies specific to rs10318 were included in the supplied evidence; the evidence base for this variant should be considered preliminary.

Tissue-specific expression effects

  • GREM1-AS1: increased expression in pancreas and liver for the rs10318 alternate allele; reduced expression in brain anterior cingulate cortex (BA24) and esophageal gastroesophageal junction tissue GTEx Portal
  • GREM1: increased expression in liver and pancreas for the alternate allele at this 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

  • colorectal cancer screening timing and frequency Moderate

    GREM1 variant associated with significantly increased colorectal cancer risk

    Discuss with gastroenterologist or primary care physician

Frequently asked questions

What does the GREM1 gene do?

GREM1 encodes Gremlin-1, a protein involved in modulating cell growth and tissue development signaling pathways. Variants in this gene region have been studied in the context of colorectal cancer risk.

Is rs10318 linked to colorectal cancer?

rs10318 falls within the GREM1 gene region, which is among the loci incorporated into polygenic risk scores for colorectal cancer. These models combine many variants to estimate disease risk at a population level; the available evidence does not include a single-variant odds ratio for rs10318 alone.

What does it mean that rs10318 is an eQTL?

An eQTL (expression quantitative trait locus) is a genetic variant associated with differences in how much RNA a nearby gene produces in a specific tissue. rs10318 is associated with higher GREM1 and GREM1-AS1 RNA levels in liver and pancreas, which may relate to its disease associations, though transcript-level changes do not directly predict health outcomes.

Which tissues are most affected by rs10318?

GTEx expression data shows that rs10318 is linked to increased GREM1 and GREM1-AS1 activity in liver and pancreas, while GREM1-AS1 activity is reduced in brain anterior cingulate cortex and esophageal junction tissue.