Expressive

rs10028441 (HSD17B11): CRP and Metabolic Variant

Key takeaways

  • rs10028441, near HSD17B11, was found among 797 genome-wide signals for C-reactive protein (CRP), a key marker of systemic inflammation, in a large multi-trait GWAS.
  • The alternate allele at this variant is linked to higher HSD17B11 expression in at least 8 tissues, from pancreas and thyroid to fat depots and blood vessel walls.
  • The discovery came from a multi-trait GWAS jointly analyzing CRP with cholesterol, triglycerides, BMI, and smoking, which identified 41 novel pleiotropic loci.
  • Many CRP-associated loci, including this one, overlap with lipid and glucose metabolism genes, suggesting shared biology between inflammation and metabolic disease.

Key takeaways

  • rs10028441, near the HSD17B11 gene (annotated to lipid and glucose metabolism pathways in CRP genome-wide studies), was identified as part of a large multi-trait GWAS finding 797 independent signals across 283 genetic loci for C-reactive protein (CRP), a systemic inflammation marker.
  • The alt allele at this locus is consistently associated with increased expression of the gene across at least eight tissues, including pancreas, thyroid, aorta, and adipose depots.
  • The underlying study used MTAG (multi-trait analysis of GWAS), jointly modeling CRP with HDL, LDL, triglycerides, BMI, and cigarettes per day, and identified 41 novel pleiotropic loci.
  • Many CRP-associated loci, including this one, overlap with lipid and glucose metabolism genes, pointing to shared biology between low-grade inflammation and cardiometabolic traits.

What the research says A 2022 multi-trait GWAS analysis jointly modeled CRP with high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, body mass index (BMI), and cigarettes per day, identifying 797 independent signals in 283 loci at genome-wide significance (p < 5 x 10^-8). The study found 41 novel pleiotropic loci and 41 variants that colocalize between CRP and cardiometabolic risk factors, with 12 displaying discordant effects across traits that translated into discordant associations with clinical outcomes. GTEx v11 eQTL data from 953 donors shows that the alt allele at this locus is linked to increased expression of this gene across eight tissues, most prominently pancreas (slope +0.40, p=7.4e-27) and thyroid (slope +0.28, p=1.6e-34) GTEx Portal.

Reported associations

  • C-reactive protein levels: Identified among 797 independent genome-wide signals for CRP in a multi-trait GWAS that annotated CRP loci to lipid and glucose metabolism genes as well as inflammation pathways.
  • Cardiometabolic trait pleiotropy: The MTAG analysis identified 41 novel pleiotropic loci for CRP and co-analyzed traits (HDL, LDL, triglycerides, BMI, cigarettes per day), with 12 colocalizing variants showing unexpected discordant effects between the shared traits.
  • Tissue expression (eQTL): The alt allele is associated with increased expression of this gene in pancreas, thyroid, aorta, tibial artery, tibial nerve, esophagus mucosa, visceral adipose (omentum), and subcutaneous adipose GTEx Portal.

Evidence quality The CRP association for this locus comes from MTAG, a method that boosts statistical power by jointly modeling correlated traits but also means signals may partly reflect the composite phenotype rather than CRP alone; results should be treated as preliminary until replicated in independent single-trait GWAS. The source study does not include a PMID in the provided metadata, limiting direct replication tracking via citation. The study identified 797 independent CRP-associated signals overall, but the provided text does not include a per-variant effect size or p-value for rs10028441 specifically. By contrast, the GTEx eQTL evidence is robust: all eight tissue associations are highly significant (best p=1.6e-34 in thyroid, worst p=3.6e-19 in aorta), consistently positive in direction, and based on 953 donors, providing strong support for a regulatory effect on tissue expression at this locus GTEx Portal.

Tissue-specific expression effects

  • HSD17B11: The alt allele drives increased expression in all eight measured tissues: pancreas (slope +0.40, p=7.4e-27), thyroid (+0.28, p=1.6e-34), aorta (+0.26, p=3.6e-19), tibial nerve (+0.25, p=6.7e-33), esophagus mucosa (+0.24, p=2.4e-22), visceral adipose/omentum (+0.24, p=8.7e-23), subcutaneous adipose (+0.22, p=5.4e-21), and tibial artery (+0.20, p=1.4e-24). Effects are uniformly positive, meaning the alt allele consistently raises expression across metabolic and vascular tissues 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

  • triglyceride levels Moderate

    rs10028441 A allele is associated with higher triglyceride levels in 361,194 participants; carriers show modest increased triglyceride risk

    Annual lipid panel; discuss with doctor if levels are elevated

Frequently asked questions

What is rs10028441 and which gene does it affect?

rs10028441 is a common genetic variant located near the HSD17B11 gene, which is annotated to lipid and glucose metabolism pathways. It was identified in a large multi-trait genome-wide study as part of the genetic architecture of C-reactive protein (CRP) levels.

How does rs10028441 affect HSD17B11 gene expression?

GTEx v11 data from 953 donors shows the alternate allele at rs10028441 is associated with increased HSD17B11 expression in eight tissues: pancreas, thyroid, aorta, tibial artery, tibial nerve, esophagus mucosa, visceral adipose, and subcutaneous adipose. All effects point in the same direction, meaning the variant consistently raises expression of this gene.

Is rs10028441 linked to inflammation or heart disease?

rs10028441 was identified among 797 independent signals for C-reactive protein (CRP), a systemic inflammation marker, in a multi-trait genome-wide study. The same study found that CRP-associated loci often share genetic signal with cardiometabolic risk factors including HDL, LDL, triglycerides, and BMI.

What is C-reactive protein and why do its genetics matter?

C-reactive protein (CRP) is a protein secreted mainly by the liver in response to inflammation, released in high concentrations as a protective response to pathogens or damaged tissue. Genetic studies have found that many CRP-associated loci are also annotated to lipid and glucose metabolism genes, suggesting shared biological pathways between inflammation and cardiometabolic disease.

What does pleiotropic mean in the context of rs10028441?

Pleiotropy means one genetic variant influences more than one biological trait. The multi-trait GWAS that flagged this locus identified 41 novel pleiotropic signals where CRP and cardiometabolic traits share overlapping genetic associations, and 12 of those colocalizing variants showed unexpected discordant effects between the traits.