Expressive

rs11703159 (JOSD1): Novel CRP Inflammation Locus

Key takeaways

  • rs11703159 near JOSD1 and GTPBP1 is a newly identified genetic locus for C-reactive protein, a blood marker of inflammation.
  • It was found using a method that jointly analyzes CRP with cholesterol, triglyceride, BMI, and smoking data to boost detection power.
  • The alternate allele reduces expression of JOSD1 in esophagus and skin tissue, and of nearby genes FAM227A, TOMM22-DT, and CBY1 in skin and fibroblast cells.
  • An unannotated nearby gene shows increased expression in the pituitary gland, though its functional role is currently unknown.
  • No drug interactions or lifestyle-specific findings are currently on record for this variant.

Key takeaways

  • rs11703159, near the JOSD1 and GTPBP1 genes, is a newly identified genetic locus for C-reactive protein (CRP), a blood marker of systemic inflammation.
  • It was found using a method that jointly analyzes CRP with cholesterol, triglyceride, BMI, and smoking data to boost statistical detection power.
  • The alternate allele reduces expression of JOSD1 in esophagus and skin tissue, and of nearby genes FAM227A, TOMM22-DT, and CBY1 in skin and fibroblast cells.
  • An unannotated nearby gene (ENSG00000273076) shows increased expression in the pituitary gland, though its functional role is unknown.
  • No drug interactions or lifestyle-specific findings are currently on record for this variant.

What the research says

A multi-trait analysis of genome-wide association study (GWAS) data, using the MTAG method (Multi-Trait Analysis of GWAS, which increases statistical power by jointly modeling genetically correlated traits), identified rs11703159 near JOSD1 (Josephin Domain Containing 1) and GTPBP1 (GTP Binding Protein 1) as one of 41 novel loci reaching genome-wide significance (p < 5 x 10^-8) for circulating CRP levels, with the full analysis yielding 797 independent signals across 283 genomic loci when CRP was modeled together with high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride levels, body mass index (BMI), and cigarettes per day. The study found that 41 variants colocalized between CRP and cardiometabolic risk factors, and 12 of those displayed discordant effects between the shared traits, which translated into divergent disease associations in phenome-wide association studies (PheWAS, broad scans linking genetic variants to thousands of health outcomes). Tissue-specific gene expression data from GTEx v11 (953 donors) show that the alternate allele at this locus is associated with reduced JOSD1 expression in esophagus mucosa and non-sun-exposed skin GTEx Portal.

Reported associations

  • C-reactive protein (CRP) levels: the locus is among 41 novel genome-wide significant loci for circulating CRP identified through MTAG analysis combining CRP with five cardiometabolic traits; a specific effect size for rs11703159 was not reported in the available study text.
  • Cardiometabolic traits (pleiotropic): the MTAG framework jointly modeled CRP with HDL, LDL, triglycerides, BMI, and cigarettes per day; whether this specific locus independently reached significance for any of those secondary traits is not detailed in the available study text.

Evidence quality

The study used MTAG, which can increase power to detect novel loci but may introduce false positives if genetic correlations between traits are misspecified. Genome-wide significance was set at p < 5 x 10^-8. The analysis identified 797 independent signals across 283 genomic loci overall, of which 41 were classified as novel CRP associations. No variant-specific beta coefficient, odds ratio, or p-value for rs11703159 alone was available in the provided study excerpt, and independent replication of this specific locus is not described in the provided text, so the finding should be treated as preliminary. The source is a peer-reviewed study published in Nature Communications (2022), lending methodological credibility, but locus-level replication remains an important criterion for robustness.

Tissue-specific expression effects

  • JOSD1: reduced expression in esophagus mucosa and non-sun-exposed skin GTEx Portal
  • FAM227A: reduced expression in sun-exposed lower-leg skin and non-sun-exposed skin GTEx Portal
  • TOMM22-DT: reduced expression in non-sun-exposed skin and sun-exposed lower-leg skin GTEx Portal
  • CBY1: reduced expression in cultured fibroblasts GTEx Portal
  • ENSG00000273076 (unannotated gene): increased expression in pituitary tissue 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

  • C-reactive protein (CRP) levels Moderate

    Variant is associated with elevated C-reactive protein, a marker of systemic inflammation linked to cardiovascular risk.

    Obtain baseline CRP measurement and repeat annually or per clinical recommendation.

Frequently asked questions

What is rs11703159 associated with?

rs11703159 was identified as a novel genome-wide significant locus for circulating C-reactive protein (CRP) levels, a blood marker of systemic inflammation, in a 2022 multi-trait genome-wide association study. A specific effect size for this locus was not reported in the available study text, and findings should be considered preliminary pending independent replication.

What does the JOSD1 gene do?

JOSD1 encodes a deubiquitinase, an enzyme that removes ubiquitin tags from proteins, a process involved in regulating protein degradation and cellular signaling. GTEx v11 data show that the alternate allele at rs11703159 is associated with reduced JOSD1 expression in esophagus mucosa and non-sun-exposed skin.

Is rs11703159 linked to heart disease or high cholesterol?

The study that flagged this locus used an analysis that jointly modeled CRP with HDL cholesterol, LDL cholesterol, triglycerides, BMI, and smoking behavior. Whether rs11703159 independently reached significance for any of those cardiometabolic traits is not detailed in the available study text.

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

C-reactive protein (CRP) is a protein produced by the liver in response to infection or tissue damage, widely used as a blood marker of systemic inflammation. Identifying genetic variants that influence CRP levels can help reveal shared biological pathways between inflammation and cardiometabolic diseases such as heart disease and type 2 diabetes.

What do the GTEx expression data show for rs11703159?

GTEx v11 data from 953 donors show the alternate allele is associated with reduced expression of JOSD1, FAM227A, TOMM22-DT, and CBY1 in skin, esophagus, and fibroblast tissue, and with increased expression of an unannotated gene (ENSG00000273076) in the pituitary gland. These are tissue expression associations, not direct measures of disease risk.