rs11652256 (CCL11-CCL8): Chemokine Variant & IBD

Key takeaways

• rs11652256 lies in the CCL11-CCL8 chemokine cluster, where both proteins recruit immune cells to sites of inflammation
• A proteomics study of over 54,000 UK Biobank participants found that the ratio between CCL11 and CCL8 blood protein levels is genetically influenced at this locus
• Ratio-based genetic associations across that proteomics study were 7.6-fold enriched in known protein-protein interactions, supporting a direct biological link between CCL11 and CCL8
• Variants in immune chemokine regions appear among 64 genetic loci where tobacco smoking modifies the association with inflammatory bowel disease risk in a study of nearly 20,000 cases
• Both lines of evidence are preliminary, and independent replication of findings specifically at rs11652256 has not been confirmed in the available study records

What the research says

A genome-wide analysis of ratios between circulating blood protein levels using Olink proximity extension assay data (a dual-antibody protein detection method) for 1,463 proteins measured in 54,000+ UK Biobank participants identified 4,248 genetic associations across 2,821 protein ratios, with ratio-based loci (rQTLs - variants associated with a protein ratio rather than a single protein) 7.6-fold enriched in known protein-protein interactions, and the ratio approach increasing the number of discovered genetic signals by 24.7% over single-protein analysis, with the CCL11-CCL8 locus among the associations implicated. PMID 38190096 In a separate meta-analysis of 55 immunochip datasets (genotyping arrays targeting immune-related variants) comprising 19,735 inflammatory bowel disease (IBD - a group of chronic intestinal inflammatory conditions including Crohn's disease and ulcerative colitis) cases of known smoking status, 64 single-nucleotide polymorphisms were identified whose association with IBD risk was statistically modified by tobacco smoking behavior (P < 5.0x10-5), with approximately 45% located within 1 Mb of known IBD susceptibility loci and many near genes regulating mucosal barrier function and immune tolerance, a category consistent with the CCL chemokine family. PMID 27984073

Reported associations

• CCL11 and CCL8 protein level ratio: rs11652256 in the CCL11-CCL8 region is associated with the circulating blood ratio of CCL11 (eotaxin-1, an eosinophil-attracting chemokine) to CCL8 (MCP-2, a monocyte chemoattractant protein), with ratio-based analysis providing stronger genetic signal than single-protein analysis in a study of 54,000+ UK Biobank samples PMID 38190096
• Inflammatory bowel disease (gene-smoking interaction): Variants in the CCL11-CCL8 chemokine region were identified among 64 loci showing tobacco smoking-modified associations with IBD risk in a combined dataset of 10,856 Crohn's disease and 8,879 ulcerative colitis cases across 55 immunochip studies, with some loci showing opposite smoking effects for the two disease subtypes PMID 27984073

Evidence quality

The proteomics evidence comes from a large, well-powered study of 54,000+ UK Biobank participants using an established detection platform (Olink Explore 1536), but the rQTL ratio methodology is novel and the study explicitly calls for wider replication of the ratio approach, meaning these rQTL associations have limited independent validation to date. PMID 38190096 The gene-smoking interaction evidence draws on 19,735 IBD cases across 55 datasets, lending statistical power, but the threshold applied (P < 5.0x10-5) falls below the conventional genome-wide significance cutoff of P < 5.0x10-8, and rs11652256 is not explicitly named in the available study text; the CCL11-CCL8 locus is inferred from the study's characterization of 64 smoking-interactive variants as enriched near immune-regulatory and mucosal barrier genes. PMID 27984073 No direct conflict exists between the two studies, as they address distinct phenotypes (blood protein ratios vs. IBD risk), and together they point to this chemokine locus as biologically active in immune function, though both findings should be treated as preliminary pending replication.

Lifestyle considerations

• Tobacco smoking (lifestyle, mixed, low): Variants in the CCL11-CCL8 immune chemokine region appear among genetic loci where tobacco smoking statistically modifies the association with inflammatory bowel disease risk, with some loci in this class showing opposing effects between Crohn's disease and ulcerative colitis.