rs11229030 — PRG2

Intergenic tag SNP in the PRG2/PRG3 eosinophil major basic protein gene cluster at 11q12.1 whose C allele increases susceptibility to Crohn's disease, implicating eosinophil granule protein-mediated epithelial damage in IBD pathogenesis

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PRG2 — When Eosinophil Granule Proteins Attack the Gut

Inside your gastrointestinal tract, a normally protective immune cell may be working against you. Eosinophils — immune cells best known for fighting parasites and driving allergic reactions — reside in the gut wall as part of normal tissue defense. When activated, they discharge their granule contents, including major basic protein (MBP)11 major basic protein (MBP)
The predominant crystalline core protein of eosinophil granules, encoded by the PRG2 gene on chromosome 11q12.1. MBP is a cationic protein that disrupts cell membranes through electrostatic interaction, causing cytotoxicity to host epithelial cells when released in excess. rs11229030 sits in the PRG2/PRG3 gene cluster — two closely related eosinophil major basic protein genes — and its C allele was identified as a Crohn's disease susceptibility signal in a large genome-wide association study of Ashkenazi Jewish populations.

The Mechanism

PRG2 encodes eosinophil major basic protein (MBP), the predominant constituent of the crystalline core of the eosinophil granule. When eosinophils degranulate in the gut wall, MBP directly increases epithelial layer permeability22 epithelial layer permeability
MBP disrupts cell membrane integrity through its highly cationic charge, causing direct toxicity to epithelial cells and increasing paracellular permeability — the same "leaky gut" mechanism central to Crohn's disease pathophysiology. Mouse studies confirm the causal link: MBP knockout mice are protected from experimental colitis, and in vitro co-culture of eosinophils with intestinal epithelial cells causes dose-dependent epithelial dysfunction attributable to MBP.

rs11229030 at chr11:57,435,536 (GRCh38) lies approximately 45 kb downstream of PRG2 (chr11:57,386,780–57,390,650) and within the broader PRG2/PRG3 regulatory neighborhood. The SNP's intergenic location suggests it acts as a regulatory tag SNP influencing expression levels in this eosinophil protein cluster rather than altering protein sequence directly. The neighboring PRG3 gene encodes a related eosinophil major basic protein homologue (MBPH), also expressed preferentially in eosinophils, providing two potential effectors at this locus.

The Evidence

The association between rs11229030 and Crohn's disease emerged from a genome-wide scan combining 10 Ashkenazi Jewish cohorts33 genome-wide scan combining 10 Ashkenazi Jewish cohorts
Ashkenazi Jews have a 2–4× higher prevalence of Crohn's disease than non-Jewish Europeans, making this population particularly informative for discovering CD susceptibility loci: 907 cases and 2,345 controls in discovery, followed by 971 cases and 2,124 controls in replication. rs11229030 reached genome-wide significance (OR 1.15, p=8×10⁻⁹), ranking among five novel loci identified in the study. While an OR of 1.15 represents a modest per-allele effect — typical for common GWAS variants in complex diseases — the biological candidacy of PRG2/PRG3 at this locus provides strong mechanistic plausibility.

Evidence for eosinophil-mediated intestinal damage in Crohn's disease is well established independently. Ultrastructural studies show eosinophil MBP granule release and cytotoxic tissue changes specifically in Crohn's disease biopsy specimens. Eosinophil cationic protein (ECP), a related granule protein, correlates with Crohn's disease activity with remarkable precision44 activity with remarkable precision
r=0.89, p<0.0001 in 10 children with Crohn's disease followed prospectively; active disease median ECP 24.5 µg/L vs remission 5.7 µg/L. And in patients with Crohn's disease, elevated eosinophilic infiltration is associated with fibrosis development and poor response to medical therapy.

Practical Actions

For CC genotype carriers, the actionable implications center on gut barrier support and early monitoring. Eosinophil-driven permeability is worsened by food antigens that trigger eosinophil degranulation; eliminating common triggers can reduce intestinal eosinophil activation. Monitoring stool calprotectin and blood eosinophil counts provides early warning of inflammatory flares before clinical symptoms escalate. In established Crohn's disease, serum ECP can be used as a disease-activity index alongside standard markers.

Interactions

The PRG2 locus operates within the broader landscape of Crohn's disease genetic risk. Variants in rs7234029 (PTPN2) reduce T-cell regulatory phosphatase activity, lowering the threshold for immune activation that drives eosinophil recruitment. The rs2631367 variant in SLC22A5 (OCTN2) impairs carnitine transport in intestinal epithelial cells, compounding the barrier dysfunction that eosinophil MBP degranulation initiates. Carriers of multiple Crohn's disease risk alleles — particularly those affecting both eosinophil effector function (PRG2) and immune activation thresholds (PTPN2, IL23R) — face additive susceptibility. Each of these interactions involves independent biological mechanisms that converge on intestinal barrier disruption and aberrant immune activation.

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal

Common genotype — no increased Crohn's disease risk at this locus

You carry two copies of the T allele at rs11229030, the most common genotype in European (37%) and global populations (36%). This genotype is not associated with increased Crohn's disease susceptibility through the PRG2/PRG3 eosinophil major basic protein pathway. Your genetic contribution at this locus to gut eosinophil activity falls within the typical range.

CT Intermediate

One C allele — mildly elevated Crohn's disease susceptibility

The C allele at rs11229030 tags regulatory variation in the PRG2/PRG3 gene cluster at chromosome 11q12.1. Under an additive model (OR 1.15 per C allele), CT heterozygotes carry approximately one unit of this genetic loading. Eosinophil major basic protein (MBP), the PRG2 product, increases intestinal epithelial permeability and promotes inflammatory tissue damage. Whether the C allele increases PRG2/PRG3 expression or alters the regulation of eosinophil activation is not yet fully characterized at the molecular level. For CT individuals without a personal or family history of IBD, this locus alone represents a modest genetic signal that is meaningful primarily in the context of other Crohn's disease risk factors.

CC High Risk

Two C alleles — elevated Crohn's disease susceptibility via eosinophil MBP pathway

The CC genotype at rs11229030 represents the homozygous risk state at the PRG2/PRG3 locus. PRG2 encodes eosinophil major basic protein (MBP), which is toxic to intestinal epithelial cells when released from activated eosinophil granules. Mouse MBP knockout models are protected from experimental colitis, and in vitro studies show MBP directly reduces epithelial barrier function. Eosinophil cationic protein (ECP), a related granule marker, tracks Crohn's disease activity with r=0.89 correlation — active disease ECP is 4× higher than remission levels.

It's important to contextualize this risk: OR 1.15 per allele is a modest common-variant effect, as is typical for GWAS hits in complex diseases. This SNP explains a fraction of Crohn's disease heritability and operates alongside multiple other loci (NOD2, IL23R, ATG16L1, PTPN2, etc.). CC carriers without a family history or GI symptoms have elevated genetic susceptibility but not certainty of developing disease. However, proactive monitoring makes the most of this genetic information.