rs4848306 — IL1B

IL1B -3737 G/A — The Peritoneal Fire Switch in Endometriosis

The IL1B gene encodes interleukin-1 beta (IL-1β)¹¹ interleukin-1 beta (IL-1β)
IL-1β is a master pro-inflammatory cytokine produced primarily by activated macrophages; it triggers NF-κB signaling and coordinates broad inflammatory gene expression, one of the most potent drivers of peritoneal inflammation in the body. In endometriosis, IL-1β plays a central and well-documented pathogenic role: it is elevated in the peritoneal fluid of affected women, secreted at higher levels by peritoneal macrophages, and creates the inflammatory milieu that allows ectopic endometrial tissue to implant, survive, and expand. The rs4848306 variant sits 3,737 base pairs upstream of the IL1B transcription start site (in the promoter region), where it can influence how much IL-1β the body produces in response to inflammatory stimuli — including the monthly retrograde menstruation that seeds the peritoneum with endometrial fragments.

The Mechanism

rs4848306 maps to chromosome 2, position 112,840,530 (GRCh38), within the promoter region of IL1B. The IL1B gene is encoded on the minus strand of chromosome 2; the promoter variant is therefore read in the complement direction, with papers frequently describing this position using the coding-strand notation as IL-1B -3737. The reference allele on the plus strand is G (~61% globally); the alternate allele is A (~39%). Haplotype studies in schizophrenia genetics²² Haplotype studies in schizophrenia genetics
A field that has intensively studied IL1B promoter variants because neuroinflammation is central to psychosis pathophysiology; the same promoter logic applies to peritoneal inflammation in endometriosis establish that the G allele at rs4848306 is part of the haplotype associated with elevated IL1B mRNA expression, while the A allele (coding-strand T) predicts reduced IL1B transcriptional output. This makes rs4848306 a regulatory variant that fine-tunes the amplitude of the IL-1β inflammatory response.

IL-1β in the peritoneal cavity acts at multiple points in endometriosis pathogenesis: it promotes adhesion of ectopic endometrial stromal cells to mesothelial surfaces, stimulates vascular endothelial growth factor (VEGF)³³ vascular endothelial growth factor (VEGF)
VEGF drives the neovascularization that sustains implant growth production to vascularize nascent implants, activates matrix metalloproteinases for tissue invasion, and suppresses natural killer cell cytotoxicity that would otherwise clear ectopic cells. A promoter variant that drives higher IL-1β output — the G allele — would amplify each of these steps during the inflammatory cascade that follows retrograde menstruation.

The Evidence

Elevated IL-1β in the peritoneal environment of women with endometriosis is one of the most replicated findings in the field. Sikora et al. found higher peritoneal fluid IL-1β and elevated macrophage IL-1β secretion in women with endometriosis compared to controls⁴⁴ Sikora et al. found higher peritoneal fluid IL-1β and elevated macrophage IL-1β secretion in women with endometriosis compared to controls
Sikora J, et al. Pro-IL-1β and macrophage IL-1β secretion in endometriosis. Ginekologia Polska, 2016, with pro-IL-1β disproportionately elevated, suggesting increased inflammasome-driven IL-1 processing. A complementary study found that IL-1β and ICE (IL-1β converting enzyme) levels were significantly higher in endometriosis peritoneal fluid⁵⁵ IL-1β and ICE (IL-1β converting enzyme) levels were significantly higher in endometriosis peritoneal fluid
Sikora J, et al. IL-1β, IL-18 and ICE in endometriosis. Ginekologia Polska, 2012, implicating dysregulated cytokine maturation in disease progression.

Akoum et al. documented a specific imbalance between IL-1β and its decoy inhibitory receptor (IL-1R2) in endometriosis peritoneal fluid⁶⁶ Akoum et al. documented a specific imbalance between IL-1β and its decoy inhibitory receptor (IL-1R2) in endometriosis peritoneal fluid
Akoum A, et al. Imbalance between IL-1β and IL-1R2 in endometriosis. Journal of Reproductive Immunology, 2008, most pronounced in infertile patients, linking the defect in local IL-1 control directly to infertility risk. This biochemical finding is complemented by genetic evidence: Mier-Cabrera et al. showed that IL1B variants (the +3954 allele, rs1143634) were enriched in stage IV endometriosis cases compared to controls (OR 2.69)⁷⁷ Mier-Cabrera et al. showed that IL1B variants (the +3954 allele, rs1143634) were enriched in stage IV endometriosis cases compared to controls (OR 2.69)
Mier-Cabrera J, et al. TNF-α, IL-1β and IL1-Ra polymorphisms and endometriosis severity. BMC Women's Health, 2022, supporting IL1B genetic variation as a modifier of disease severity rather than merely a bystander.

For rs4848306 specifically, the direct endometriosis evidence is pathway-based rather than variant-specific: the A allele reduces IL1B promoter activity, and lower IL-1β production capacity would logically dampen the peritoneal inflammatory cascade. This is classified as emerging evidence — the pathway plausibility is strong, but genome-wide significant association data for rs4848306 in endometriosis cohorts is not yet published.

Practical Actions

The G allele at rs4848306 is associated with higher IL-1β promoter activity. In the context of endometriosis, where peritoneal IL-1β excess is a documented and replicated finding, GG homozygotes may carry a heightened inflammatory tone that could favor lesion establishment and progression. Because this is an emerging-evidence variant, actions should focus on monitoring and evidence-based lifestyle factors known to modulate the IL-1β/IL-1Ra balance — specifically, dietary omega-3 fatty acids, which suppress IL-1β production, and awareness of symptoms that suggest active peritoneal inflammation.

Interactions

IL1A rs6542095: The IL-1α cytokine (encoded by IL1A) shares the same receptor as IL-1β and operates in the same peritoneal inflammatory cascade. Women carrying both the IL1A rs6542095-C risk allele (elevated IL-1α susceptibility) and the IL1B rs4848306 GG genotype (elevated IL-1β promoter activity) may experience compounded peritoneal IL-1 signaling — two branches of the same inflammatory pathway simultaneously amplified.

IL1RN rs2234663 (IL1B VNTR): The interleukin-1 receptor antagonist (IL-1Ra) competitively inhibits both IL-1α and IL-1β signaling. The IL1RN intron 2 VNTR (rs2234663, IL-1RN*2 allele) has been associated with lower IL-1Ra production in some tissues. A compounded state of high IL-1β (GG at rs4848306) with low IL-1Ra (IL1RN*2 carrier) would represent maximal unchecked IL-1 signaling in the peritoneal cavity.

IL1B rs1143634 (+3954): This IL1B exon 5 synonymous variant is the most studied IL1B variant in endometriosis; the *2 allele was associated with OR 2.69 for stage IV endometriosis in the Mier-Cabrera 2022 cohort. The two variants tag different haplotypes within the IL1B locus and may independently contribute to IL-1β expression amplitude.