Expressive

rs114751021 (DDX39B/NOTCH4): C. diff infection risk

Key takeaways

  • This MHC-region variant was the only genome-wide significant hit for C. diff infection in antibiotic users across 16,000+ study participants.
  • Carriers showed roughly 2.4 times greater odds of developing C. diff infection compared to non-carriers in the antibiotic-exposed group.
  • The association appeared only in antibiotic users, not the broader study population, and has not yet been independently replicated.
  • Functional analyses implicated MICA, C4A/C4B, and NOTCH4 as the likely immune-gene effectors of the MHC-region signal.
  • GTEx data show the variant increases NOTCH4 expression in blood and MIR6891 across multiple tissues, pointing to immune-regulatory mechanisms.

Key takeaways

  • This MHC-region variant was the only genome-wide significant hit for C. diff infection in antibiotic users across 16,000+ study participants.
  • Carriers showed roughly 2.4 times greater odds of developing C. diff infection compared to non-carriers in the antibiotic-exposed group.
  • The association appeared only in antibiotic users, not the broader study population, and has not yet been independently replicated.
  • Functional analyses implicated MICA, C4A/C4B, and NOTCH4 as the likely immune-gene effectors of the MHC-region signal.
  • GTEx data show the variant increases NOTCH4 expression in blood and MIR6891 across multiple tissues, pointing to immune-regulatory mechanisms.

What the research says A genome-wide association study (GWAS) - a large-scale scan linking common genetic variants to disease - applied to 1,160 Clostridioides difficile infection (CDI) cases and 15,304 controls from linked electronic health records identified rs114751021 as the sole genome-wide significant variant for CDI susceptibility in the antibiotic-exposed subgroup (odds ratio 2.42, 95% confidence interval 1.84-3.11, p = 4.50 × 10^-8); no significant association emerged in the full dataset PMID 34671368. Colocalization and MetaXcan analyses - statistical methods that integrate GWAS signals with tissue gene-expression data to identify likely causal genes - implicated MICA, C4A/C4B, and NOTCH4 as probable effector genes in the MHC region, with lower MICA expression and higher C4A and NOTCH4 expression each associated with elevated CDI risk PMID 34671368.

Reported associations

  • Clostridioides difficile infection (antibiotic-user subgroup): Genome-wide significant association (OR = 2.42, 95% CI 1.84-3.11, p = 4.50 × 10^-8) derived from 1,160 CDI cases and 15,304 controls in the MyCode EHR-genomic cohort. PMID 34671368
  • Clostridioides difficile infection (full cohort): No genome-wide significant association was found in the overall meta-analysis across all CDI cases and controls. PMID 34671368

Evidence quality The association rests on a single study of 1,160 CDI cases and 15,304 controls (MyCode cohort), reaching genome-wide significance only within the antibiotic-user subgroup and not in the full dataset PMID 34671368. Subgroup-restricted signals carry an elevated risk of inflated effect estimates; the study authors explicitly state that future replication and functional validation are needed PMID 34671368. Prior CDI genetic studies involved fewer than 60 cases, making this the largest GWAS for this phenotype reported to date, yet by standard criteria - single study, subgroup finding, no independent replication - the evidence remains preliminary.

Tissue-specific expression effects

  • NOTCH4: Increased expression in whole blood, suggesting this immune-signaling receptor gene is upregulated by the variant in circulating immune cells. GTEx Portal
  • MIR6891: Increased expression across tibial nerve, subcutaneous adipose tissue, sun-exposed lower leg skin, lung, and whole blood, indicating broad multi-tissue upregulation of this microRNA gene. GTEx Portal
  • MICA-AS1 (an antisense RNA adjacent to the immune gene MICA): Increased expression in brain cerebellum; the significance of this finding in the primarily immune and gut-infection context of the GWAS association is not established. GTEx Portal
  • ENSG00000272501: Increased expression in non-sun-exposed suprapubic skin; the functional role of this uncharacterized gene in the CDI context has not been described. 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.

Discuss with your doctor

  • antibiotic necessity before treatment High

    G-allele carriers have 2.4-fold increased susceptibility to C. difficile infection when exposed to antibiotics, due to altered innate immune response (MICA/NOTCH4 dysregulation)

    Before accepting antibiotic treatment for any infection, ask your doctor if non-antibiotic alternatives are available

  • antibiotic necessity given CDI genetic risk Moderate

    rs114751021 confers 2.4-fold increased C. difficile infection risk with antibiotic exposure through altered immune response (NOTCH4 and MICA pathways)

Screening

  • C. difficile infection symptoms High

    Elevated genetic predisposition to C. difficile infection in context of antibiotic-induced microbiota disruption and immune dysregulation

    Contact doctor if you develop diarrhea, fever, or severe abdominal pain during or after antibiotic use

  • C. difficile symptoms if prescribed antibiotics Moderate

    Genetic predisposition at rs114751021 increases CDI susceptibility when antibiotic-exposed

    Watch for diarrhea, abdominal pain, fever within days of antibiotic use

Frequently asked questions

What is rs114751021 associated with?

rs114751021 is a variant in the MHC region of chromosome 6, physically near the genes SNORD117, DDX39B, and ATP6V1G2-DDX39B. A genome-wide study found it was linked to roughly 2.4 times greater odds of Clostridioides difficile gut infection in people who had taken antibiotics, though the finding needs independent replication.

Is rs114751021 linked to C. diff infection risk?

In one study of over 16,000 people, this variant was associated with about 2.4 times greater odds of C. diff infection among antibiotic users. However, the association was not significant in the broader study population, and no independent replication has been reported, so the evidence is considered preliminary.

What genes are affected by rs114751021?

Functional analyses point to three MHC-region genes as likely effectors: MICA, C4A/C4B, and NOTCH4. Lower MICA expression and higher C4A and NOTCH4 expression were each associated with greater C. diff infection risk. GTEx data additionally show the variant increases NOTCH4 expression in blood and MIR6891 expression across multiple tissues.

How reliable is the genetic evidence for this variant?

The finding comes from a single study with 1,160 C. diff cases and 15,304 controls, and reached statistical significance only within the antibiotic-user subgroup, not the full cohort. Subgroup-restricted signals can inflate effect sizes, and the study authors themselves call for future replication and functional validation before strong conclusions can be drawn.

Why is the MHC region relevant to gut infection?

The major histocompatibility complex (MHC) on chromosome 6 encodes many proteins central to immune recognition and response. The genes implicated near this variant - MICA, C4A/C4B, and NOTCH4 - are all involved in immune signaling, and changes in their expression levels were statistically linked to differential C. diff infection risk in the study.