rs3748067 — IL17A

3'UTR variant in IL-17A that alters post-transcriptional regulation via miRNA targeting, modulating IL-17A protein output and Th17-driven inflammatory disease susceptibility

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IL-17A 3'UTR: The Post-Transcriptional Dimmer Switch

While rs2275913 acts like a volume dial at the IL-17A promoter — controlling how much mRNA is produced when T cells activate — rs3748067 works at the other end of the gene, in the 3' untranslated region (3'UTR)11 3' untranslated region (3'UTR)
the section of mRNA after the protein-coding sequence, which contains binding sites for microRNAs and other regulatory molecules that control how much protein is ultimately made. Together, these two variants shape the IL-17A Th17 axis through complementary but distinct mechanisms.

The Mechanism

The rs3748067 variant lies at position c.*1249 in the IL17A 3'UTR, placing it in a region where microRNAs (miRNAs)22 microRNAs (miRNAs)
small non-coding RNA molecules that bind to mRNA 3'UTRs and suppress protein translation or trigger mRNA degradation regulate IL-17A protein output.

Unlike the promoter variant rs2275913, which has a well-characterized NFAT-binding mechanism, the exact miRNA responsible for 3'UTR regulation at rs3748067 has not been conclusively identified in published functional studies. The clinical associations across multiple diseases nevertheless suggest this 3'UTR position exerts meaningful regulatory influence on post-transcriptional IL-17A output.

This variant is part of the same IL17A linkage disequilibrium (LD) block33 IL17A linkage disequilibrium (LD) block
a chromosomal region where SNPs tend to be inherited together as rs2275913, and the two variants are studied together in haplotype analyses. Despite being in partial LD, each variant retains independent information, and their combination is the most clinically studied unit for IBD susceptibility.

The Evidence

Ulcerative colitis (UC): The clearest evidence for rs3748067's clinical relevance comes from a Japanese case-control study of 202 UC patients and 475 controls (Kageyama et al., Clin Exp Med 2013)44 (Kageyama et al., Clin Exp Med 2013). The haplotype combining rs2275913 AA (high-transcription promoter) and rs3748067 CC (unmodified 3'UTR) conferred a 3.38-fold UC risk compared to the low-risk haplotype (p=0.0007) — substantially higher than either variant alone.

Gastric cancer: A Japanese study examining rs3748067 in 337 gastric cancer cases and 587 controls found the T allele to be protective for intestinal-type GC (OR 0.511, 95%CI 0.272–0.962)55 (OR 0.511, 95%CI 0.272–0.962), and inversely correlated with lymph node metastasis. However, a 2018 meta-analysis of 9 studies did not find a significant overall association66 did not find a significant overall association, suggesting the gastric cancer finding may be population-specific.

Tuberculosis susceptibility: Two meta-analyses found the TT genotype associated with increased TB susceptibility in Asian populations (OR 1.36, 95%CI 1.03–1.79)77 (OR 1.36, 95%CI 1.03–1.79). If T allele reduces IL-17A output, users have lower Th17-mediated mucosal immunity against pathogens like Mycobacterium tuberculosis.

Practical Actions

Because rs3748067 and rs2275913 operate through the same IL-17A protein, the practical interventions targeting the Th17 axis apply to both variants. For individuals carrying the CC genotype at rs3748067 — especially in combination with the rs2275913 A allele — the key priority is supporting natural regulation of IL-17A output.

Three interventions with evidence in the Th17 pathway are particularly relevant for the CC genotype: maintaining vitamin D3 status in the 40–60 ng/mL range (active vitamin D suppresses IL-17A transcription at the promoter level, complementing 3'UTR regulation), EPA/DHA omega-3 supplementation (EPA-derived prostaglandin D3 suppresses Th17 differentiation and IL-17A production), and multi-strain probiotics with Lactobacillus and Bifidobacterium strains that shift Th17/Treg balance.

For individuals with the TT genotype, the concern is less about inflammatory overactivation and more about potentially reduced Th17 immune defense. This is most clinically relevant in high-risk infectious environments or in individuals with known TB exposure.

Interactions

The most important interaction is with rs227591388 rs2275913
the IL-17A promoter variant at -197G>A that directly controls IL-17A transcription via NFAT binding. The rs2275913 AA + rs3748067 CC haplotype confers 3.38-fold UC risk. Check your rs2275913 result alongside this variant for the full picture of your IL-17A axis activity.

IL17F rs76378099 IL17F rs763780
a coding variant that reduces IL-17F bioactivity further modulates the Th17 output profile.

PTPN22 rs24766011010 PTPN22 rs2476601
a phosphatase variant that lowers the T cell activation threshold can compound autoimmune susceptibility in individuals who also carry high-IL-17A genotypes.

Genotype Interpretations

What each possible genotype means for this variant.

CT Intermediate IL-17A 3'UTR Normal

One copy each — intermediate post-transcriptional IL-17A regulation

You carry one C and one T allele at this 3'UTR position. Heterozygotes fall between the CC and TT states. About 16% of people globally carry this genotype. The clinical risk associated with CT is intermediate; the strongest published disease signals apply to the CC and TT homozygotes. Your Th17 axis activity from this variant is broadly in the typical range.

CC High IL-17A 3'UTR Activity Intermediate

Common 3'UTR genotype associated with higher IL-17A protein output and elevated inflammatory risk

The 3'UTR of IL17A contains regulatory elements — including miRNA binding sites — that fine-tune how much IL-17A protein is produced from each mRNA molecule. The C allele at rs3748067 represents the unmodified state where these 3'UTR regulatory elements operate at baseline. The clinical significance of CC alone is modest; the major evidence comes from haplotype analyses showing CC combined with the rs2275913 A allele (the promoter transcription amplifier) creates the highest-risk combination for ulcerative colitis.

The CC genotype is also consistent with the TB susceptibility data, where the T allele (not CC) is associated with increased TB risk — suggesting CC individuals have better Th17 mucosal immunity against bacterial pathogens. This is a case where the "risk" allele for autoimmune inflammation is the "protective" allele for infectious disease.

TT Low IL-17A 3'UTR Activity Decreased

Minor 3'UTR genotype associated with lower IL-17A output and reduced inflammatory risk — with trade-offs in infection susceptibility

The TT genotype represents the fully modified 3'UTR state, where both copies of the IL17A mRNA carry the T-allele regulatory variant. If the T allele creates or restores a miRNA binding site at this 3'UTR position, both mRNA copies would be more effectively silenced post-transcriptionally, reducing overall IL-17A protein production.

The protective effect in gastric cancer (OR 0.511 for intestinal GC in a Japanese study) is consistent with lower IL-17A-driven mucosal inflammation. However, the TB susceptibility finding (OR 1.36–1.87) is an important trade-off: Th17 cells and IL-17A are essential for recruiting neutrophils to contain mycobacterial infections, and impaired IL-17A output increases susceptibility to these pathogens.

In clinical practice, TT individuals with confirmed or suspected TB exposure, or those in high-TB-burden environments, should be aware that their IL-17A output may provide a suboptimal first-line response. For autoimmune concerns, TT individuals have a naturally lower Th17 inflammatory drive from this locus.