rs3748067 — IL17A

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. The common C allele is associated with higher IL-17A protein levels in population studies — this may reflect impaired miRNA-mediated suppression at this site. A parallel study identified that pri-miR-938, which targets the IL17A 3'UTR, is associated with gastric cancer susceptibility through this same regulatory region, suggesting that 3'UTR variants and their miRNA regulators act together on IL-17A expression.

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, higher protein output) conferred a 3.38-fold UC risk compared to the low-risk haplotype (p=0.0007) — substantially higher than either variant alone. This synergy between promoter and 3'UTR variants illustrates how the two variants cooperate to amplify total IL-17A output.

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). This apparent paradox — the T allele protective in cancer but harmful in infection — is consistent with IL-17A's dual biology: it drives pathological inflammation in autoimmune disease but provides essential protection against extracellular bacteria and fungi. If T allele reduces IL-17A output, users have lower Th17-mediated mucosal immunity against pathogens like Mycobacterium tuberculosis.

Coronary artery disease: A meta-analysis of 6 studies in 3,542 CAD cases and 3,212 controls found the TT genotype significantly protective in Asians (OR 0.37)⁸⁸ (OR 0.37), consistent with the idea that lower IL-17A output reduces vascular inflammation and atherosclerosis risk.

The collective evidence supports a model where the C allele at rs3748067 is associated with higher IL-17A protein levels, increasing risk for inflammatory and autoimmune conditions but potentially providing stronger Th17-mediated bacterial defenses, while the T allele correlates with lower IL-17A output, reducing inflammatory disease risk but decreasing Th17 immune protection.

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 rs2275913⁹⁹ 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 — the highest IL-17A output state when both transcriptional (promoter) and post-transcriptional (3'UTR) mechanisms drive high protein production. Check your rs2275913 result alongside this variant for the full picture of your IL-17A axis activity.

IL17F rs763780¹⁰¹⁰ IL17F rs763780
a coding variant that reduces IL-17F bioactivity further modulates the Th17 output profile: individuals with high IL-17A output (rs2275913 AA, rs3748067 CC) and functional IL-17F have the highest combined Th17 cytokine activity.

PTPN22 rs2476601¹¹¹¹ 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.