rs3805435 — TNIP1

GPX3/TNIP1 — A Shared Regulatory Locus at the Edge of Inflammatory Control

Two adjacent genes on chromosome 5 occupy opposite ends of the same molecular story. GPX3¹¹ GPX3
Glutathione Peroxidase 3, a secreted antioxidant enzyme that neutralizes hydrogen peroxide in blood and tissues sits upstream on the forward strand. Downstream on the reverse strand lies TNIP1²² TNIP1
TNF Alpha-Induced Protein 3 Interacting Protein 1, encoding ABIN-1, the scaffolding partner required for A20-mediated NF-κB termination. The two genes are separated by roughly 100 kilobases but share a chromatin interaction network — regulatory variants in this region influence both genes simultaneously. rs3805435 sits in an intron of GPX3, but the haplotype it tags has been studied principally through its effects on ABIN-1 levels and NF-κB regulation in immune cells.

The Mechanism

ABIN-1, encoded by TNIP1, acts as a molecular scaffold that delivers A20 (encoded by TNFAIP3) to its ubiquitinated substrates within the NF-κB signaling complex. Without adequate ABIN-1, A20 cannot locate and edit the polyubiquitin chains on RIPK1, TRAF6, and NEMO that sustain NF-κB activation — the off-switch for the inflammatory cascade remains partly disconnected even when A20 protein is present.

Variants at the GPX3/TNIP1 locus affect TNIP1 expression in immune cells. Haplotypes carrying certain combinations across this region are associated with reduced ABIN-1 protein levels³³ reduced ABIN-1 protein levels
Bolin et al. 2012 showed two independent TNIP1 risk haplotypes in SLE cohorts produced lower TNIP1 mRNA and ABIN1 protein, consistent with hypomorphic expression, which blunts NF-κB termination after inflammatory stimuli. rs3805435 tags one component of the GPP-associated TNIP1 haplotype H4 identified by Han et al.; the C allele (which is considerably more common in East Asian populations, reaching ~42% frequency, versus ~8% in Europeans) is associated with maintained or enhanced regulatory capacity — resulting in lower GPP susceptibility in its carriers.

The GPX3/TNIP1 locus also has a chromatin-level regulatory structure in which variants at multiple positions interact to set net TNIP1 expression. Functional characterization of this region in ALS⁴⁴ Functional characterization of this region in ALS
Lall et al. 2022, Genome Medicine: eQTL and chromatin analyses of the GPX3/TNIP1 locus identified candidate regulatory SNPs affecting both GPX3 and TNIP1 expression across cell types found that the same chromatin architecture implicated in autoimmune risk also appears in neuroinflammatory disease — underscoring the pleiotropic nature of this locus.

The Evidence

The primary association evidence for rs3805435 comes from Han et al. 2016⁵⁵ Han et al. 2016
Han et al., Chin Med J 2016; 73 GPP patients, 67 PPP patients, 476 Chinese Han controls, which genotyped six TNIP1 SNPs in a Chinese Han cohort. The C allele (reported as G in that paper, which used reverse-strand notation for the TNIP1 coding strand) was significantly less frequent in GPP cases (34%) versus controls (46%), yielding a protective OR of 0.61 (95% CI 0.42–0.88, P=7.22×10⁻³). Conversely, the T allele (paper's A) is carried at significantly higher frequency among GPP cases.

The same study defined a four-SNP haplotype H4 — carrying rs3805435 alongside rs17728338 and other TNIP1 variants — with OR=4.16 (P=4.46×10⁻⁷) for GPP versus controls at 13.1% versus 3.4% frequency. This haplotype-level association is considerably stronger than the individual SNP signals, supporting the view that rs3805435 tags a regulatory haplotype rather than being the sole causal variant.

The evidence is categorized as moderate: the association is statistically significant and biologically plausible within the established TNIP1-A20-NF-κB framework, but it derives from a single cohort study in one ancestry group (Han Chinese). The C allele frequency difference between populations (European ~8% vs East Asian ~42%) means this variant primarily affects risk stratification within East Asian ancestry groups; its population-attributable fraction in Europeans is small.

Practical Actions

For TT homozygotes — the overwhelming majority globally (~83%) and approximately 34% of East Asians — the clinical implication is that this locus contributes to the TNIP1 haplotype H4 associated with elevated GPP risk. The actionable context is primarily through its interaction with rs17728338: individuals who are TT at rs3805435 AND carry the A risk allele at rs17728338 belong to the highest-risk GPP haplotype. The primary interventions for NF-κB dysregulation at the TNIP1 locus — vitamin D optimization and omega-3 supplementation — are addressed in the rs17728338 entry.

For CT heterozygotes and CC homozygotes, the presence of one or two protective C alleles is associated with reduced GPP susceptibility within the Han et al. haplotype framework. Carriers of CC are rare outside East Asian populations (<1% in Europeans) but represent approximately 17% of East Asians by Hardy-Weinberg calculation from the C allele frequency.

Interactions

rs3805435 and rs17728338 are part of the same TNIP1 haplotype block. The H4 risk haplotype defined in the Han et al. GPP study includes both SNPs; the compounded haplotype signal (OR=4.16) substantially exceeds either individual SNP's OR, consistent with the two variants jointly tagging the causal regulatory configuration at this locus. Carriers of both risk alleles (TT at rs3805435 and AA/AG at rs17728338) are candidates for a compound action representing the highest-risk TNIP1 haplotype for GPP and psoriatic inflammation.

The TNIP1 locus interacts functionally with rs610604 (TNFAIP3): ABIN-1 (TNIP1) scaffolds A20 (TNFAIP3) in the same NF-κB termination complex. Risk alleles at both loci impair complementary arms of the same braking system.