rs3805435 — TNIP1

Intronic variant in the GPX3/TNIP1 regulatory locus on chromosome 5; the C allele is protective against generalized pustular psoriasis (OR≈0.61 per C allele)

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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.

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 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 six-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.

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.

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

The H4 risk haplotype defined in the Han et al. GPP study includes both SNPs.

Genotype Interpretations

What each possible genotype means for this variant.

CT One Protective C Allele Normal

One protective C allele — modestly reduced GPP susceptibility compared to TT homozygotes

You carry one copy of the protective C allele at rs3805435. In the Han et al. Chinese Han GPP cohort, the C allele (reported as G in the minus-strand paper notation) was significantly enriched in controls versus GPP cases (OR=0.61 per C allele, P=7.22×10⁻³), indicating partial protective effect in heterozygous carriers. This heterozygous genotype represents approximately 16% of the global population but is substantially more common in East Asian populations (~40% by Hardy-Weinberg from the 42% C allele frequency).

CC Homozygous Protective C Allele Beneficial

Two protective C alleles — lowest rs3805435-associated GPP susceptibility; rare outside East Asian populations

You carry two copies of the protective C allele at rs3805435. CC homozygosity is rare globally (~0.8% by Hardy-Weinberg from the 9% C allele frequency) but is more prevalent in East Asian populations (~17% by Hardy-Weinberg from the 42% C frequency). In the GPP cohort study, individuals with the C allele (protective, OR=0.61 per allele) were substantially under-represented among GPP cases. CC homozygotes would be expected to carry the greatest protective effect under an additive model, essentially decoupling them from the high-risk TNIP1 H4 haplotype. This means the TNIP1 locus rs3805435 component confers its lowest GPP risk in your genotype.

TT TNIP1 Baseline — No Protective C Allele Intermediate

Two T alleles — no protective C allele

The C allele at rs3805435 is considerably enriched in East Asian populations (~42% frequency) compared to Europeans (~8%) and Africans (~2%). This means that in Chinese Han and other East Asian populations, approximately 40% of people carry at least one protective C allele — substantially more than in European populations. The GPP association study was conducted entirely in Chinese Han patients and controls, so the relative risk attributable to TT versus CT/CC is most directly interpretable in East Asian ancestry contexts. For European ancestry individuals, TT is so common (~92% of the population) that it does not meaningfully stratify risk beyond what the companion rs17728338 variant captures.