rs35699176 — ZNF77 ZNF77 Q100*

ZNF77 Q100* — A Genetic Brake on Bronchial Barrier Integrity

The bronchial epithelium is the first line of defense against airborne pathogens, including the ubiquitous mould Aspergillus fumigatus¹¹ Aspergillus fumigatus
Aspergillus fumigatus is a common airborne fungus that causes little harm in healthy lungs but can colonize and invade in those with compromised barriers or suppressed immunity. ZNF77 — zinc finger protein 77 — is a transcription factor expressed in bronchial epithelial cells that helps regulate the structural proteins keeping the airway lining sealed. The rs35699176 variant creates a premature stop codon (Q100*) that truncates ZNF77 protein at position 100, eliminating most of its functional zinc-finger DNA-binding domains and compromising this regulatory role.

The Mechanism

ZNF77 is encoded on the minus strand of chromosome 19 (GRCh38 position 2,936,537). The variant is a G-to-A change on the plus strand, which corresponds to a C-to-T change in the coding sequence (c.298C>T), converting the glutamine codon (CAG) at position 100 to a stop codon (TAG) — hence the designation p.Gln100Ter.

Gago et al. 2018²² Gago et al. 2018
Gago S et al. Lung colonization by Aspergillus fumigatus is controlled by ZNF77. Nature Communications 9:3835 used genome-edited bronchial epithelial cells carrying rs35699176 to show that the truncated protein causes:

• Reduced transepithelial electrical resistance (p < 0.0001) — a direct measure of barrier tightness
• Elevated extracellular matrix (ECM) proteins on the cell surface
• Enhanced A. fumigatus conidial adhesion at 30 and 120 minutes post-exposure
• Faster conidial germination and greater hyphal extension
• Increased fungal cytotoxicity to the epithelial layer

RNA-seq and mass spectrometry (LC-MS/MS) revealed that the variant upregulates vesicle trafficking pathways, increasing secretion of ECM adhesion proteins that fungal conidia exploit as attachment anchors. The end result is a more permissive landing surface for Aspergillus.

The Evidence

The clinical arm of the Gago et al. study compared A. fumigatus airway loads in patients with fungal asthma stratified by rs35699176 genotype. Patients heterozygous for the variant (AG) had significantly higher airway fungal loads³³ Patients heterozygous for the variant (AG) had significantly higher airway fungal loads
Heterozygous rs35699176+/- patients with fungal asthma showed higher A. fumigatus loads compared to wild-type patients in the Gago 2018 clinical cohort than those carrying two wild-type G alleles. The authors proposed ZNF77 genotype as a potential "risk marker for patient stratification" in allergic bronchopulmonary aspergillosis (ABPA) and related fungal airway diseases.

A separate population study (Hallengren et al. 2015⁴⁴ Hallengren et al. 2015
Hallengren E et al. Analysis of Low Frequency Protein Truncating Stop-Codon Variants and Fasting Concentration of Growth Hormone. PLoS One 10(6)) identified the same variant in 5,451 individuals from the Malmö Diet and Cancer cohort and found a modest association with higher fasting growth hormone (β = 0.12 SD per minor allele, p = 0.02) and borderline taller stature. The authors considered this preliminary and requiring replication; the growth hormone finding has no direct relevance to fungal susceptibility.

The evidence base is currently a single well-mechanised study (Gago 2018) with in vitro and patient-cohort support but no independent replication, placing this variant firmly in the emerging evidence tier. No GWAS catalog entries or ClinVar classifications exist for this rsid.

Practical Actions

For carriers of the A allele — particularly those with asthma, structural lung disease, or who are immunosuppressed — the ZNF77 Q100* variant is a signal to take airway fungal exposure seriously. The bronchial epithelium is less able to exclude Aspergillus conidia, increasing the probability that inhaled spores establish meaningful colonization rather than being cleared.

Reducing environmental mould load and having a low threshold for investigating persistent respiratory symptoms are the most evidence-consistent responses. Spirometry and bronchial challenge testing can help characterise baseline airway function. In atopic individuals, serum IgE and Aspergillus-specific IgE (RAST) can quantify sensitisation.

Interactions

ZNF77 operates as a transcription factor upstream of structural epithelial proteins; interactions with other barrier-integrity loci (e.g., filaggrin FLG variants associated with atopic march) are biologically plausible but not yet studied for this specific variant. ABPA susceptibility also involves IL-4R, IL-13, and HLA-DR loci — gene-gene interaction data for rs35699176 with these variants does not yet exist in the literature.