rs28730619 — ADH5

ADH5 / GSNOR — The Airway's Nitric Oxide Rheostat

Deep in the airways, a molecular balancing act governs whether bronchial smooth muscle stays relaxed or tightens toward an asthma attack. One of the key players is ADH5 — formally S-nitrosoglutathione reductase (GSNOR) — an enzyme that degrades S-nitrosoglutathione (GSNO)¹¹ S-nitrosoglutathione (GSNO)
GSNO is the predominant bioactive form of nitric oxide in airway lining fluid; it relaxes smooth muscle at nanomolar concentrations, roughly 100 times more potently than the asthma drug theophylline, the lung's primary endogenous bronchodilator. rs28730619 sits within an intron of the ADH5 gene on chromosome 4 and tags a haplotype associated with elevated GSNOR activity and childhood asthma risk.

The Mechanism

GSNOR catalyses the NADH-dependent conversion of GSNO to oxidized glutathione and ammonia, irreversibly removing GSNO from airway lining fluid. When GSNOR activity is elevated, S-nitrosothiol (SNO) levels fall²² S-nitrosothiol (SNO) levels fall
SNOs include GSNO and protein-bound nitrosothiols; they are potent bronchodilators depleted in asthmatic lungs, smooth muscle tone rises, and airway hyperresponsiveness follows. The enzyme also detoxifies formaldehyde (via the spontaneous glutathione adduct S-hydroxymethylglutathione), providing a secondary role in airway protection from irritants.

rs28730619 is an intronic variant and does not alter the GSNOR protein directly. Its asthma association most likely reflects linkage disequilibrium³³ linkage disequilibrium
LD means this SNP travels with nearby functional variants across generations; the C allele at rs28730619 marks a chromosomal haplotype rather than being directly causal with functional variants elsewhere in the gene. A closely related promoter SNP, rs1154404, shows near-complete LD with rs28730619 in some haplotypes and has been proposed to disrupt an NF-κB binding site, potentially increasing baseline GSNOR transcription. Other ADH5 promoter variants (rs2602899, rs2851301) at suspected NF-κB sites are associated with decreased asthma risk through reduced GSNOR expression — the inverse of what rs28730619 tags — reinforcing the idea that GSNOR expression level, rather than protein function, is the key modifiable variable.

The Evidence

The primary association study enrolled 532 nuclear families⁴⁴ 532 nuclear families
Case-parent triad design: each triad comprises one asthmatic child and both biological parents; family-based association testing controls for population stratification artifacts with asthmatic children aged 4–17 years in Mexico City. Children homozygous for the minor (C/plus-strand) allele at rs28730619 had a relative risk of 1.60 (95% CI 1.13–2.26, P = 0.0077) for asthma. The heterozygous genotype showed a trend toward increased risk (RR 1.20, 95% CI 0.92–1.55) but did not reach significance, suggesting a broadly additive or recessive dose-response pattern. The most common haplotype containing this minor C allele also conferred elevated asthma risk (RR 1.57, 95% CI 1.08–2.27, P = 0.017) in haplotype analysis.

Functional data from human bronchoalveolar lavage Que et al. 2009⁵⁵ Que et al. 2009
GSNOR activity measured in lavage fluid from 13 asthmatic and 11 healthy adults; activity correlated inversely with PC20 methacholine threshold (airway hyperresponsiveness) confirms the mechanism: GSNOR activity was twice as high in asthmatics (1,223 vs 537 AU/mg protein, p = 0.03), and total SNO levels were halved (11.2 vs 23.1 pmol/ml, p = 0.01). This aligns with mouse knockout data — ADH5-null mice are protected from allergen-induced airway hyperresponsiveness and maintain higher tissue RSNO levels.

A 2017 review Barnett & Buxton⁶⁶ Barnett & Buxton
Critical Reviews in Biochemistry and Molecular Biology; covers all human diseases where GSNOR dysregulation has been implicated notes that GSNOR inhibitors (N6022, N91115) have entered clinical trials for asthma and cystic fibrosis, underscoring the therapeutic tractability of the enzyme as a target — and, by extension, the clinical significance of genetic variants that mimic its overactivity.

The limitation of current evidence is that the genetic association derives from a single study in a Latin American pediatric cohort. Replication in European or East Asian populations is lacking, keeping the evidence level at moderate despite the strong functional plausibility.

Practical Actions

The rs28730619 C/C genotype is found in roughly 3% of the global population (higher in African and Latino populations at ~10% and ~7% respectively). For CC carriers, the practical priority is minimising triggers that further stress the GSNOR-GSNO axis and maximising endogenous nitric oxide availability in the airways.

Formaldehyde exposure — from new furniture, building materials, and cigarette smoke — is directly relevant: GSNOR is the primary enzyme that clears the formaldehyde-glutathione adduct, and high environmental formaldehyde load competes for enzyme capacity, potentially worsening the GSNO deficit. Low-nitrate vegetable intake can limit substrate for airway NO synthesis; nitrate-rich foods (beetroot, leafy greens, celery) provide dietary nitrate that the inorganic nitrate → nitrite → NO pathway can convert to NO independently of eNOS, partially bypassing the GSNOR-mediated GSNO depletion.

Interactions

rs1154404 (also in ADH5) forms part of the same haplotype as rs28730619 and is the more likely functional driver of the NF-κB–mediated transcription change. Carrying risk alleles at both SNPs compounds the signal. The beta-2 adrenergic receptor variant rs1042713 (ADRB2 Arg16Gly) interacts with GSNOR haplotypes in bronchodilator responsiveness to albuterol in Hispanic children — GSNOR and ADRB2 genotypes together predict ~70% of non-response to albuterol therapy, suggesting a compound action between these two pathways.