{"doi":"10.1111/all.15622","title":"A gene variant of <scp>AKR1C3</scp> contributes to interindividual susceptibilities to atopic dermatitis triggered by particulate air pollution","abstract":"The pathogenesis of atopic dermatitis (AD) involves an impairment of the skin barrier by an interplay of genetic and environmental factors. The resulting inappropriate defense against allergens, microbes, and pollutants results in a chronic, mainly T-helper (Th) 2 cell-driven skin inflammation.1 Environmental factors that may increase the risk for AD are airborne particulate matter (PM) and commonly associated polycyclic aromatic hydrocarbons (PAHs).1, 2 However, the available epidemiological data provide a heterogeneous picture. While some studies found a significant association between PM exposure and AD symptoms, in particular in children, other studies reported null associations.1, 2 This data inconsistency in airborne PM exposure-related AD may depend on interindividual genetic susceptibilities.3 A gene that is highly expressed in lesional AD skin4 and upregulated in PAH-exposed keratinocytes in an aryl hydrocarbon receptor-dependent manner5 encodes aldo-keto reductase (AKR)1C3. AKR1C3 reduces prostaglandin (PG)D2 to 9α,11β-PGF2, a metabolically stable stimulator of Th2 cells that serves as a systemic biomarker for allergen-induced mast cell activation.6 Herein, we demonstrate the functional and clinical relevance of the AKR1C3 gene variant rs12529 for the PM exposure-associated development of AD. Study individuals enrolled in the GINIplus/LISA birth cohort were restricted to 457 participants (49.5% male; age: mean = 15.1 years, sd = 0.2; BMI: mean = 21.2, sd = 3.3) with available AD diagnosis at the 15-year follow-up examination, air pollution, and genetic data. AD, defined as ever diagnosed by a physician, was present in 174 individuals. Median chronic exposures to PMs with interquartile ranges were for PM2.5 17.3 μg/m3 (0.9), for PM10 25.2 μg/m3 (1.5), for PM2.5 absorbance 1.16 10−5/m (0.2), and for PMcoarse 8.4 μg/m3 (0.6). The single nucleotide polymorphism (SNP) rs12529 was genotyped with sufficient quality (estimated R2 = 0.997), and the minor/effect allele frequency (EAF) was G: 0.400. We found consistent effects for all PM exposures showing a higher chance for adolescent carriers of the rs12529 effect allele (G) to develop AD as compared to rs12529 major allele (C) carriers under constant airborne PM exposure (Figure 1). With the increase per one effect allele, the odds ratio for developing AD significantly increases by 38% (PM10, PM2.5, PM2.5 absorbance) and 37% (PMcoarse), respectively. Next, we investigated whether the rs12529 effect allele, causing an amino acid exchange in codon 5 from His to Gln, affects the catalytic activity of AKR1C3. In comparison with the major allele variant, the overexpression of an effect allele-resembling AKR1C3 variant in CRISPR/Cas9-generated AKR1C3-knockout (HaCaT-AKR1C3-KO) keratinocytes (Figure S1A–C) resulted in an enhanced 11-ketoreduction of PGD2 to 9α,11β-PGF2 (Figure 2A). However, after normalization of the LC–MS data to the protein level, this effect was diminished (Figure 2B,C), indicating that the rs12529 effect allele affects AKR1C3 enzyme activity indirectly by enhancing its protein stability. Accordingly, treatment of transfected HaCaT-AKR1C3-KO cells with the translation blocker cycloheximide revealed a delayed degradation of the effect allele-resembling AKR1C3 enzyme over time (Figure 2D), indicating that the SNP-related amino acid exchange indeed enhances protein stability. Importantly, AKR1C3 expression is not only inducible by PAHs, such as benzo[a]pyrene, but also by PAH-rich PM. In fact, treatment of HaCaT keratinocytes with an organic extract of PM2.5 collected from traffic-related air pollution and a repetitive topical exposure of human ex vivo skin with diesel exhaust particles increased the expression of AKR1C3 (Figure 2E, Figure S2A) and the prototypic aryl hydrocarbon receptor target gene cytochrome P450 (CYP)1A1 (Figure S2). Taken together, our data show that under constant chronic PM exposure, the increase per one AKR1C3 SNP rs12529 effect allele incr","journal":"Allergy","year":2022,"id":270495,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":934750,"name":"Sara Kress","orcid":"0000-0002-8007-5357","position":1,"is_corresponding":false},{"id":934751,"name":"Dieter Lang","orcid":"0000-0002-2968-638X","position":2,"is_corresponding":false},{"id":227298,"name":"Christoph F. A. Vogel","orcid":"0000-0002-7561-4598","position":3,"is_corresponding":false},{"id":845087,"name":"Frederick Hartung","orcid":null,"position":4,"is_corresponding":false},{"id":935265,"name":"Heidi Brenden","orcid":null,"position":5,"is_corresponding":false},{"id":934752,"name":"Motoki Nakamura","orcid":"0000-0003-4431-7782","position":6,"is_corresponding":false},{"id":934753,"name":"Susanne Grether‐Beck","orcid":"0000-0002-8318-2625","position":7,"is_corresponding":false},{"id":3231,"name":"Andrea Rossi","orcid":"0000-0001-5863-6448","position":8,"is_corresponding":false},{"id":19455,"name":"Jean Krutmann","orcid":"0000-0001-8433-1517","position":9,"is_corresponding":false},{"id":51929,"name":"Tamara Schikowski","orcid":"0000-0002-4559-9374","position":10,"is_corresponding":false},{"id":227301,"name":"Thomas Haarmann‐Stemmann","orcid":"0000-0002-0397-2046","position":11,"is_corresponding":false},{"id":692427,"name":"Christian Vogeley","orcid":"0000-0002-9013-5288","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-19T00:27:31.019242Z","pmid":"36524327","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}