PMID- 36114491 OWN - NLM STAT- MEDLINE DCOM- 20220920 LR - 20230111 IS - 1465-993X (Electronic) IS - 1465-9921 (Print) IS - 1465-9921 (Linking) VI - 23 IP - 1 DP - 2022 Sep 16 TI - Peroxisome proliferator-activated receptor gamma gene variants modify human airway and systemic responses to indoor dibutyl phthalate exposure. PG - 248 LID - 10.1186/s12931-022-02174-8 [doi] LID - 248 AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptor gamma (PPAR-gamma; gene: PPARG) and oxidative stress genes are associated with asthma risk. However, whether such variants modulate responses to dibutyl phthalate (DBP), a common plasticizer associated with increased asthma development, remains unknown. The purpose of this study is to investigate how SNPs in PPARG and oxidative stress genes, as represented by two separate genetic risk scores, modify the impact of DBP exposure on lung function and the airway and systemic response after an inhaled allergen challenge. METHODS: We conducted a double-blinded human crossover study with sixteen allergen-sensitized participants exposed for three hours to DBP and control air on distinct occasions separated by a 4-week washout. Each exposure was followed by an allergen inhalation challenge; subsequently, lung function was measured, and blood and bronchoalveolar lavage (BAL) were collected and analyzed for cell counts and allergen-specific immunoglobulin E (IgE). Genetic risk scores for PPAR-gamma (P-GRS; weighted sum of PPARG SNPs rs10865710, rs709158, and rs3856806) and oxidative stress (OS-GRS; unweighted sum of 16 SNPs across multiple genes) were developed, and their ability to modify DBP effects were assessed using linear mixed-effects models. RESULTS: P-GRS and OS-GRS modified DBP effects on allergen-specific IgE in blood at 20 h (interaction effect [95% CI]: 1.43 [1.13 to 1.80], p = 0.005) and 3 h (0.99 [0.98 to 1], p = 0.03), respectively. P-GRS also modified DBP effects on Th2 cells in blood at 3 h (- 25.2 [- 47.7 to - 2.70], p = 0.03) and 20 h (- 39.1 [- 57.9 to - 20.3], p = 0.0005), and Th2 cells in BAL at 24 h (- 4.99 [- 8.97 to - 1.01], p = 0.02). An increasing P-GRS associated with reduced DBP effect on Th2 cells. Neither GRS significantly modified DBP effects on lung function parameters. CONCLUSIONS: PPAR-gamma variants modulated several airway and systemic immune responses to the ubiquitous chemical plasticizer DBP. Our results suggest that PPAR-gamma variants may play a greater role than those in oxidative stress-related genes in airway allergic responses to DBP. TRIAL REGISTRATION: This study reports results from The Phthalate-Allergen Immune Response Study that was registered on ClinicalTrials.gov with identification NCT02688478. CI - (c) 2022. The Author(s). FAU - Leung, Clarus AU - Leung C AD - Department of Medicine, University of British Columbia, 7th Floor, 2775 Laurel St, VancouverVancouver, BC, V5Z1M9, Canada. FAU - Ryu, Min Hyung AU - Ryu MH AD - Department of Medicine, University of British Columbia, 7th Floor, 2775 Laurel St, VancouverVancouver, BC, V5Z1M9, Canada. FAU - Bolling, Anette Kocbach AU - Bolling AK AD - Department of Air Pollution and Noise, Norwegian Institute of Public Health, Oslo, Norway. FAU - Maestre-Batlle, Danay AU - Maestre-Batlle D AD - Department of Medicine, University of British Columbia, 7th Floor, 2775 Laurel St, VancouverVancouver, BC, V5Z1M9, Canada. FAU - Rider, Christopher F AU - Rider CF AD - Department of Medicine, University of British Columbia, 7th Floor, 2775 Laurel St, VancouverVancouver, BC, V5Z1M9, Canada. FAU - Huls, Anke AU - Huls A AD - Department of Epidemiology and Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA. FAU - Urtatiz, Oscar AU - Urtatiz O AD - Department of Medical Genetics, University of British Columbia-BC Children's Hospital Research Institute, Vancouver, BC, Canada. FAU - MacIsaac, Julie L AU - MacIsaac JL AD - Department of Medical Genetics, University of British Columbia-BC Children's Hospital Research Institute, Vancouver, BC, Canada. FAU - Lau, Kevin Soon-Keen AU - Lau KS AD - Department of Medicine, University of British Columbia, 7th Floor, 2775 Laurel St, VancouverVancouver, BC, V5Z1M9, Canada. FAU - Lin, David Tse Shen AU - Lin DTS AD - Department of Medical Genetics, University of British Columbia-BC Children's Hospital Research Institute, Vancouver, BC, Canada. FAU - Kobor, Michael S AU - Kobor MS AD - Department of Medical Genetics, University of British Columbia-BC Children's Hospital Research Institute, Vancouver, BC, Canada. FAU - Carlsten, Chris AU - Carlsten C AD - Department of Medicine, University of British Columbia, 7th Floor, 2775 Laurel St, VancouverVancouver, BC, V5Z1M9, Canada. carlsten@mail.ubc.ca. LA - eng SI - ClinicalTrials.gov/NCT02688478 GR - P30 ES019776/ES/NIEHS NIH HHS/United States PT - Controlled Clinical Trial PT - Journal Article DEP - 20220916 PL - England TA - Respir Res JT - Respiratory research JID - 101090633 RN - 0 (Allergens) RN - 0 (PPAR gamma) RN - 0 (Plasticizers) RN - 2286E5R2KE (Dibutyl Phthalate) RN - 37341-29-0 (Immunoglobulin E) SB - IM MH - Allergens MH - *Asthma MH - Cross-Over Studies MH - *Dibutyl Phthalate/toxicity MH - Humans MH - Immunoglobulin E MH - PPAR gamma/genetics MH - Plasticizers PMC - PMC9482266 OTO - NOTNLM OT - Airway inflammation OT - Allergen challenge OT - PPAR-gamma OT - Peroxisome proliferator-activated receptor gamma OT - Phthalates OT - Polymorphism COIS- The authors declare that they have no competing interests. EDAT- 2022/09/17 06:00 MHDA- 2022/09/21 06:00 PMCR- 2022/09/16 CRDT- 2022/09/16 23:41 PHST- 2022/03/27 00:00 [received] PHST- 2022/09/08 00:00 [accepted] PHST- 2022/09/16 23:41 [entrez] PHST- 2022/09/17 06:00 [pubmed] PHST- 2022/09/21 06:00 [medline] PHST- 2022/09/16 00:00 [pmc-release] AID - 10.1186/s12931-022-02174-8 [pii] AID - 2174 [pii] AID - 10.1186/s12931-022-02174-8 [doi] PST - epublish SO - Respir Res. 2022 Sep 16;23(1):248. doi: 10.1186/s12931-022-02174-8.