Oxidative Gaseous Air Pollutant Exposure Interacts with PNPLA3-I148M Genotype to Influence Liver Fat Fraction and Multi-omics Profiles in Young Adults

Overview

Journal Environ Pollut

Date 2025 Jan 26

PMID 39864653

Authors

William B Patterson

Nathan D Young

Elizabeth A Holzhausen

Frederick Lurmann

Donghai Liang

Douglas I Walker

Dean P Jones

Jiawen Liao

Zhanghua Chen

David V Conti

Leda Chatzi

Lida Chatzi

Jesse A Goodrich

Tanya L Alderete

Affiliations

Soon will be listed here.

Abstract

PNPLA3-I148M genotype is the strongest predictive single-nucleotide polymorphism for liver fat. We examine whether PNPLA3-I148M modifies associations between oxidative gaseous air pollutant exposure (O) with i) liver fat and ii) multi-omics profiles of miRNAs and metabolites linked to liver fat. Participants were 69 young adults (17-22 years) from the Meta-AIR cohort. Prior-month residential O exposure (redox-weighted oxidative capacity of nitrogen dioxide and ozone) was spatially interpolated from monitoring stations via inverse-distance-squared weighting. Liver fat fraction was assessed by MRI. Serum miRNAs and metabolites were assayed via NanoString nCounter and LC-HRMS, respectively. Multi-omics factor analysis (MOFA) was used to identify latent factors with shared variance across omics layers. Multivariable linear regression models adjusted for age, sex, body mass index, and genotype with liver fat or MOFA factors as an outcome and examined PNPLA3 (rs738409; CC/CG vs. GG) as a multiplicative interaction term. Overall, a standard deviation difference in O exposure was associated with 8.9% relative increase in liver fat (p = 0.04) and this relationship differed by PNPLA3 genotype (p-value for interaction term: p<0.001), whereby relative increases in liver fat for GG and CC/CG participants were 71.8% and 2.4%, respectively. There was no main effect of O on MOFA Factor 1 expression (p = 0.85), but there was an interaction with PNPLA3 genotype (p = 0.01), whereby marginal slopes were 0.211 and -0.017 for GG and CC/CG participants, respectively. MOFA Factor 1 in turn was associated with liver fat (p = 0.006). MOFA Factor 1 miRNAs targeted genes in Fatty Acid Biosynthesis and Metabolism and Lysine Degradation pathways. MOFA Factor 9 was also associated with liver fat and was comprised of branched-chain keto acid and amino acid metabolites. The effects of O exposure on liver fat is exacerbated in young adults with two PNPLA3 risk alleles, potentially through differential effects on miRNA and/or metabolite profiles.

References

Schneider A, Neas L, Graff D, Herbst M, Cascio W, Schmitt M . Association of cardiac and vascular changes with ambient PM2.5 in diabetic individuals. Part Fibre Toxicol. 2010; 7:14. PMC: 2896918. DOI: 10.1186/1743-8977-7-14. View

Riazi K, Azhari H, Charette J, Underwood F, King J, Afshar E . The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022; 7(9):851-861. DOI: 10.1016/S2468-1253(22)00165-0. View

Panasevich S, Leander K, Ljungman P, Bellander T, de Faire U, Pershagen G . Interaction between air pollution exposure and genes in relation to levels of inflammatory markers and risk of myocardial infarction. BMJ Open. 2013; 3(9):e003058. PMC: 3780315. DOI: 10.1136/bmjopen-2013-003058. View

Wong D, Yuan L, Perlin S . Comparison of spatial interpolation methods for the estimation of air quality data. J Expo Anal Environ Epidemiol. 2004; 14(5):404-15. DOI: 10.1038/sj.jea.7500338. View

Zhang H, Chen J, Wang H, Lu X, Li K, Yang C . Serum Metabolomics Associating With Circulating MicroRNA Profiles Reveal the Role of miR-383-5p in Rat Hippocampus Under Simulated Microgravity. Front Physiol. 2020; 11:939. PMC: 7461998. DOI: 10.3389/fphys.2020.00939. View

Pardo M, Xu F, Qiu X, Zhu T, Rudich Y . Seasonal variations in fine particle composition from Beijing prompt oxidative stress response in mouse lung and liver. Sci Total Environ. 2018; 626:147-155. DOI: 10.1016/j.scitotenv.2018.01.017. View

Martinez L, Larrieta E, Kershenobich D, Torre A . The Expression of PNPLA3 Polymorphism could be the Key for Severe Liver Disease in NAFLD in Hispanic Population. Ann Hepatol. 2017; 16(6):909-915. DOI: 10.5604/01.3001.0010.5282. View

Ward-Caviness C . A review of gene-by-air pollution interactions for cardiovascular disease, risk factors, and biomarkers. Hum Genet. 2019; 138(6):547-561. PMC: 9185701. DOI: 10.1007/s00439-019-02004-w. View

Williams M, Atkinson R, Anderson H, Kelly F . Associations between daily mortality in London and combined oxidant capacity, ozone and nitrogen dioxide. Air Qual Atmos Health. 2014; 7(4):407-414. PMC: 4239710. DOI: 10.1007/s11869-014-0249-8. View

10.

Szczepaniak L, Nurenberg P, Leonard D, Browning J, Reingold J, Grundy S . Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2004; 288(2):E462-8. DOI: 10.1152/ajpendo.00064.2004. View

11.

Hu H, Nayak K . Quantification of absolute fat mass using an adipose tissue reference signal model. J Magn Reson Imaging. 2008; 28(6):1483-91. PMC: 2732124. DOI: 10.1002/jmri.21603. View

12.

Eslam M, Valenti L, Romeo S . Genetics and epigenetics of NAFLD and NASH: Clinical impact. J Hepatol. 2017; 68(2):268-279. DOI: 10.1016/j.jhep.2017.09.003. View

13.

Liao J, Goodrich J, Walker D, Lin Y, Lurmann F, Qiu C . Metabolic pathways altered by air pollutant exposure in association with lipid profiles in young adults. Environ Pollut. 2023; 327:121522. PMC: 10243191. DOI: 10.1016/j.envpol.2023.121522. View

14.

Bruschi F, Claudel T, Tardelli M, Caligiuri A, Stulnig T, Marra F . The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology. 2017; 65(6):1875-1890. DOI: 10.1002/hep.29041. View

15.

Du X, Zhang Q, Jiang Y, Li H, Zhu X, Zhang Y . Dynamic molecular choreography induced by traffic exposure: A randomized, crossover trial using multi-omics profiling. J Hazard Mater. 2021; 424(Pt A):127359. DOI: 10.1016/j.jhazmat.2021.127359. View

16.

Ren C, Baccarelli A, Wilker E, Suh H, Sparrow D, Vokonas P . Lipid and endothelium-related genes, ambient particulate matter, and heart rate variability--the VA Normative Aging Study. J Epidemiol Community Health. 2009; 64(1):49-56. PMC: 3935361. DOI: 10.1136/jech.2008.083295. View

17.

Ezaz G, Trivedi H, Connelly M, Filozof C, Howard K, L Parrish M . Differential Associations of Circulating MicroRNAs With Pathogenic Factors in NAFLD. Hepatol Commun. 2020; 4(5):670-680. PMC: 7193128. DOI: 10.1002/hep4.1501. View

18.

Ruiz-Lara K, Garcia-Medina S, Galar-Martinez M, Parra-Ortega I, Morales-Balcazar I, Hernandez-Rosas N . The evaluation of liver dysfunction and oxidative stress due to urban environmental pollution in Mexican population related to Madin Dam, State of Mexico: a pilot study. Environ Sci Pollut Res Int. 2022; 30(3):6950-6964. PMC: 9411834. DOI: 10.1007/s11356-022-22724-3. View

19.

Ravina M, Caramitti G, Panepinto D, Zanetti M . Air quality and photochemical reactions: analysis of NO and NO concentrations in the urban area of Turin, Italy. Air Qual Atmos Health. 2022; 15(3):541-558. PMC: 8832090. DOI: 10.1007/s11869-022-01168-1. View

20.

Kurlawala Z, Singh P, Hill B, Haberzettl P . Fine Particulate Matter (PM2.5)-Induced Pulmonary Oxidative Stress Contributes to Changes in the Plasma Lipidome and Liver Transcriptome in Mice. Toxicol Sci. 2023; . PMC: 10109534. DOI: 10.1093/toxsci/kfad020. View