Table 1

Exposures associated with DNA methylation changes and their associations with SLE as well as other diseases

ExposureDNA methylation changesDisease associationsSLE associationsRef
ArsenicHypomethylation of genes involved in cell adhesion and communication; LINE-1 hypomethylation; hypomethylation in genesKCNQ1, SQSTM, MMP-9, TIMP-1, FYN, BST1, XYLT1, PTPRN2 and PARD3 Cancer, lung conditions, diabetes, CVD. Prenatal exposure was associated with increased incidence of infection, neurocognitive effects and increased neonatal mortalityArsenic exposed population had increase in positive ANA, serum levels of IL6 and IL8 110–114
Air pollutionGlobal hypomethylation; LINE-1 hypomethylation;Specific genes: MAPK pathway members, ACE, iNOS, ICAM-1, TLR2, IL-6 and TET1, Accelerated lung ageing, loss of lung capacity, asthma, bronchitis, emphysema and cancerIncrease in SLEDAI score, increase in risk of SLE and other rheumatic diseases 115–120
Bisphenol AHypomethylation of CpG targets on the X chromosome; hypomethylation in genes associated with immune function, transport activity and metabolism; hypomethylation of SNORD, SULT2A1, COMT; reduced expression of DNMT1Neurocognitive effects, increased incidence of cancer and heart conditions from prenatal exposureAutoantibody production in a murine model for SLE; BPA-induced signalling in murine and human myeloid cells stimulates the type I IFN-signalling 121–126
Cadmium MGMT, MT2A, DNMT3B and LINE-1 hypomethylation in a sex-specific manner; DNMT1 hypomethylationCancer, lung, bone and kidney disease, developmental toxicityAutoimmunity in animal models, including increased expression of ANA, immune complex deposition in the kidneys and antibody production in susceptible mouse models 127–132
Mercury Hypomethylation in genes EMID2, PON1 NeurotoxicityHigher risk of SLE in dental workers exposed to mercury 127 133–138
Persistent organic pollutantsHypomethylation of LINE-1 and Alu elements; Hypomethylation of genes IGF2, TNF-α, and NR3C1 Various health effectsANA positivity; increased risk of SLE mortality 29 139–142
PesticidesGlobal hypomethylation; Hypomethylation in genes GPR33, KCNE2, ANXA1, GSTp1, MGMT; LINE-1 hypomethylationCancer, neurotoxicity, birth defects, impaired fertilityHigher risk of SLE in exposed individuals 3 143–152
Polycyclic aromatic hydrocarbonsGlobal hypomethylation; hypermethylation of genes HIN1, ESR1, TWIST1, RARβ, APC CancerHigher risk of SLE in exposed individuals 101 145 153–155
PhthalatesDMRs in genes related to growth and development, cellular function and maintenance; Hypomethylation of genes ERalpha, IRAK4, ESM1, BRCA1, LASP1, CNPY1, IFT140, TESC, PRDM8 Infertility, cancerdsDNA production in lupus-prone mice, glomerulonephritis in lupus prone mice 156–162
Tobacco smokeGlobal hypomethylation; Hypomethylation of genes AHRR, CNTNAP2, MYO1G Cancer, developmental toxicity, cardiovascular disease, chronic respiratory conditionsHigher risk of SLE in exposed individuals, increased dsDNA production and cancer in patients with SLE 106 163–170
SaltTET2-induced global DNA demethylation of Tfh cellsA high-salt diet markedly increased lupus features in MRL/lpr mice 171
StressGlobal hypomethylation; Hypomethylation of genes NR3C1, OXTR, CORIN, CFTR, SMYD3, BARX1, CRF, SLC6A4 Infant stress reactivity, resilience, depression, increased cardiovascular disease, cancerIncreased risk of SLE in exposed individuals, higher rate of SLE flares, early onset of disease 172–177
  • CVD,cardiovascular disease; DMR, differentially methylated region; IFN, interferon; IL, interleukin; LINE-1, long interspersed nuclear element 1; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.