Exposures associated with DNA methylation changes and their associations with SLE as well as other diseases
| Exposure | DNA methylation changes | Disease associations | SLE associations | Ref |
| Arsenic | Hypomethylation 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 mortality | Arsenic exposed population had increase in positive ANA, serum levels of IL6 and IL8 | 110–114 |
| Air pollution | Global 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 cancer | Increase in SLEDAI score, increase in risk of SLE and other rheumatic diseases | 115–120 |
| Bisphenol A | Hypomethylation 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 DNMT1 | Neurocognitive effects, increased incidence of cancer and heart conditions from prenatal exposure | Autoantibody 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 hypomethylation | Cancer, lung, bone and kidney disease, developmental toxicity | Autoimmunity 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 | Neurotoxicity | Higher risk of SLE in dental workers exposed to mercury | 127 133–138 |
| Persistent organic pollutants | Hypomethylation of LINE-1 and Alu elements; Hypomethylation of genes IGF2, TNF-α, and NR3C1 | Various health effects | ANA positivity; increased risk of SLE mortality | 29 139–142 |
| Pesticides | Global hypomethylation; Hypomethylation in genes GPR33, KCNE2, ANXA1, GSTp1, MGMT; LINE-1 hypomethylation | Cancer, neurotoxicity, birth defects, impaired fertility | Higher risk of SLE in exposed individuals | 3 143–152 |
| Polycyclic aromatic hydrocarbons | Global hypomethylation; hypermethylation of genes HIN1, ESR1, TWIST1, RARβ, APC | Cancer | Higher risk of SLE in exposed individuals | 101 145 153–155 |
| Phthalates | DMRs in genes related to growth and development, cellular function and maintenance; Hypomethylation of genes ERalpha, IRAK4, ESM1, BRCA1, LASP1, CNPY1, IFT140, TESC, PRDM8 | Infertility, cancer | dsDNA production in lupus-prone mice, glomerulonephritis in lupus prone mice | 156–162 |
| Tobacco smoke | Global hypomethylation; Hypomethylation of genes AHRR, CNTNAP2, MYO1G | Cancer, developmental toxicity, cardiovascular disease, chronic respiratory conditions | Higher risk of SLE in exposed individuals, increased dsDNA production and cancer in patients with SLE | 106 163–170 |
| Salt | TET2-induced global DNA demethylation of Tfh cells | A high-salt diet markedly increased lupus features in MRL/lpr mice | 171 | |
| Stress | Global hypomethylation; Hypomethylation of genes NR3C1, OXTR, CORIN, CFTR, SMYD3, BARX1, CRF, SLC6A4 | Infant stress reactivity, resilience, depression, increased cardiovascular disease, cancer | Increased 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.