Background/Purpose:

Systemic lupus erythematosus (SLE) is a heterogeneous disease characterized by autoantibody formation in which multiple genetic, epigenetic and environmental risk factors have been implicated. We previously demonstrated that methylation levels differ significantly among SLE patients according to auto-antibody status and presence/absence of lupus nephritis. The study of epigenetics provides a mechanistic bridge to understand the effects of environmental exposures with disease risk and outcome. Air pollution has been linked not only to an increase in overall mortality but also to an increased incidence of rheumatoid arthritis. There are few studies evaluating air pollution and SLE development and outcomes.  However, anti-dsDNA antibody titers have been associated with high levels of air particulate matter. The goal of this study was to evaluate methylation differences in relation to residential proximity to highways in patients with SLE. 

Methods:

We studied 307 Caucasian females with SLE, all non-smokers, who were previously enrolled in a Lupus Genetics Project.  Residence at the time of blood draw was recorded and geocoded.  The distance to the nearest roads from the geocoded locations were calculated for the four major Tele Atlas Feature Class Codes (FCC) road classes. The Geographic Data Technology, Inc. (GDT) road network data were used for these calculations.  Genome-wide methylation profiling was performed using the Illumina Infinium HumanMethylation 450 BeadChip. After quality control measures 467,314 CpG sites were analyzed. 

Results:

Patients residing within a 300 meter radius from a major highway were defined as at high risk for significant hazardous health outcomes¹. Thirty-eight patients (12.4%) were residing in a high risk area. Multivariate analysis did not reveal any statistically significant association between proximity to highways and disease phenotypes, however there was a trend for higher incidence of malar rash (OR 2.4, CI[1.1, 5]) and photosensitivity (OR 2.7, CI[1.2, 5.9]). Analysis of genome-wide methylation data revealed 3 methylation sites that were significantly hypomethylated in patients who resided in a high risk zone (P value <1.7 E-07).  These three sites belonged to a single gene, UBE2U, which encodes one of the E2 enzymes involved in the ubiquitination of proteins and histones, as well as DNA repair.  Genome wide association studies (GWAS) in SLE have identified a risk variant at UBE2L3, also an E2 ubiquitination enzyme. In a large ongoing GWAS marked overexpression of UBE2L3 was seen in plasmablasts of patients of SLE with an associated upregulation of NF-κB.

Conclusion:

Hypomethylation of UBE2U was associated with residing close to a highway in our cohort of SLE patients.  To our knowledge, this study represents the first genome-wide assessment of DNA methylation in relationship to residential proximity to highways. Additional work is warranted to confirm these findings, examine other potentially relevant exposures, and determine whether these epigenetic changes are associated with SLE severity and outcome.

1.        Residential proximity to major highways – United States, 2010. MMWR Surveill Summ. 2013;62 Suppl 3:46-50.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/residential-proximity-to-highways-dna-methylation-and-systemic-lupus-erythematosus/