Browsing by Author "Bernatsky, Sasha"
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- ItemOpen AccessLong-term exposure to a mixture of industrial SO2, NO2, and PM2.5 and anti-citrullinated protein antibody positivity(2020-07-29) Zhao, Naizhuo; Smargiassi, Audrey; Hatzopoulou, Marianne; Colmegna, Ines; Hudson, Marie; Fritzler, Marvin J; Awadalla, Philip; Bernatsky, SashaAbstract Background Studies of associations between industrial air emissions and rheumatic diseases, or diseases-related serological biomarkers, are few. Moreover, previous evaluations typically studied individual (not mixed) emissions. We investigated associations between individual and combined exposures to industrial sulfur dioxide (SO2), nitrogen dioxide (NO2), and fine particles matter (PM2.5) on anti-citrullinated protein antibodies (ACPA), a characteristic biomarker for rheumatoid arthritis (RA). Methods Serum ACPA was determined for 7600 randomly selected CARTaGENE general population subjects in Quebec, Canada. Industrial SO2, NO2, and PM2.5 concentrations, estimated by the California Puff (CALPUFF) atmospheric dispersion model, were assigned based on residential postal codes at the time of sera collection. Single-exposure logistic regressions were performed for ACPA positivity defined by 20 U/ml, 40 U/ml, and 60 U/ml thresholds, adjusting for age, sex, French Canadian origin, smoking, and family income. Associations between regional overall PM2.5 exposure and ACPA positivity were also investigated. The associations between the combined three industrial exposures and the ACPA positivity were assessed by weighted quantile sum (WQS) regressions. Results Significant associations between individual industrial exposures and ACPA positivity defined by the 20 U/ml threshold were seen with single-exposure logistic regression models, for industrial emissions of PM2.5 (odds ratio, OR = 1.19, 95% confidence intervals, CI: 1.04–1.36) and SO2 (OR = 1.03, 95% CI: 1.00–1.06), without clear associations for NO2 (OR = 1.01, 95% CI: 0.86–1.17). Similar findings were seen for the 40 U/ml threshold, although at 60 U/ml, the results were very imprecise. The WQS model demonstrated a positive relationship between combined industrial exposures and ACPA positivity (OR = 1.36, 95% CI: 1.10–1.69 at 20 U/ml) and suggested that industrial PM2.5 may have a closer association with ACPA positivity than the other exposures. Again, similar findings were seen with the 40 U/ml threshold, though 60 U/ml results were imprecise. No clear association between ACPA and regional overall PM2.5 exposure was seen. Conclusions We noted positive associations between ACPA and industrial emissions of PM2.5 and SO2. Industrial PM2.5 exposure may play a particularly important role in this regard.
- ItemOpen AccessNitrated nucleosome levels and neuropsychiatric events in systemic lupus erythematosus; a multi-center retrospective case-control study(2017-12-22) Ferreira, Isabel; Croca, Sara; Raimondo, Maria G; Matharu, Manjit; Miller, Sarah; Giles, Ian; Isenberg, David; Ioannou, Yiannis; Hanly, John G; Urowitz, Murray B; Anderson, Nicole; Aranow, Cynthia; Askanase, Anca; Bae, Sang-Cheol; Bernatsky, Sasha; Bruce, Ian N; Buyon, Jill; Clarke, Ann E; Dooley, Mary A; Fortin, Paul; Ginzler, Ellen; Gladman, Dafna; Gordon, Caroline; Inanc, Murat; Jacobsen, Søren; Kalunian, Kenneth; Kamen, Diane; Khamashta, Munther; Lim, Sam; Manzi, Susan; Merrill, Joan; Nived, Ola; Peschken, Christine; Petri, Michelle; Ramsey-Goldman, Rosalind; Ruiz-Irastorza, Guillermo; Sanchez-Guerrero, Jorge; Steinson, Kristjan; Sturfelt, Gunnar K; van Vollenhoven, Ronald; Wallace, Daniel J; Zoma, Asad; Rahman, AnisurAbstract Background In patients with systemic lupus erythematosus (SLE) there is no serological test that will reliably distinguish neuropsychiatric (NP) events due to active SLE from those due to other causes. Previously we showed that serum levels of nitrated nucleosomes (NN) were elevated in a small number of patients with NPSLE. Here we measured serum NN in samples from a larger population of patients with SLE and NP events to see whether elevated serum NN could be a marker for NPSLE. Methods We obtained serum samples from patients in the Systemic Lupus International Collaborative Clinics (SLICC) inception cohort. This included 216 patients with NP events and two matched controls with SLE but no NP events for each of these patients. For the NP patients we tested samples taken before, during and after the NP event. Results Twenty-six patients had events attributed to SLE according to the most stringent SLICC attribution rule. In these patients there was no association between onset of event and elevated serum NN. In 190 patients in whom events were not attributed to SLE by the SLICC rules, median serum NN was elevated at the onset of event (P = 0.006). The predominant clinical features in this group of 190 patients were headache, mood disorders and anxiety. Conclusions Serum NN levels rise at the time of an NP event in a proportion of patients with SLE. Further studies are needed to determine the value of serum NN as a biomarker for NPSLE.
- ItemOpen AccessRheumatoid arthritis-relevant DNA methylation changes identified in ACPA-positive asymptomatic individuals using methylome capture sequencing(2019-07-31) Shao, Xiaojian; Hudson, Marie; Colmegna, Ines; Greenwood, Celia M T; Fritzler, Marvin J; Awadalla, Philip; Pastinen, Tomi; Bernatsky, SashaAbstract Objective To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk. Methods With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. An independent set of T cells from RA patients was used to “validate” the differentially methylated sites. Results We measured DNA methylation in 137 subjects, of whom 63 were ACPA-positive, 66 were ACPA-negative, and 8 had self-reported RA. We identified 1303 DMRs of relevance, of which one third (402) had underlying genetic effects. These DMRs were enriched in intergenic CpG islands (CGI) and CGI shore regions. Furthermore, the genes associated with these DMRs were enriched in pathways related to Epstein-Barr virus infection and immune response. In addition, 80 (38%) of 208 RA-specific DMRs were replicated in T cells from RA samples. Conclusions Sequencing-based high-resolution methylome mapping revealed biologically relevant DNA methylation changes in asymptomatic individuals positive for ACPA that overlap with those seen in RA. Pathway analyses suggested roles for viral infections, which may represent the effect of environmental triggers upstream of disease onset.