Gene–environment interactions increase the risk of pediatric-onset multiple sclerosis associated with ozone pollution

Background: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure. Objectives: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86, and HLA- DRB1*15, the strongest genetic variant associated with POMS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC’s Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86, and the presence of DRB1*15:01 ( DRB1*15) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother’s education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated. Results: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69–3.59 and 1.95, 95% CI: 1.32–2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15, with a RERI of 2.21 (95% CI: 0.83–3.59) and an AP of 0.56 (95% CI: 0.33–0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14–3.06) and an AP of 0.37 (95% CI: 0.001–0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype. Conclusions: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene–environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.

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A Scoping Review of Modifiable Risk Factors in Pediatric Onset Multiple Sclerosis: Building for the Future

Children ◽

10.3390/children5110146 ◽

2018 ◽

Vol 5 (11) ◽

pp. 146 ◽

Cited By ~ 2

Author(s):

Julie Pétrin ◽

Max Fiander ◽

Prenitha Doss ◽

E. Yeh

Keyword(s):

Physical Activity ◽

Multiple Sclerosis ◽

Vitamin D ◽

Relapse Rate ◽

Scoping Review ◽

Full Text ◽

Lifestyle Factors ◽

Increased Risk ◽

Modifiable Lifestyle Factors ◽

Pediatric Onset

Knowledge of the effect of modifiable lifestyle factors in the pediatric multiple sclerosis (MS) population is limited. We therefore conducted a scoping review, following the framework provided by Arksey and O’Malley. Four databases were searched for pediatric MS and modifiable lifestyle factors using index terms and keywords, from inception to May 2018. All quantitative and qualitative primary articles were included and limited to English and full text. Of the 7202 articles identified and screened, 25 full-text articles were relevant to our objective and were included. These articles focused on diet obesity, physical activity, and sleep. In cross-sectional analyses, these lifestyle factors were associated with increased risk of pediatric onset MS (POMS), and increased disease activity. Diet, particularly vitamin D and vegetable intake, was associated with reduced relapse rate. Obesity was linked to increased risk of POMS, and physical activity was associated with reduced relapse rate and sleep/rest fatigue. Thus, available studies of lifestyle related outcomes in pediatric MS suggest specific lifestyle related factors, including obesity, higher vitamin D levels, and higher physical activity may associate with lower disease burden in POMS. Studies reviewed are limited by their observational designs. Future studies with longitudinal and experimental designs may further clarify the role of modifiable lifestyle factors in this population.

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Distributions of Human Exposure to Ozone During Commuting Hours in Connecticut Using the Cellular Device Network

Journal of Agricultural Biological and Environmental Statistics ◽

10.1007/s13253-019-00378-y ◽

2019 ◽

Vol 25 (1) ◽

pp. 54-73

Author(s):

Owais Gilani ◽

Simon Urbanek ◽

Michael J. Kane

Keyword(s):

Urban Areas ◽

Spatial Models ◽

Epidemiologic Studies ◽

Air Pollutant ◽

Ozone Exposure ◽

Ozone Pollution ◽

Adverse Health Outcomes ◽

Mobility Data ◽

Pollutant Concentrations ◽

The Difference

Abstract Epidemiologic studies have established associations between various air pollutants and adverse health outcomes for adults and children. Due to high costs of monitoring air pollutant concentrations for subjects enrolled in a study, statisticians predict exposure concentrations from spatial models that are developed using concentrations monitored at a few sites. In the absence of detailed information on when and where subjects move during the study window, researchers typically assume that the subjects spend their entire day at home, school, or work. This assumption can potentially lead to large exposure assignment bias. In this study, we aim to determine the distribution of the exposure assignment bias for an air pollutant (ozone) when subjects are assumed to be static as compared to accounting for individual mobility. To achieve this goal, we use cell-phone mobility data on approximately 400,000 users in the state of Connecticut, USA during a week in July 2016, in conjunction with an ozone pollution model, and compare individual ozone exposure assuming static versus mobile scenarios. Our results show that exposure models not taking mobility into account often provide poor estimates of individuals commuting into and out of urban areas: the average 8-h maximum difference between these estimates can exceed 80 parts per billion (ppb). However, for most of the population, the difference in exposure assignment between the two models is small, thereby validating many current epidemiologic studies focusing on exposure to ozone. Supplementary materials accompanying this paper appear online.

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Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458513477231 ◽

2013 ◽

Vol 19 (10) ◽

pp. 1355-1358 ◽

Cited By ~ 8

Author(s):

Giulio Disanto ◽

Carolina Hall ◽

Robyn Lucas ◽

Anne-Louise Ponsonby ◽

Antonio J Berlanga-Taylor ◽

...

Keyword(s):

Multiple Sclerosis ◽

Infectious Mononucleosis ◽

Additive Model ◽

Causal Process ◽

Case Control Studies ◽

Logistic Regression Models ◽

Gene Environment ◽

Increased Risk ◽

History Of ◽

Additive Scale

Gene–environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). Individuals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92–10.90). In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79–2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59–2.59; excess risk due to interaction=3.30, 95%CI=0.47–6.12; attributable proportion due to interaction=45%, 95% CI=22–68%). This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene–environment interactions on both a multiplicative and additive scale.

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Early infectious exposures are not associated with increased risk of pediatric-onset multiple sclerosis

Multiple Sclerosis and Related Disorders ◽

10.1016/j.msard.2018.03.015 ◽

2018 ◽

Vol 22 ◽

pp. 103-107

Author(s):

Leena Suleiman ◽

Emmanuelle Waubant ◽

Gregory Aaen ◽

Anita Belman ◽

Leslie Benson ◽

...

Keyword(s):

Multiple Sclerosis ◽

Increased Risk ◽

Pediatric Onset

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A Possible Role of an Interaction of the Age at Common Childhood Infections and Selected Dietary Factors at Young Age, for the Risk of Multiple Sclerosis

10.20944/preprints201611.0114.v1 ◽

2016 ◽

Author(s):

Klaus Lauer ◽

Annette Wahl ◽

Marcel Geilenkeuser

Keyword(s):

Multiple Sclerosis ◽

Linear Regression Analysis ◽

Multiple Linear Regression Analysis ◽

Dietary Factors ◽

Young Age ◽

Processed Meat ◽

Additive Interaction ◽

Regression Estimate ◽

Childhood Infections ◽

Increased Risk

An increased risk of multiple sclerosis (MS) had been found when individuals had consumed large amounts of processed meat and sausages at young age (Lauer, 2014). Furthermore it was found in many studies that MS patients had acquired a number of common childhood infections at higher ages than controls. Therefore, MS patients from an epidemiological long-term investigation in Germany and different hospital controls, were evaluated for a statistical interaction of these two factors. 324 MS patients and 242 hospital controls were inquired. The study focussed on age 0 - 16. Subjects were tested for additive interaction by multiple linear regression analysis (Knol et al., 2007). There was an additive interaction of the age at any common childhood infection with the consumption of scalded sausages (regression estimate = 0.1370; standard error = 0.0603; p = 0.0239). In contrast, no such interaction could be shown for: animal fats; smoked meat (e.g. ham and bacon); and cold - smoked German salami. Thus there was a synergy of the intake of scalded sausages (e.g. frankfurters, bolognas, etc.) and age at common childhood infections, for the later risk of MS.

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Pro-inflammatory adiponectin in pediatric-onset multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458521989090 ◽

2021 ◽

pp. 135245852198909

Author(s):

Mukanthu H Nyirenda ◽

Giulia Fadda ◽

Luke M Healy ◽

Ina Mexhitaj ◽

Laurence Poliquin-Lasnier ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Disease Activity ◽

Human Peripheral Blood ◽

Enzyme Linked Immunosorbent Assay ◽

Functional Responses ◽

Human Microglia ◽

Increased Risk ◽

Normal Human Peripheral Blood ◽

Pediatric Onset

Background: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. Objectives: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. Methods: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. Results: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN and pediatric MS serum-induced APN-dependent pro-inflammatory activation of CD14+ monocytes and of activated CD4+ and CD8+ T cells (both directly and indirectly through myeloid cells). APN induced human microglia activation while inhibiting their expression of molecules associated with quiescence. Conclusions: Elevated APN levels in children with MS may contribute to enhanced pro-inflammatory states of innate and adaptive peripheral immune responses and breach CNS-resident microglia quiescence, providing a plausible and potentially targetable mechanism by which APN contributes to MS disease activity.

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