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      Is Geo-Environmental Exposure a Risk Factor for Multiple Sclerosis? A Population-Based Cross-Sectional Study in South-Western Sardinia

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          Abstract

          Background

          South-Western Sardinia (SWS) is a high risk area for Multiple Sclerosis (MS) with high prevalence and spatial clustering; its population is genetically representative of Sardinians and presents a peculiar environment. We evaluated the MS environmental risk of specific heavy metals (HM) and geographical factors such as solar UV exposure and urbanization by undertaking a population-based cross-sectional study in SWS.

          Methods

          Geochemical data on HM, UV exposure, urbanization and epidemiological MS data were available for all SWS municipalities. Principal Component Analysis (PCA) was applied to the geochemical data to reduce multicollinearity and confounding criticalities. Generalized Linear Mixed Models (GLMM) were applied to evaluate the causal effects of the potential risk factors, and a model selection was performed using Akaike Information Criterion.

          Results

          The PCA revealed that copper (Cu) does not cluster, while two component scores were extracted: 'basic rocks', including cobalt, chromium and nickel, and 'ore deposits', including lead and zinc. The selected multivariable GLMM highlighted Cu and sex as MS risk factors, adjusting for age and 'ore deposits'. When the Cu concentration increases by 50 ppm, the MS odds are 2.827 (95% CI: 1.645; 5.07) times higher; females have a MS odds 2.04 times (95% CI: 1.59; 2.60) higher than males.

          Conclusions

          The high frequency of MS in industrialized countries, where pollution by HM and CO poisoning is widespread, suggests a relationship between environmental exposure to metals and MS. Hence, we suggested a role of Cu homeostasis in MS. This is a preliminary study aimed at generating hypotheses that will need to be confirmed further.

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          Most cited references33

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          Temporal trends in the incidence of multiple sclerosis: a systematic review.

          A. Alonso, M Hernán (2008)
          Multiple sclerosis (MS) has been traditionally considered to be more frequent in women and in regions more distant from the equator. However, recent reports suggest that the latitude gradient could be disappearing and that the female-to-male ratio among patients with MS has increased in the last decades. We have conducted a systematic review of incidence studies of MS to assess the overall incidence of MS and explore possible changes in the latitude gradient and the female-to-male ratio over time. Systematic review of incidence studies of MS published in Medline between 1966 and February 2007. Age- and sex-specific incidence rates were collected from eligible publications. We computed age-adjusted rates using the world population as standard, and assessed differences in rates according to latitude and period of case ascertainment. Additionally, we evaluated the association between period of case ascertainment and the female-to-male ratio. The overall incidence rate of MS was 3.6 cases per 100,000 person-years (95% CI 3.0, 4.2) in women and 2.0 (95% CI 1.5, 2.4) in men. Higher latitude was associated with higher MS incidence, though this latitude gradient was attenuated after 1980, apparently due to increased incidence of MS in lower latitudes. The female-to-male ratio in MS incidence increased over time, from an estimated 1.4 in 1955 to 2.3 in 2000. The latitude gradient present in older incidence studies of multiple sclerosis (MS) is decreasing. The female-to-male MS ratio has increased in the last five decades.
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            Multiple sclerosis genetics.

            Stephen S Sawcer, Robin J M Franklin, Maria Ban (2014)
            Genome-wide association studies have revolutionised the genetic analysis of multiple sclerosis. Through international collaborative efforts involving tens of thousands of cases and controls, more than 100 associated common variants have now been identified. These variants consistently implicate genes associated with immunological processes, overwhelmingly lie in regulatory rather than coding regions, and are frequently associated with other autoimmune diseases. The functional implications of these associated variants are mostly unknown; however, early work has shown that several variants have effects on splicing that result in meaningful changes in the balance between different isoforms in relevant tissues. Including the well established risk attributable to variants in genes encoding human leucocyte antigens, only about a quarter of reported heritability can now be accounted for, suggesting that a substantial potential for further discovery remains. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system.

              P Morell, K Matsushima (2000)
              Myelin of the adult CNS is vulnerable to a variety of metabolic, toxic, and autoimmune insults. That remyelination can ensue, following demyelinating insult, has been well demonstrated. Details of the process of remyelination are, however difficult to ascertain since in most experimental models of demyelination/remyelination the severity, localization of lesion site, or time course of the pathophysiology is variable from animal to animal. In contrast, an experimental model in which massive demyelination can be reproducibly induced in large areas of mouse brain is exposure to the copper chelator, cuprizone, in the diet. We review work from several laboratories over the past 3 decades, with emphasis on our own recent studies, which suggest an overall picture of cellular events involved in demyelination/remyelination. When 8 week old C57BL/6 mice are fed 0.2% cuprizone in the diet, mature olidgodendroglia are specifically insulted (cannot fulfill the metabolic demand of support of vast amounts of myelin) and go through apoptosis. This is closely followed by recruitment of microglia and phagoctytosis of myelin. Studies of myelin gene expression, coordinated with morphological studies, indicate that even in the face of continued metabolic challenge, oligodendroglial progenitor cells proliferate and invade demyelinated areas. If the cuprizone challenge is terminated, an almost complete remyelination takes place in a matter of weeks. Communication between different cell types by soluble factors may be inferred. This material is presented in the context of a model compatible with present data -- and which can be tested more rigorously with the cuprizone model. The reproducibility of the model indicates that it may allow for testing of manipulations (e.g. available knockouts or transgenics on the common genetic background, or pharmacological treatments) which may accelerate or repress the process of demyelination and or remyelination.
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                Author and article information

                Contributors
                Sreeram V. Ramagopalan: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 26 September 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 9
                Electronic Location Identifier: e0163313
                Affiliations
                [1 ]Department of Public Health, Experimental and Forensic Medicine, Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia, Italy
                [2 ]Department of Public Health, Clinical and Medical Science, University of Cagliari, Cagliari, Italy
                [3 ]Department of Civil-Environmental Engineering and Architecture, University of Cagliari, Cagliari, Italy
                [4 ]Department of Medical Science, University of Cagliari, Cagliari, Italy
                University of Oxford, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: MCM DG CM PV MGM EC.

                • Data curation: LL AS SP CS.

                • Formal analysis: MCM DG CM PV.

                • Funding acquisition: MCM PV EC.

                • Investigation: LL CS SP AS.

                • Methodology: MCM DG CM CS PV EC MGM LL AS SP.

                • Project administration: MCM PV EC.

                • Resources: MCM PV EC.

                • Supervision: CM MGM.

                • Writing – original draft: MCM DG PV EC.

                • Writing – review & editing: CM CS MGM LL AS SP.

                ‡ These authors also contributed equally to this work.

                Author information
                http://orcid.org/0000-0003-1586-527X
                Article
                Publisher ID: PONE-D-16-21063
                DOI: 10.1371/journal.pone.0163313
                PMC ID: 5036813
                PubMed ID: 27669512
                SO-VID: 11c83f7b-8934-4180-8c67-c069b17f0f0a
                Copyright © © 2016 Monti et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 25 May 2016
                Date accepted : 7 September 2016
                Page count
                Figures: 2, Tables: 3, Pages: 13
                Funding
                Funded by: Fondazione Italiana Sclerosi Multipla (IT)
                Award ID: FISM 2012/R3
                Award Recipient :
                This work was supported by the Fondazione Italiana Sclerosi Multipla (Grant FISM 2012/R3).
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Clinical Immunology
                Subject: Autoimmune Diseases
                Subject: Multiple Sclerosis
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Clinical Immunology
                Subject: Autoimmune Diseases
                Subject: Multiple Sclerosis
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Clinical Immunology
                Subject: Autoimmune Diseases
                Subject: Multiple Sclerosis
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Demyelinating Disorders
                Subject: Multiple Sclerosis
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Neurodegenerative Diseases
                Subject: Multiple Sclerosis
                Subject: Research and Analysis Methods
                Subject: Mathematical and Statistical Techniques
                Subject: Statistical Methods
                Subject: Multivariate Analysis
                Subject: Principal Component Analysis
                Subject: Physical Sciences
                Subject: Mathematics
                Subject: Statistics (Mathematics)
                Subject: Statistical Methods
                Subject: Multivariate Analysis
                Subject: Principal Component Analysis
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Geochemistry
                Subject: Earth Sciences
                Subject: Geochemistry
                Subject: Biology and Life Sciences
                Subject: Evolutionary Biology
                Subject: Population Genetics
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Population Genetics
                Subject: Biology and Life Sciences
                Subject: Population Biology
                Subject: Population Genetics
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Elements
                Subject: Heavy Metals
                Subject: Biology and Life Sciences
                Subject: Toxicology
                Subject: Toxic Agents
                Subject: Toxins
                Subject: Heavy Metals
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Toxicology
                Subject: Toxic Agents
                Subject: Toxins
                Subject: Heavy Metals
                Subject: Research and Analysis Methods
                Subject: Research Design
                Subject: Cross-Sectional Studies
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Elements
                Subject: Zinc
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Elements
                Subject: Lead (Element)
                Custom metadata
                Data Availability Some relevant data are within the paper and its Supporting Supplementary files. Some data in this manuscript are from the cited Cocco et al. 2011 study, whose authors may be contacted at ecocco@ 123456unica.it . We cannot make the row data public for privacy issues. In particular, the ethics committee recommended to exclude detailed data from the paper due to issues with patient confidentiality.

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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