We propose to investigate the role of the Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV- 6) in the etiology of multiple sclerosis (MS) among participants in two large prospective cohort studies: the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II). Our study population comprises over 230,000 women, including 62,547 who have provided blood samples for serological and genetic analyses and over 20,809 who have provided mouthwash samples. Over 400 incident cases of MS have been documented in this cohort and we project a total of 600 incident cases by the end of the follow-up. We have previously reported that healthy women with elevated serum liters of anti-EBV antibodies have a significantly increased risk of developing MS. These serological results, however, are insufficient to establish causality. We propose therefore to apply molecular methods to elucidate the biological mechanisms that may relate MS to the EBV. As part of the proposed investigation we will determine the EBV viral load in cases and controls, and examine the roles of genetic variations in the host (HLA-DR and DQ and other candidate gene polymorphisms) and the virus (variations in the EBNA-1, LMP-1, EBNA-2, and EBNA-3c genes). Futher, we will examine whether elevated plasma titers of anti-HHV-6 antibodies or detectable plasma levels of HHV-6 DNA predict the risk of MS. Strengths of the proposed investigation include sampling from two well-characterized cohorts that have already contributed several findings on the epidemiology of MS, a control group randomly chosen from the population that generated the cases, and the availability of blood samples collected before the onset of MS in a subset of cases. Most important is the interdisciplinary approach of the proposed project, which includes collaboration with experts in EBV virology, immunology, and MS genetics. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Study Section
Epidemiology of Clinical Disorders and Aging Study Section (ECDA)
Program Officer
Utz, Ursula
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Harvard University
Schools of Public Health
United States
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Hagan, Kaitlin A; Munger, Kassandra L; Ascherio, Alberto et al. (2016) Epidemiology of Major Neurodegenerative Diseases in Women: Contribution of the Nurses' Health Study. Am J Public Health 106:1650-5
Simon, Kelly Claire; Munger, K L; Kraft, P et al. (2011) Genetic predictors of 25-hydroxyvitamin D levels and risk of multiple sclerosis. J Neurol 258:1676-82
Mirzaei, Fariba; Michels, Karin B; Munger, Kassandra et al. (2011) Gestational vitamin D and the risk of multiple sclerosis in offspring. Ann Neurol 70:30-40
Munger, Kassandra L; Chitnis, Tanuja; Frazier, A Lindsay et al. (2011) Dietary intake of vitamin D during adolescence and risk of multiple sclerosis. J Neurol 258:479-85
Simon, K C; Yang, X; Munger, K L et al. (2011) EBNA1 and LMP1 variants in multiple sclerosis cases and controls. Acta Neurol Scand 124:53-8
Simon, K Claire; Munger, Kassandra L; Xing Yang et al. (2010) Polymorphisms in vitamin D metabolism related genes and risk of multiple sclerosis. Mult Scler 16:133-8
Simon, Kelly Claire; Gao, Xiang; Chen, Honglei et al. (2010) Calcium channel blocker use and risk of Parkinson's disease. Mov Disord 25:1818-22
Weisskopf, M G; Knekt, P; O'Reilly, E J et al. (2010) Persistent organochlorine pesticides in serum and risk of Parkinson disease. Neurology 74:1055-61
Gao, Xiang; Schwarzschild, Michael A; O'Reilly, Eilis J et al. (2010) Restless legs syndrome and Parkinson's disease in men. Mov Disord 25:2654-7
Ascherio, Alberto; Bar-Or, Amit (2010) EBV and brain matter(s)? Neurology 74:1092-5

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