Pre-diagnostic markers of infection and risk of MS
This study investigates prediagnostic serological markers of infection and risk of MS. During the first period of this project, we found evidence that a significant increase in serum antibodies to the Epstein-Barr Virus (EBV) occurs years before the onset of the first symptoms of multiple sclerosis (MS). In contrast, serum titers of anti-Chlamydia pneumoniae (Cpn) were not significantly related to risk of MS. We are now expanding our findings on EBV, to extend the investigation to human herpes virus 6 (HHV-6) and the hepatitis A virus, and to examine whether the presence of IgM antibodies to myelin oligodendrocyte glycoprotein (MOG) or myelin basic protein (MBP) in asymptomatic individuals predicts the risk of MS. This investigation continues to take advantage of the Department of Defense Serum Repository, a unique facility now comprising multiple serum samples collected from over 7 million US military personnel. In the first project period, we have only included in the study cases and controls from the Army. To increase the power of the study, we have now extended the identification of MS cases and selection of controls to the Navy. By this mean, and by extending the follow up for case identification to the year 2007, we expect to increase the number of cases to 501 and to extend the interval between the date of collection of the first blood samples to the onset of the first MS symptoms to over 10 years. This large sample size and the availability for each subject of serum samples collected at multiple points in time will allow sufficient power to examine the relation between changes in the serological markers and risk of developing MS.
Prospective Study of Vitamin D and Multiple Sclerosis
The results of ecological studies and animal experiments suggest that high levels of vitamin D may prevent multiple sclerosis (MS), but there are no prospective epidemiological data addressing this hypothesis. As a part of this study, we are conducting a nested case-control study to determine prospectively the relation between vitamin D status and risk of developing MS. The primary aim of the investigation is to determine whether circulating levels of 25-Hydroxyvitamin D measured in healthy young adults predict the future risk of developing MS. The source population of the study includes over 3 million US Army and Navy personnel whose blood samples are stored in the Department of Defense (DOD) Serum Repository. The identification of cases of MS in this population is ongoing; by the end of January 2003 we confirmed 149 incident cases of MS in the Army with onset of first neurological symptoms after the date of blood collection and we expect to confirm 173 MS cases occurring between January 1, 2000 and December 31,2003 in the Navy. The estimated interval between blood collection and MS onset will be on average 4 years and repeated blood samples collected from the same person before MS onset will be available for over 80 percent of the cases. For each case, two controls matched by age, gender, ethnicity, and time of blood collection are selected from the source population. The proposed study is unique in relying on a large series of cases with blood collected several years before the onset of symptoms. Further, the availability of repeated samples for the same individuals permits a better assessment of long-term circulating vitamin D levels and adjustment for seasonal variations. The finding of an inverse association between 25-OH D in serum and risk of MS would provide strong support for a role of vitamin D in the prevention of MS. On the other hand, the lack of such association would suggest that other hypotheses need to be addressed to explain the strong latitude gradient in MS incidence.
Molecular Epidemiology of EBV and Multiple Sclerosis
As a part of this project, we are investigating 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.