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ABSTRACT: To determine whether serum levels of 25-hydroxyvitamin D (25(OH)D) in young adults are associated with risk of type 1 diabetes mellitus (T1D), we conducted a prospective, nested case-control study among US active-duty military personnel with serum in the US Department of Defense Serum Repository, identifying 310 T1D cases diagnosed between 1997 and 2009 with at least 2 serum samples collected before disease onset and 613 controls matched to cases on age, sex, race/ethnicity, branch of military service, and dates of serum collection. Conditional logistic regression was used to estimate rate ratios and 95% confidence intervals. Among non-Hispanic whites, those with average 25(OH)D levels of ≥100 nmol/L had a 44% lower risk of developing T1D than those with average 25(OH)D levels <75 nmol/L (rate ratio = 0.56, 95% confidence interval: 0.35, 0.90, P for trend = 0.03) over an average follow-up of 5.4 years. In quintile analyses, T1D risk was highest among individuals whose 25(OH)D levels were in the lowest 20% of those measured. There was no association between 25(OH)D levels and risk of T1D among non-Hispanic blacks or Hispanics. Low 25(OH)D levels may predispose healthy, young, non-Hispanic white adults to the development of T1D.
American journal of epidemiology 02/2013; · 5.59 Impact Factor
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ABSTRACT: Although strong genetic determinants of multiple sclerosis (MS) exist, the findings of migration studies support a role for environmental factors in this disease. Through rigorous epidemiological investigation, Epstein-Barr virus infection, vitamin D nutrition and cigarette smoking have been identified as likely causal factors in MS. In this Review, the strength of this evidence is discussed, as well as the potential biological mechanisms underlying the associations between MS and environmental, lifestyle and dietary factors. Both vitamin D nutrition and cigarette smoking are modifiable; as such, increasing vitamin D levels and smoking avoidance have the potential to substantially reduce MS risk and influence disease progression. Improving our understanding of the environmental factors involved in MS will lead to new and more-effective approaches to prevent this disease.
Nature Reviews Neurology 10/2012; · 12.46 Impact Factor
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ABSTRACT: This review provides a brief update of new research findings on the role of vitamin D in multiple sclerosis (MS).
Evidence continues to accumulate supporting a protective role for vitamin D in MS risk and progression. Notable recent findings are that high 25-hydroxyvitamin D [25(OH)D] at the time of a first demyelinating event predicts a lower MS risk and a decreased risk of MS among offspring whose mothers had high predicted 25(OH)D levels. While a small vitamin D intervention study did not find an association between vitamin D and MS progression, this study had little statistical power, and larger trials will be needed to assess the therapeutic potential of vitamin D. Recent immunological studies also show modulation of the immune system by vitamin D that may be favorable for preventing or slowing the progression of MS. The demonstration that rare variants in CYP27B1, which encodes the enzyme that converts vitamin D to its active form, are strongly associated with MS risk supports a causal role of vitamin D deficiency as a risk factor for MS.
Research on the nature of the association between vitamin D and MS risk and progression continues to progress; however, additional research on the timing and dose-response relationship will be crucial for designing future prevention and treatment trials.
Current opinion in neurology 06/2012; 25(3):246-51. · 5.43 Impact Factor
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ABSTRACT: Previous infection with Epstein-Barr virus (EBV) and infectious mononucleosis are established multiple sclerosis (MS) risk factors, and elevated serum titers of anti-EBV nuclear antigen (anti-EBNA) antibodies in healthy adults are strongly correlated with future MS risk. In this prospective study, we investigated the association between EBV neutralizing antibodies and MS risk. MS risk tended to be higher in individuals with high titers of neutralizing antibodies compared to those with low titers (relative risk [RR] = 2.2, 95% confidence interval [CI] 0.97-5.1). This association was attenuated after adjustment for anti-EBNA1 IgG Ab titers (RR = 1.4, 95% CI 0.5-3.5). This preliminary finding warrants further study in a larger population.
Multiple Sclerosis 01/2012; 18(8):1185-7. · 4.26 Impact Factor
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Kassandra L Munger
Multiple Sclerosis 12/2011; · 4.26 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a relatively common debilitating neurologic disease that affects people in early adulthood. While the characteristic pathology of MS has been well described, the etiology of the disease is not well understood, despite decades of research and the identification of strong genetic and environmental candidates for susceptibility. A question central to all diseases, but posed specifically for MS at the XVI European Charcot Foundation Lecture, was 'Can MS be prevented?' To address this question, we have evaluated the available data regarding nutritional and environmental factors that may be related to MS susceptibility and suggest the extent to which a potential intervention may reduce disease burden. It is our opinion that intervention, particularly supplementation with vitamin D, could have a dramatic impact on disease prevalence. Understanding that any intervention or behavioral modification will surely act in the context of genetic susceptibility and unidentified stochastic events, it is likely that not all MS is 'preventable'. Epidemiologic observation has provided key insights into environmental and nutritional factors that may alter one's susceptibility to MS, however, there are still many questions in unraveling the etiology of this complex disease.
Journal of the neurological sciences 12/2011; 311(1-2):1-8. · 2.32 Impact Factor
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ABSTRACT: Observational studies suggest that adequate vitamin D nutrition may reduce the risk of MS and affect the course of the disease. Inherent limitations in these studies, however, preclude a causal interpretation. Randomized controlled clinical trials are the next step to addressing whether vitamin D prevents MS or can favorably affect the course and progression of MS. Here we briefly review the current literature on vitamin D and MS, both as a risk factor and potential treatment for MS with a focus on the issues and challenges in designing prevention and treatment clinical trials.
Multiple Sclerosis 12/2011; 17(12):1405-11. · 4.26 Impact Factor
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Neurology 10/2011; 77(14):1405; author reply 1405-6. · 8.31 Impact Factor
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ABSTRACT: The prospective Nurses' Health Study II (NHS-II), which enrolled over 116,000 female nurses, provides a unique opportunity to test the hypothesis of whether migraine is associated with multiple sclerosis (MS) and to explore the temporal aspects of the interrelationship.
To calculate relative risk of MS among NHS-II participants with and without migraine and to estimate odds ratio (OR) of being diagnosed with migraine in women with and without pre-existing MS.
Cox proportional hazards regression was used to estimate rate ratios and 95% confidence intervals (CIs) of being diagnosed with MS in women with and without pre-existing migraine adjusted for potential confounders. Multivariate adjusted ORs of being diagnosed with migraine in women with and without pre-existing MS were estimated using logistic regression.
The prevalence of migraine in women with MS at baseline (26%, p = 0.11) and those diagnosed with MS after enrolment (29%, p < 0.0001) was higher than in the non-MS cases (21%). The relative risk of developing MS in migraineurs was 1.39 times higher than in non-migraineurs (95% CI 1.10-1.77, p = 0.008). The absolute risk of developing MS in women migraineurs over a 15-year follow-up was 0.47% and among non-migraineurs 0.32%. The odds of being diagnosed with migraine was higher in women with pre-existing MS compared with those without MS, but did not reach statistical significance (OR = 1.57, 95% CI 0.97-2.52; p = 0.06).
Using a large, cohort of women-nurses, history of migraine was associated with an increased risk of MS. However, the difference in absolute risk of MS in migraineurs and non-migraineurs was small.
Multiple Sclerosis 08/2011; 18(1):90-7. · 4.26 Impact Factor
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ABSTRACT: Adolescence may be an important etiological period in the development of multiple sclerosis (MS), and studies suggest that adequate vitamin D nutrition is protective. Here, the authors examined whether dietary intake of vitamin D during adolescence decreases the risk of MS in adulthood. In 1986 in the Nurses' Health Study and in 1998 in the Nurses' Health Study II (NHSII), women completed a food frequency questionnaire regarding their dietary intake during adolescence. From this, daily intake of vitamin D was calculated. Adolescent diet was available for 379 incident MS cases confirmed over the combined 44 years of follow-up in both cohorts, and for 67 prevalent cases in the NHSII who had MS at baseline (1989). Cox proportional hazards models were used to calculate relative risk estimates and 95% confidence intervals. Total vitamin D intake during adolescence was not associated with MS risk. Intake of ≥ 400 IU/day of vitamin D from multivitamins was associated with a non-statistically significant reduced risk (RR compared to no intake = 0.73, 95% CI: 0.50-1.07, P = 0.11), whereas intake of whole milk, an important source of dietary vitamin D, was associated with an increased risk. The possibility of opposite effects of vitamin D and milk intake on MS risk should be considered in future studies.
Journal of Neurology 10/2010; 258(3):479-85. · 3.47 Impact Factor
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ABSTRACT: To determine whether multiple sclerosis (MS) risk increases following primary infection with the Epstein-Barr virus (EBV), we conducted a nested case-control study including 305 individuals who developed MS and 610 matched controls selected among the >8 million active-duty military personnel whose serum has been stored in the Department of Defense Serum Repository. Time of EBV infection was determined by measuring antibody titers in serial serum samples collected before MS onset among cases, and on matched dates among controls. Ten (3.3%) cases and 32 (5.2%) controls were initially EBV negative. All of the 10 EBV-negative cases became EBV positive before MS onset; in contrast, only 35.7% (n = 10) of the 28 controls with follow-up samples seroconverted (exact p value = 0.0008). We conclude that MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection.
Annals of Neurology 06/2010; 67(6):824-30. · 11.09 Impact Factor
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ABSTRACT: The hypothesis that adequate vitamin D nutrition can contribute to the prevention of multiple sclerosis (MS) was originally proposed to explain the geographical distribution of MS, but only recently has the relation between various measures of vitamin D (eg, sun exposure, dietary sources, and serum concentrations of 25-hydroxyvitamin D) and risk of developing MS been rigorously investigated. Overall, the results of these studies support a protective effect of vitamin D, but there are uncertainties and many unanswered questions, including how vitamin D exerts a protective effect, how genetic variations modify the effect, and whether vitamin D can influence the course of MS progression.
The Lancet Neurology 06/2010; 9(6):599-612. · 23.46 Impact Factor
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ABSTRACT: Epstein-Barr virus (EBV) infection results in a life-long persistence of the virus in the host's B-lymphocytes and has been associated with numerous cancers including Burkitt's lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. There is considerable evidence that EBV infection is a strong risk factor for the development of multiple sclerosis. Early age at primary EBV infection is typically asymptomatic, but primary infection during adolescence or adulthood often manifests as infectious mononucleosis, which has been associated with a two- to threefold increased risk of MS. Most importantly, MS risk is extremely low in individuals who are EBV negative, but it increases several folds following EBV infection. Additional evidence supporting a role for EBV in MS pathogenesis includes the observations of elevated antibodies to EBV antigens (especially EBV nuclear antigen-1) prior to the onset of MS, and an increased risk of MS among EBV-positive children. The biological mechanism by which EBV may cause MS is not known, but several possibilities are discussed.
Journal of Neuroimmune Pharmacology 04/2010; 5(3):271-7. · 4.57 Impact Factor
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ABSTRACT: The extent to which potential genetic determinants of vitamin D levels may be related to multiple sclerosis (MS) risk has not been thoroughly explored. The objective of this study was to determine whether polymorphisms in VDR, CYP27B1, CYP24A1, CYP2R1 and DBP are associated with the risk of MS and whether these variants may modify associations between environmental or dietary vitamin D on MS risk. A nested case-control study was conducted in two, large cohorts of US nurses, including 214 MS cases and 428 age-matched controls. Conditional logistic regression models were used to calculate relative risks (RR) and 95% confidence intervals (CIs) and to assess the significance of gene-environment interactions. No associations were observed for any of the single-nucleotide polymorphisms (SNPs) in VDR, CYP27B1, CYP24A1, CYP2R1 or DBP (p > 0.05 for all). The authors did observe an interaction (p = 0.04) between dietary intake of vitamin D and the vitamin D receptor FokI polymorphism on MS risk. The protective effect of increasing vitamin D was evident only in individuals with the 'ff ' genotype (RR = 0.2, 95% CI: 0.06, 0.78; p = 0.02 for 400 IU/day increase). It was concluded that this does not support a role for the selected SNPs involved in vitamin D metabolism in the etiology of MS. The finding of a marginally significant gene-environment interaction requires replication in larger datasets, but suggests future genetic studies may benefit from considering relevant environmental context.
Multiple Sclerosis 12/2009; 16(2):133-8. · 4.26 Impact Factor
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ABSTRACT: To examine whether obesity during childhood, adolescence, or adulthood is associated with an increased risk of multiple sclerosis (MS).
Women in the Nurses' Health Study (n = 121,700) and Nurses' Health Study II (n = 116,671) provided information on weight at age 18 and weight and height at baseline, from which body mass index was derived. Women also selected silhouettes representing their body size at ages 5, 10, and 20. Over the total 40 years of follow-up in both cohorts combined, we confirmed 593 cases of MS. Cox proportional hazards models, adjusting for age, latitude of residence, ethnicity, and cigarette smoking, were used to estimate the rate ratios and 95% confidence intervals (CI).
Obesity at age 18 (body mass index > or =30 kg/m(2)) was associated with a greater than twofold increased risk of MS (multivariate relative risk(pooled) = 2.25, 95% CI: 1.50-3.37, p trend <0.001). After adjusting for body size at age 20, having a large body size at ages 5 or 10 was not associated with risk of MS, whereas a large body size at age 20 was associated with a 96% increased risk of MS (95% CI: 1.33-2.89, p trend = 0.009). No significant association was found between adult body mass and MS risk.
Obese adolescents have an increased risk of developing multiple sclerosis (MS). Although the mechanisms of this association remain uncertain, this result suggests that prevention of adolescent obesity may contribute to reduced MS risk.
Neurology 11/2009; 73(19):1543-50. · 8.31 Impact Factor
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ABSTRACT: Several dietary factors have been associated with risk of amyotrophic lateral sclerosis (ALS) in case-control studies, but no prospective studies have investigated diet and ALS.
We prospectively assessed the association of selected foods and beverages with ALS mortality among participants of the Cancer Prevention Study II, a cohort of over 1 million men and women enrolled in 1982. Habitual diet was assessed with a 44-item food frequency questionnaire. Participant follow-up was conducted from 1989 through 2002 for ALS mortality.
During the follow-up period, 862 cohort participants died of ALS. The strongest finding was an inverse association between chicken consumption and risk of ALS (P for trend = 0.0006). We also observed an increased risk of ALS among study participants with a high consumption of brown rice/whole wheat/barley (P for trend = 0.006) and decaffeinated coffee (P for trend = 0.01), and a decreased risk of ALS for high consumption of tea (P for trend = 0.02) and French fries (P for trend = 0.02); however, none of these latter associations remained significant after adjusting for multiple comparisons.
Overall, these results do not provide convincing evidence that the investigated food items are related to ALS mortality. The association observed between chicken consumption and ALS mortality should be assessed in other studies.
Epidemiology 04/2008; 19(2):324-37. · 5.57 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a T-cell-mediated demyelinating disease of the CNS with no known cure or cause. However, it is widely believed that MS is caused by an environmental trigger(s) in genetically susceptible individuals. Several lines of evidence suggest that infection with Epstein-Barr virus and cigarette smoking increase the risk of MS, whereas vitamin D plays a protective role. This review discusses the current evidence supporting a link between these factors and MS.
Expert Review of Clinical Immunology 09/2007; 3(5):739-48. · 2.07 Impact Factor
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ABSTRACT: As discussed in Part I of this review, the geographic distribution of multiple sclerosis (MS) and the change in risk among migrants provide compelling evidence for the existence of strong environmental determinants of MS, where "environmental" is broadly defined to include differences in diet and other behaviors. As we did for infections, we focus here primarily on those factors that may contribute to explain the geographic variations in MS prevalence and the change in risk among migrants. Among these, sunlight exposure emerges as being the most likely candidate. Because the effects of sun exposure may be mediated by vitamin D, we also examine the evidence linking vitamin D intake or status to MS risk. Furthermore, we review the evidence on cigarette smoking, which cannot explain the geographic variations in MS risk, but may contribute to the recently reported increases in the female/male ratio in MS incidence. Other proposed risk factors for MS are mentioned only briefly; although we recognize that some of these might be genuine, evidence is usually sparse and unpersuasive.
Annals of Neurology 07/2007; 61(6):504-13. · 11.09 Impact Factor
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ABSTRACT: Although genetic susceptibility explains the clustering of multiple sclerosis (MS) cases within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographic variations in MS frequency and the changes in risk that occur with migration. Epidemiological data provide some support for the "hygiene hypothesis," but with the additional proviso for a key role of Epstein-Barr virus (EBV) in determining MS risk. We show that whereas EBV stands out as the only infectious agent that can explain many of the key features of MS epidemiology, by itself the link between EBV and MS cannot explain the decline in risk among migrants from high to low MS prevalence areas. This decline implies that either EBV strains in low-risk areas have less propensity to cause MS, or that other infectious or noninfectious factors modify the host response to EBV or otherwise contribute to determine MS risk. The role of infectious factors is discussed here; in a companion article, we will examine the possible role of noninfectious factors and provide evidence that high levels of vitamin D may have a protective role, particularly during adolescence. The primary purpose of these reviews is to identify clues to the causes of MS and to evaluate the possibility of primary prevention.
Annals of Neurology 05/2007; 61(4):288-99. · 11.09 Impact Factor
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ABSTRACT: Although genetic susceptibility explains the clustering of multiple sclerosis (MS) cases within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographic variations in MS frequency and the changes in risk that occur with migration. Epidemiological data provide some support for the “hygiene hypothesis,” but with the additional proviso for a key role of Epstein–Barr virus (EBV) in determining MS risk. We show that whereas EBV stands out as the only infectious agent that can explain many of the key features of MS epidemiology, by itself the link between EBV and MS cannot explain the decline in risk among migrants from high to low MS prevalence areas. This decline implies that either EBV strains in low-risk areas have less propensity to cause MS, or that other infectious or noninfectious factors modify the host response to EBV or otherwise contribute to determine MS risk. The role of infectious factors is discussed here; in a companion article, we will examine the possible role of noninfectious factors and provide evidence that high levels of vitamin D may have a protective role, particularly during adolescence. The primary purpose of these reviews is to identify clues to the causes of MS and to evaluate the possibility of primary prevention. Ann Neurol 2007;61:288–299
Annals of Neurology 03/2007; 61(4):288 - 299. · 11.09 Impact Factor
