Exposure to particulate matter air pollution and risk of multiple sclerosis in two large cohorts of US nurses.

BACKGROUND: Air pollution is thought to raise the risk of neurological disease by promoting neuroinflammation, oxidative stress, glial activation and cerebrovascular damage. Multiple Sclerosis is a common auto-immune disorder, primarily affecting young women. We conducted, to a large prospective study of particulate matter (PM) exposure and multiple sclerosis (MS) risk in two prospective cohorts of women: the Nurses Health Study (NHS) and the Nurses Health Study II (NHS II). METHODS: Cumulative average exposure to different size fractions of PM up to the onset of MS was estimated using spatio-temporal models. We used multivariable Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of MS associated with each size fraction of PM independently. Participants were followed from 1998 through 2004 in NHS and from 1988 through 2007 for NHS II. We conducted additional sensitivity analyses stratified by smoking, region of the US, and age, as well as analyses restricted to women who did not move during the study. Analyses were adjusted for age, ancestry, smoking, body mass index at age 18, region, tract level population density, latitude at age 15, and UV index. RESULTS: We did not observe significant associations between air pollution and MS risk in our cohorts. Among women in the NHS II, the HRs comparing the top vs. bottom quintiles of PM was 1.11 (95% Confidence Intervals (CI): 0.74, 1.66), 1.04 (95% CI: 0.73, 1.50) and 1.09 (95% CI: 0.73, 1.62) for PM10 (≤10µm in diameter), PM2.5 (≤2.5µm in diameter), and PM2.5-10 (2.5 to 10µm in diameter) respectively, and tests for linear trends were not statistically significant. No association between exposure to PM and risk of MS was observed in the NHS. CONCLUSIONS: In this study, exposure to PM air pollution was not related to MS risk.

Caffeine and alcohol intakes have no association with risk of multiple sclerosis.

BACKGROUND: The association between alcohol and caffeine intakes and risk of multiple sclerosis (MS) is unclear; no prospective studies have examined this relationship. OBJECTIVE: We examined intakes of alcohol and caffeine in relation to risk of multiple sclerosis. METHODS: Intakes of alcohol and caffeine were examined in relation to the risk of MS in two large cohorts of women, the Nurses' Health Study (NHS; 92,275 women followed from 1980 to 2004) and Nurses' Health Study II (NHS II; 95,051 women followed from 1991 to 2005). Their diet was assessed at baseline and every four years thereafter. During the follow-up, 282 cases of MS were confirmed with onset of symptoms after baseline. Twenty-four cases were missing information on alcohol intake, leaving a total of 258 cases for the alcohol analyses. RESULTS: Neither total alcohol consumption, nor consumption of beer, wine, or liquor was related to MS risk. The multivariable-adjusted pooled relative risk (RR) found by comparing categories of alcohol intake to 0 gm/day was 1.07 (95% CI: 0.32-1.99) for 0.1-4.9 gm/day, 1.01 (0.32-1.99) for 5.0-14.9 gm/day, 1.21 (0.69-2.15) for 15.0-29.9 gm/day, and 0.80 (0.32-1.99) for 30+ gm/day; (p for trend=0.89). Caffeine intake was also not significantly associated with MS risk. The multivariable adjusted pooled RR comparing highest to lowest quintile of caffeine intake was 1.14; 95% CI: 0.79-1.66; p for trend=0.71. Consideration of caffeinated and decaffeinated coffee separately also yielded null results. CONCLUSION: These results do not support an association between alcohol and caffeine intakes and MS risk.

Association of multiple sclerosis with restless legs syndrome and other sleep disorders in women.

OBJECTIVE: To assess the association of multiple sclerosis (MS) with concurrent restless legs syndrome (RLS) and daytime sleepiness. We also prospectively examined whether women with MS had an increased risk of developing RLS during 4 years of follow-up. METHODS: The main analysis was based on a cross-sectional study of 65,544 women (aged 41-58 years) free of diabetes, arthritis, and pregnancy, who were participating in the Nurses' Health Study II cohort. Participants were considered to have RLS if they met 4 RLS diagnostic criteria recommended by the International Restless Leg Syndrome Study Group and had restless legs ≥ 5 times/month. MS was self-reported and confirmed by medical record review. RESULTS: Among women with MS, the prevalence of RLS and severe RLS (15+ times/month) were 15.5% and 9.9% in 2005, respectively, relative to 6.4% and 2.6% among women without MS. After adjustment for potential confounders and the presence of other sleep disorders, women with MS had a higher likelihood of having RLS (odds ratio [OR] = 2.72, 95% confidence interval [CI] 1.89-3.93), severe RLS (OR = 4.12, 95% CI 2.65-6.42), and daily daytime sleepiness (OR = 2.11, 95% CI 1.31-3.42) compared with women without MS. Among the 172 women who had MS and were free of RLS in 2005, 9 developed RLS (5.2%) during a 4-year period and all had severe RLS. The adjusted relative risk of severe RLS was 3.58 (95% CI 1.53-8.35), comparing women with MS at baseline with those without MS. CONCLUSION: Women with MS had a significantly higher prevalence of RLS and daytime sleepiness and an increased risk of developing RLS in the future.

Stress and the risk of multiple sclerosis.

OBJECTIVE: Several studies have shown that stressful life events are associated with a subsequent significant increase in risk of multiple sclerosis (MS) exacerbations. We wanted to study prospectively whether stress can increase the risk of developing the disease itself. METHODS: We studied 2 cohorts of female nurses: the Nurses' Health Study (NHS) (n = 121,700) followed from 1976 and the Nurses' Health Study II (NHS II) (n = 116,671) followed from 1989. The risk of MS after self-report on general stress at home and at work in the NHS in 1982 was studied prospectively using Cox regression. Logistic regression was used to retrospectively estimate the effects of physical and sexual abuse in childhood and adolescence collected in the NHS II 2001. We identified 77 cases of MS in the NHS by 2005 and 292 in the NHS II by 2004. All analyses were adjusted for age, ethnicity, latitude of birth, body mass index at age 18, and smoking. RESULTS: We found no increased risk of MS associated with severe stress at home in the NHS (hazard ratio 0.85 [95% confidence interval (CI)] 0.32-2.26). No significantly increased risk of MS was found among those who reported severe physical abuse during childhood (odds ratio [OR] 0.68, 95% CI 0.41-1.14) or adolescence (OR 0.77, 95% CI 0.46-1.28) or those having been repeatedly forced into sexual activity in childhood (OR 1.47, 95% CI 0.87-2.48) or adolescence (OR 1.21, 95% CI 0.68-2.17). CONCLUSIONS: These results do not support a major role of stress in the development of the disease, but repeated and more focused measures of stress are needed to firmly exclude stress as a potential risk factor for MS.

Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel.

BACKGROUND: Elevated Epstein-Barr virus (EBV) antibody titers are risk factors for multiple sclerosis (MS), but the strength and consistency of this association are not well characterized. OBJECTIVES: The objectives of this study were to determine whether this association is confounded by vitamin D or modified by gender or race, and the usefulness of EBV nuclear antigen (EBNA) antibodies as a marker for MS. METHODS: We conducted a prospective study among US military personnel. Antibody titers against EBV antigens were measured in serum samples from 222 individuals who developed MS and 444 age, sex, and race/ethnicity matched controls. Conditional logistic regression was used to estimate relative risks. RESULTS: MS risk increased with increasing titers of anti-EBNA complex (p < 10(-9)) and anti-EBNA-1 (p = 5.8 × 10(-9)) titers. MS risk was 36-fold higher among individuals with anti-EBNA complex IgG titers ≥320 than among those with titers <20 (95% confidence interval [CI] 9.6-136), and 8-fold higher among those with anti-EBNA-1 ≥320 than among those with anti-EBNA-1 <20 (95% CI 2.6-23). These associations were consistent across gender and race/ethnicity groups and independent from 25-hydroxyvitamin D levels. Areas under the receiver operating characteristic (ROC) curves were 0.67 for EBNA complex and 0.65 for EBNA-1. CONCLUSIONS: Serum titers of pre-onset anti-EBNA antibodies are strong, robust markers of MS risk and could be useful in an MS risk score.

Genetic predictors of 25-hydroxyvitamin D levels and risk of multiple sclerosis.

Risk of multiple sclerosis (MS) decreases with increasing plasma levels of 25-hydroxyvitamin D [25(OH)D]. If this association reflected a protective effect of vitamin D, MS risk should be lower among individuals carrying genetic variants that predict high 25(OH)D levels. The aim of the study was to determine whether individuals with genotypes predicting higher 25(OH)D levels have decreased MS risk. Logistic regression was used to assess the association between single nucleotide polymorphisms (SNPs) associated with 25(OH)D levels and MS risk in 1,655 cases and 6,349 controls. Analyses were further stratified by HLA-DR15 status, assessed by genotyping a single SNP strongly correlated with the HLA DRB1 1501 risk haplotype, and complemented by considering a SNP near CYP27B1. SNPs in GC were predictors of 25(OH)D levels, but not MS risk, in either HLA-DR15 negative or HLA-DR15 positive individuals. In contrast, there was a suggestion of a difference in the effect of a CYP2R1 allele dependent on HLA-DR15 genotype. The 'A' allele of CYP2R1 rs10741657 was associated with increased 25(OH)D levels and a non-significant reduced MS risk among HLA-DR15 negative (OR = 0.89, 95% CI: 0.79, 1.01) that was not apparent in HLA-DR15 positive individuals. The 'C' allele of CYP27B1 rs703842 was inversely associated with MS risk; this association appeared stronger among HLA-DR15 negative (OR = 0.79, 95% CI: 0.69, 0.90) compared to HLA-DR15 positive individuals (OR = 0.91, 95% CI: 0.80, 1.04). This preliminary finding suggests the possibility that the putative beneficial effect of vitamin D on MS risk maybe attenuated in individuals carrying the HLA-DR15 MS risk allele.

EBNA1 and LMP1 variants in multiple sclerosis cases and controls.

BACKGROUND: Prior infection with Epstein-Barr virus (EBV) is an established risk factor for multiple sclerosis (MS). Some findings from observational studies, including possible epidemics and differences in prevalence, may be explained if different strains of EBV conferred different MS risk. METHODS: DNA was extracted from peripheral lymphocytes obtained from 66 MS cases and 66 age- and cohort-matched controls. Nested polymerase chain reaction (PCR) was performed to amplify the N- and C-terminus regions of EBNA1 and the hyper-variable region of the LMP1 gene. For EBNA1, we compared the presence of the prototype B95.8 vs variant sequence and the presence of multiple strains in MS cases and controls. For LMP1, we considered differences in the proportions of mutations between cases and controls. RESULTS: Comparing the proportion of mutant sequence between MS cases and controls in the EBNA1 N-terminal (0/28 vs 1/27) and C-terminal regions (3/40 vs 8/36) revealed no significant differences (P > 0.05). No individual variants in LMP1 were associated with risk of MS (all P > 0.05). Neither EBNA1 nor LMP1 variation was associated with anti-EBNA1 IgG antibody titers. CONCLUSIONS: These findings do not support a strong role for variation in EBNA1 N-terminus, EBNA1 C-terminus or LMP1 contributing to MS risk.

99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Epstein-Barr virus and multiple sclerosis: epidemiological evidence.

While the causes of multiple sclerosis (MS) are unknown, there is strong evidence that infection with Epstein-Barr virus (EBV) is an important factor. In this review, we discuss the epidemiological evidence and argue for a causal role of EBV in MS aetiology. One of the most striking and consistent observations is that MS is extremely rare among EBV-negative individuals. Further, the timing of EBV infection appears to be critical, with individuals who are infected during adolescence and young adulthood, when the infection is more likely to manifest as mononucleosis, having a two- to threefold greater risk of MS compared to individuals infected in early life. These observations challenge the hygiene hypothesis which states that being in a high hygiene environment in early life increases future risk of MS - if this general formulation were true, EBV-negative individuals would be expected to have an increased risk of MS. Additional support for the causal role of EBV comes from longitudinal, prospective studies which show remarkable consistency, in that antibodies against EBV are elevated prior to MS onset. However, while infection with EBV is consistent with many observations of MS epidemiology, there are some that remain unexplained, suggesting that other factors are also involved in determining risk.

Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk.

OBJECTIVE: To examine the interplay between smoking, serum antibody titers to the Epstein-Barr virus nuclear antigens (anti-EBNA), and HLA-DR15 on multiple sclerosis (MS) risk. METHODS: Individual and pooled analyses were conducted among 442 cases and 865 controls from 3 MS case-control studies-a nested case-control study in the Nurses' Health Study/Nurses' Health Study II, the Tasmanian MS Study, and a Swedish MS Study. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for the association between smoking, anti-EBNA titers, HLA-DR15, and MS risk. Study estimates were pooled using inverse variance weights to determine a combined effect and p value. RESULTS: Among MS cases, anti-EBNA titers were significantly higher in ever smokers compared to never smokers. The increased risk of MS associated with high anti-EBNA Ab titers was stronger among ever smokers (OR = 3.9, 95% CI = 2.7-5.7) compared to never smokers (OR = 1.8, 95% CI = 1.4-2.3; p for interaction = 0.001). The increased risk of MS associated with a history of smoking was no longer evident after adjustment for anti-EBNA Ab titers. No modification or confounding by HLA-DR15 was observed. The increased risk of MS associated with ever smoking was only observed among those who had high anti-EBNA titers (OR = 1.7, 95% CI = 1.1-2.6). CONCLUSIONS: Smoking appears to enhance the association between high anti-EBNA titer and increased multiple sclerosis (MS) risk. The association between HLA-DR15 and MS risk is independent of smoking. Further work is necessary to elucidate possible biologic mechanisms to explain this finding.

Serum uric acid and risk of multiple sclerosis.

Because of evidence implicating oxidative stress in multiple sclerosis pathogenesis, it has been postulated that high levels of urate, a potent antioxidant, could reduce risk or favorably influence disease progression. We conducted a prospective study to determine whether serum urate levels contribute to prediction of multiple sclerosis risk. Analyses included 31 cases with blood collected a median of 1.9 years before multiple sclerosis onset from the Nurses' Health Study and Nurses' Health Study II cohorts, and 42 cases with collection a median of 14.5 years before onset from the Kaiser Permanente Northern California health plan cohort. Relative risks were estimated by unconditional logistic regression, including 26 controls in the Nurses' cohorts and 130 controls in the Kaiser cohort. In analyses including only cases in the Nurses' cohorts where blood was collected shortly before onset, there was a trend toward a lower risk of multiple sclerosis among individuals with higher serum urate, but the association was not significant (multivariable relative risk 0.52, 95% CI 0.22, 1.20, p value 0.13). In contrast, there was no evidence of a decline in risk with increasing serum urate in the Kaiser cohort where there was a longer period of time between blood collection and onset (multivariable relative risk 1.36, 95% CI 0.87, 2.14, p value 0.18). The results of this study suggest that serum urate is not a strong predictor of MS risk. This lack of association is consistent with the interpretation that the lower urate levels among multiple sclerosis cases are a consequence rather than a cause of the disease.

The relationship between handedness and risk of multiple sclerosis.

BACKGROUND: Left-handedness has been studied as a marker for in-utero exposure to sex steroid hormones, and an increased risk of autoimmune and immune disorders among left-handed individuals has been suggested. OBJECTIVE: This study examines the relationship between hand preference and risk of multiple sclerosis, a presumed autoimmune disorder of unknown etiology. METHODS: The study population comprised participants in the Nurses' Health Study, an ongoing prospective cohort study of 121,701 female nurses in the United States with followup from 1976 to 2002. The nurses were asked to report their natural hand preference (right, left, ambidextrous, forced to change). RESULTS: During followup 210 incident cases with multiple sclerosis were confirmed. A 62% increased risk of multiple sclerosis was observed among women who were naturally left handed as compared to those who were naturally right handed (95% CI: 1.04-2.53). CONCLUSIONS: This study suggests a modest increase in risk of multiple sclerosis among left-handed women. Further investigation of this relationship is suggested in other populations including both males and females. While the current results suggest that prenatal exposure to sex hormones may play a role in multiple sclerosis risk, direct examination of the relationship between in-utero hormone exposure and hand preference is necessary before any conclusions can be drawn.

Serum titers of IgG antibodies against tetanus and diphtheria toxoids and risk of multiple sclerosis.

We conducted a prospective nested case-control study among military service members to investigate whether antibodies against tetanus or diphtheria predict multiple sclerosis (MS) risk. Paired T-tests were used to compare means of anti-tetanus and diphtheria toxoids among 56 MS cases and 112 matched controls. Conditional logistic regression was used to estimate odds ratios (OR). There were no differences between the mean serum IgG antibodies against tetanus (p-value 0.28) or diphtheria (p-value 0.45) in the baseline samples. The OR of MS associated with 1 standard deviation difference in antibody titers was 0.76 (95% CI: 0.48-1.21) for tetanus (SD=4.71) and 1.03 (0.73-1.45) for diphtheria (SD=0.87). Results of this study suggest serum IgG antibodies against tetanus or diphtheria are not predictors of MS risk.

Human endogenous retrovirus-K18 Env as a risk factor in multiple sclerosis.

BackgroundThe human endogenous retrovirus (HERV)-K18 Env is an Epstein-Barr virus (EBV)-associated superantigen. Given the evidence for a role of EBV in the etiology of multiple sclerosis (MS), HERV-K18 Env is a plausible candidate for association with MS.ObjectiveTo assess whether variation in HERV-K18 Env is a risk factor for MS.MethodsWe developed a single nucleotide polymorphism-based genotyping method to determine the distribution of the three alleles of HERV-K18 env. We then conducted a nested case-control study including 207 MS cases and 403 matched controls. Analyses were replicated in an independent series of 909 MS cases and 339 controls.ResultsOverall, there was a significant association between HERV-K18 env genotype and MS risk (chi2 P = 0.03). As compared with K18.2/K18.2 individuals, risk of MS was three fold higher among K18.3/K18.3 individuals (P = 0.03). An increase in MS risk among carriers of the K18.3 allele was also observed in the replication study, but did not reach statistical significance. In pooled analyses, K18.3/K18.3 individuals had a significantly increased risk of MS (relative risks [RR] comparing K18.3/K18.3 vs K18.2/K18.2 = 2.7; 95% confidence interval: 1.1-6.4).ConclusionVariation in EBV-associated superantigen HERV-K18 Env could influence the genetic susceptibility to MS.

Myelin oligodendrocyte glycoprotein antibodies and multiple sclerosis in healthy young adults.

BACKGROUND: It remains uncertain whether the presence of serum anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in healthy individuals contributes to predict their risk of developing multiple sclerosis (MS). METHODS: Prospective, nested case-control study of more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. A total of 126 MS cases and 252 controls matched by age, sex, race/ethnicity, and dates of blood collection were included in the analysis. An ELISA was used to detect IgM and IgG antibodies to MOG. Analyses were conducted with and without adjustment for serum titers of antibodies to the Epstein-Barr nuclear antigen (EBNA), which are an established risk factor for MS. RESULTS: The presence of anti-MOG IgG antibodies in serum was associated with an increase in risk of developing MS (relative risk for anti-MOG IgG+/IgM- vs seronegativity to both anti-MOG IgM and IgG: 2.03; 95% CI: 1.19-3.46; p = 0.01). This association, however, was attenuated and no longer significant after adjustment for titers of antibodies to EBNA, which were higher among individuals positive for anti-MOG antibodies. CONCLUSION: Our findings suggest that although individuals with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies have an increased risk of developing multiple sclerosis, this association may at least in part reflect cross-reactivity between MOG and Epstein-Barr nuclear antigen.

Integrating risk factors: HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis.

BACKGROUND: Individuals with high levels of antibodies to the Epstein-Barr virus nuclear antigen 1 (EBNA-1) have an increased risk of developing multiple sclerosis (MS), but this association could be confounded by genetic susceptibility. METHODS: We conducted a nested case-control study including 148 women with MS (18 with blood collected before disease onset) and 296 age-matched healthy women to determine whether the human leukocyte antigen (HLA) DRB1*1501 allele (DR15) and anti-Epstein-Barr virus (anti-EBV) antibody titers are independent risk factors for MS. RESULTS: The association between anti-EBNA-1 antibody titers and MS risk was not affected by adjustment for DR15 and was similar in DR15-positive and DR15-negative women. The relative risk of MS among DR15-positive women with elevated (>1:320) anti-EBNA-1 titers was ninefold higher than that of DR15-negative women with low (<1:80) anti-EBNA-1 titers. CONCLUSIONS: Anti-Epstein-Barr virus nuclear antigen 1 (anti-EBNA-1) antibody titers are a risk factor for multiple sclerosis (MS), independently from the DR15 allele. Carriers of the DR15 allele with elevated anti-EBNA-1 antibody titers may have a markedly increased risk of MS.

Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification.

The potential tumor suppressor antizyme and its endogenous inhibitor (antizyme inhibitor, AZI) have been implicated in the ubiquitin-independent proteasomal degradation of proteins involved in cell proliferation as well as in the regulation of polyamine levels. We show here that both antizyme and AZI concentrate at centrosomes and that antizyme preferentially associates with the maternal centriole. Interestingly, alterations in the levels of these proteins have opposing effects on centrosomes. Depletion of antizyme in various cell lines and primary cells leads to centrosome overduplication, whereas overexpression of antizyme reduces numerical centrosome abnormalities. Conversely, silencing of the antizyme inhibitor, AZI, results in a decrease of numerical centrosome abnormalities, whereas overexpression of AZI leads to centrosome overduplication. We further show that the numerical centrosome abnormalities are due to daughter centriole amplification. In summary, our results demonstrate that alterations in the antizyme/AZI balance cause numerical centrosomal defects and suggest a role for ubiquitin-independent proteasomal degradation in centrosome duplication.

Interference of the dominant negative helix-loop-helix protein ID1 with the proteasomal subunit S5A causes centrosomal abnormalities.

The inhibitor of DNA-binding (ID) proteins are dominant-negative inhibitors of basic helix-loop-helix transcription factors that have multiple functions during development and cellular differentiation. High-level expression of some ID family members has been observed in human malignancies, and in some cases was correlated with poor clinical prognosis. Ectopic ID1 expression extends the life span of primary human epithelial cells, inhibits cellular differentiation and induces centrosome duplication errors, thus suggesting that ID1 may have oncogenic activities. ID1 can bind to the proteasomal subunit S5A/Rpn10, but the biological consequences of the interaction have not been studied in detail. Here, we show that ID1's ability to induce supernumerary centrosomes correlates with S5A binding. Similar to ID1, a fraction of the S5A protein localizes to centrosomal structures. Furthermore, partial depletion of S5A by RNA interference causes accumulation of cells with supernumerary centrosomes. These results are consistent with the model that ID1 dysregulates centrosome homeostasis at least in part by interfering with S5A activities at the centrosome.

Plasma titers of antibodies against Epstein-Barr virus BZLF1 and risk of multiple sclerosis.

BACKGROUND/AIMS: Results of recently conducted prospective studies have demonstrated that the presence of high titers of anti-EBNA-1 or anti-EBNA complex IgG antibodies in healthy individuals is a strong risk factor for multiple sclerosis (MS). Antibodies to BZLF1, the product of the homonymous early lytic gene, have been found to be related to risk of nasopharyngeal carcinoma, but have not been previously measured in MS studies. METHODS: We examined whether high levels of anti-BZLF1 IgG antibodies also predict MS risk in a nested case-control study among women in the Nurses Health Study and Nurses Health Study II cohorts. RESULTS: Results of this prospective study suggest that antibody titers to EBNAs are the strongest predictor of MS risk. CONCLUSION: Little further contribution may be provided by measuring anti-BZLF1 antibodies in regard to MS risk.

A prospective study of Chlamydia pneumoniae infection and risk of MS in two US cohorts.

BACKGROUND: Chlamydia pneumoniae (Cpn) has been proposed as a possible etiologic agent in multiple sclerosis (MS). However, previous studies were cross-sectional and could not assess whether Cpn infection preceded the onset of MS. METHODS: The authors conducted a prospective nested case-control study among 3 million US Army personnel and 121,466 members of the Kaiser Permanente Medical Care Program (KPMCP) cohort. Serum samples collected prior to onset of MS symptoms were available for 83 MS cases in the Army and 46 in the KPMCP cohort. Two controls were matched to each case on age, sex, and date of blood collection. Microimmunofluorescence was used to measure serum immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody titers to Cpn; IgG titers > or 1:16 were considered positive for past Cpn infection. RESULTS: Seropositivity for Cpn was not significantly associated with risk of MS in either cohort (Army: OR = 1.0; 95% CI 0.6, 1.8; KPMCP: OR = 1.5; 95% CI 0.7, 3.1) or in the pooled analysis (OR = 1.2; 95% CI 0.8, 1.9). Serum levels of anti-Cpn IgG antibody were also not associated with an increased risk of MS in the Army (OR for a fourfold difference in antibody titers = 0.9; 95% CI 0.7, 1.2) or in the pooled analysis (OR = 1.2; 95% CI 0.9, 1.4), but a significant increase in risk was seen in the KPMCP cohort (OR = 1.7; 95% CI 1.2, 2.5). The difference between these results in the Army and the KPMCP cohort was significant (p = 0.01). CONCLUSIONS: Neither Cpn seropositivity nor serum anti-Cpn IgG antibody titers predicted risk of developing MS. However, due to the heterogeneity of results between cohorts, we cannot exclude the possibility that infection with Cpn may modify the risk of MS.

Vitamin D intake and incidence of multiple sclerosis.

BACKGROUND: A protective effect of vitamin D on risk of multiple sclerosis (MS) has been proposed, but no prospective studies have addressed this hypothesis. METHODS: Dietary vitamin D intake was examined directly in relation to risk of MS in two large cohorts of women: the Nurses' Health Study (NHS; 92,253 women followed from 1980 to 2000) and Nurses' Health Study II (NHS II; 95,310 women followed from 1991 to 2001). Diet was assessed at baseline and updated every 4 years thereafter. During the follow-up, 173 cases of MS with onset of symptoms after baseline were confirmed. RESULTS: The pooled age-adjusted relative risk (RR) comparing women in the highest quintile of total vitamin D intake at baseline with those in the lowest was 0.67 (95% CI = 0.40 to 1.12; p for trend = 0.03). Intake of vitamin D from supplements was also inversely associated with risk of MS; the RR comparing women with intake of >or=400 IU/day with women with no supplemental vitamin D intake was 0.59 (95% CI = 0.38 to 0.91; p for trend = 0.006). No association was found between vitamin D from food and MS incidence. CONCLUSION: These results support a protective effect of vitamin D intake on risk of developing MS.