Kelly Claire Simon

Vitamin D as an Early Predictor of Multiple Sclerosis Activity and Progression

IMPORTANCE It remains unclear whether vitamin D insufficiency, which is common in individuals with multiple sclerosis (MS), has an adverse effect on MS outcomes. OBJECTIVES To determine whether serum concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, predict disease activity and prognosis in patients with a first event suggestive of MS (clinically isolated syndrome). DESIGN, SETTING, AND PARTICIPANTS The Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment study was a randomized trial originally designed to evaluate the impact of early vs delayed interferon beta-1b treatment in patients with clinically isolated syndrome. Serum 25(OH)D concentrations were measured at baseline and 6, 12, and 24 months. A total of 465 of the 468 patients randomized had at least 1 25(OH)D measurement, and 334 patients had them at both the 6- and 12-month (seasonally asynchronous) measurements. Patients were followed up for 5 years clinically and by magnetic resonance imaging. MAIN OUTCOMES AND MEASURES New active lesions, increased T2 lesion volume, and brain volume on magnetic resonance imaging, as well as MS relapses and disability (Expanded Disability Status Scale score). RESULTS Higher 25(OH)D levels predicted reduced MS activity and a slower rate of progression. A 50-nmol/L (20-ng/mL) increment in average serum 25(OH)D levels within the first 12 months predicted a 57% lower rate of new active lesions (P < .001), 57% lower relapse rate (P = .03), 25% lower yearly increase in T2 lesion volume (P < .001), and 0.41% lower yearly loss in brain volume (P = .07) from months 12 to 60. Similar associations were found between 25(OH)D measured up to 12 months and MS activity or progression from months 24 to 60. In analyses using dichotomous 25(OH)D levels, values greater than or equal to 50 nmol/L (20 ng/mL) at up to 12 months predicted lower disability (Expanded Disability Status Scale score, -0.17; P = .004) during the subsequent 4 years. CONCLUSIONS AND RELEVANCE Among patients with MS mainly treated with interferon beta-1b, low 25(OH)D levels early in the disease course are a strong risk factor for long-term MS activity and progression.

Hypertension, hypercholesterolemia, diabetes, and risk of Parkinson disease

Objective: To determine whether history of hypertension, hypercholesterolemia, or diabetes is associated with risk of Parkinson disease (PD). Methods: Prospective study among participants in two large cohorts: the Nurses’ Health Study (121,046 women) and the Health Professionals Follow-up Study (50,833 men). Mean duration of follow-up was 22.9 years in women, aged 30 to 55 years at baseline, and 12.6 years in men, aged 40 to 75 years at baseline. Relative risks (RRs) of PD were estimated from a Cox proportional hazards model adjusting for potential confounders. Results: We identified a total of 530 incident cases of PD during the follow-up. Risk of PD was not associated with self-reported history of hypertension (RR = 0.96, 95% CI = 0.80 to 1.15), high cholesterol (RR = 0.98, 95% CI = 0.82 to 1.19), or diabetes (RR = 1.04, 95% CI = 0.74 to 1.46), after adjusting for age and smoking in pack-years. Risk of PD decreased modestly with increasing levels of self-reported total cholesterol (RR for a 50-mg/dL increase in total cholesterol = 0.86, 95% CI = 0.78 to 0.95, p for trend = 0.02), but use of cholesterol-lowering drugs was not associated with PD risk (RR comparing users with nonusers = 0.85, 95% CI = 0.59 to 1.23). Among individuals with PD, systolic blood pressure was similar to noncases up to the time of diagnosis but declined afterward. Conclusions: Results of this large prospective study suggest that Parkinson disease risk is not significantly related to history of hypertension, hypercholesterolemia, or diabetes but may modestly decline with increasing blood cholesterol levels. GLOSSARY: ACE = angiotensin-converting enzyme; BMI = body mass index; DBP = diastolic blood pressure; HPFS = Health Professionals Follow-up Study; METS = metabolic equivalent tasks; NHS = Nurses’ Health Study; NSAID = nonsteroidal anti-inflammatory drug; PD = Parkinson disease; RR = relative risk; SBP = systolic blood pressure.

Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics.

PURPOSE OF REVIEW This review provides a brief update of new research findings on the role of vitamin D in multiple sclerosis (MS). RECENT FINDINGS 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. SUMMARY 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.

Human Endogenous Retrovirus-K18 env as a risk factor in multiple sclerosis

Background The 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. Objective To assess whether variation in HERV-K18 Env is a risk factor for MS. Methods We 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. Results Overall, there was a significant association between HERV-K18 env genotype and MS risk (χ2 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). Conclusion Variation in EBV-associated superantigen HERV-K18 Env could influence the genetic susceptibility to MS.

Mendelian randomization of serum urate and parkinson disease progression

Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach.

Exploring the Genetic Architecture of Circulating 25‐Hydroxyvitamin D

The primary circulating form of vitamin D is 25‐hydroxy vitamin D (25(OH)D), a modifiable trait linked with a growing number of chronic diseases. In addition to environmental determinants of 25(OH)D, including dietary sources and skin ultraviolet B (UVB) exposure, twin‐ and family‐based studies suggest that genetics contribute substantially to vitamin D variability with heritability estimates ranging from 43% to 80%. Genome‐wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) located in four gene regions associated with 25(OH)D. These SNPs collectively explain only a fraction of the heritability in 25(OH)D estimated by twin‐ and family‐based studies. Using 25(OH)D concentrations and GWAS data on 5,575 subjects drawn from five cohorts, we hypothesized that genome‐wide data, in the form of (1) a polygenic score comprised of hundreds or thousands of SNPs that do not individually reach GWAS significance, or (2) a linear mixed model for genome‐wide complex trait analysis, would explain variance in measured circulating 25(OH)D beyond that explained by known genome‐wide significant 25(OH)D‐associated SNPs. GWAS identified SNPs explained 5.2% of the variation in circulating 25(OH)D in these samples and there was little evidence additional markers significantly improved predictive ability. On average, a polygenic score comprised of GWAS‐identified SNPs explained a larger proportion of variation in circulating 25(OH)D than scores comprised of thousands of SNPs that were on average, nonsignificant. Employing a linear mixed model for genome‐wide complex trait analysis explained little additional variability (range 0–22%). The absence of a significant polygenic effect in this relatively large sample suggests an oligogenetic architecture for 25(OH)D.

Molecular mechanism underlying the impact of vitamin D on disease activity of MS

Some previous studies suggest modest to strong effects of 25‐hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.

Polymorphisms of caffeine metabolism and estrogen receptor genes and risk of Parkinson's disease in men and women.

Caffeine intake has been associated with a decreased risk of Parkinsons disease (PD) in men but the effect in women is less clear, and appears to be modified by use of post-menopausal estrogens. In a nested case-control study within the Nurses Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), we examined associations between single nucleotide polymorphisms (SNPs) of caffeine metabolizing genes (CYP1A2 and NAT2) and estrogen receptors (ESR1 and ESR2), their interaction with caffeine intake and hormone replacement therapy (PMH) use (collected prospectively) and risk of PD. We matched 159 female cases to 724 controls and 139 male cases to 561 controls on birth year, source of DNA (blood or buccal smear), age and sex. The CYP1A2 rs762551 polymorphism (lower enzyme inducibility) was marginally associated with an increased risk of PD (RR, for increasing number of minor alleles=1.34; 95% CI 1.02, 1.78 in women, but not in men. None of the NAT2 (classified as slow vs. fast acetylator), ESR1 or ESR2 polymorphisms were significantly associated with an altered risk of PD. Marginally significant interactions were observed between caffeine intake and the ESR1 polymorphism rs3798577 (p=0.07) and ESR2 polymorphism rs1255998 (p=0.07). The observed increased risk of PD among female but not male carriers of the rs762551 polymorphism of CYP1A2 and the interactions of caffeine with ESR1 rs3798577 and ESR2 rs1255998 may provide clues to explain the relationship between gender, caffeine intake, estrogen status and risk of PD and need to be replicated.

EBNA1 and LMP1 variants in multiple sclerosis cases and controls.

Simon KC, Yang X, Munger KL, Ascherio A. EBNA1 and LMP1 variants in multiple sclerosis cases and controls.
Acta Neurol Scand: 2011: 124: 53–58.
© 2010 John Wiley & Sons A/S.

Epstein-Barr virus neutralizing antibody levels and risk of multiple sclerosis

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.