The AusD Study: a population-based study of the determinants of serum 25-hydroxyvitamin D concentration across a broad latitude range.

Observational studies suggest that people with a high serum 25-hydroxyvitamin D (25(OH)D) concentration may have reduced risk of chronic diseases such as osteoporosis, multiple sclerosis, type 1 diabetes, cardiovascular disease, and some cancers. The AusD Study (A Quantitative Assessment of Solar UV Exposure for Vitamin D Synthesis in Australian Adults) was conducted to clarify the relationships between ultraviolet (UV) radiation exposure, dietary intake of vitamin D, and serum 25(OH)D concentration among Australian adults residing in Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S), and Hobart (42.8°S). Participants aged 18-75 years were recruited from the Australian Electoral Roll between 2009 and 2010. Measurements were made of height, weight, waist:hip ratio, skin, hair, and eye color, blood pressure, and grip strength. Participants completed a questionnaire on sun exposure and vitamin D intake, together with 10 days of personal UV dosimetry and an associated sun-exposure and physical-activity diary that was temporally linked to a blood test for measurement of 25(OH)D concentration. Ambient solar UV radiation was also monitored at all study sites. We collected comprehensive, high-quality data from 1,002 participants (459 males, 543 females) assessed simultaneously across a range of latitudes and through all seasons. Here we describe the scientific and methodological issues considered in designing the AusD Study.

Current and past Epstein-Barr virus infection in risk of initial CNS demyelination.

OBJECTIVES: To assess risk of a first clinical diagnosis of CNS demyelination (FCD) in relation to measures of Epstein-Barr virus (EBV) infection within the context of other known risk factors. METHODS: This was a multicenter incident case-control study. FCD cases (n = 282) aged 18-59 years and controls (n = 558, matched on age, sex, and region) were recruited from 4 Australian centers between November 1, 2003, and December 31, 2006. A nested study (n = 215 cases, n = 216 controls) included measurement of whole blood quantitative EBV DNA load and serum EBV-specific antibodies. Conditional logistic regression was used to analyze case-control differences. RESULTS: There were no significant case-control differences in the proportion with detectable EBV DNA (55.8% vs 50.5%, respectively, p = 0.28), or in quantitative EBV DNA load (p = 0.33). Consistent with previous work, higher anti-EBV-specific immunoglobulin G (IgG) titers and a history of infectious mononucleosis were associated with increased FCD risk and there was an additive interaction with HLA-DRB1*1501 status. We found additional interactions between high anti-EBNA IgG titer and SNPs in HLA-A (adjusted odds ratios [AOR] = 19.84 [95% confidence interval (CI) 5.95 to 66.21] for both factors compared to neither) and CTLA-4 genes (AOR = 0.31 [95% CI 0.13 to 0.76] for neither factor compared to both). EBV DNA load was lower at higher serum 25-hydroxyvitamin D concentrations in controls (r = -0.17, p = 0.01). An adverse effect of higher EBV DNA load on FCD risk was increased with higher 25-hydroxyvitamin D concentration (p[interaction] = 0.02). CONCLUSION: Past infection with EBV, but not current EBV DNA load in whole blood, is significantly associated with increased FCD risk. These associations appear to be modified by immune-related gene variants.

Individual and joint action of environmental factors and risk of MS.

In this review, the evidence for the leading environmental and lifestyle factors thought to play a role in multiple sclerosis (MS) onset, including Epstein-Barr virus, sun exposure or vitamin D, and smoking, will be discussed. The Causal Pie Model is used as a conceptual framework to understand the causation. Given that no single factor leads to the development of MS, the joint action or interaction of these factors, along with genetic factors, most particularly the HLA-DR15*1501 genotype, is a primary focus.

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.

Validity and reliability of adult recall of past sun exposure in a case-control study of multiple sclerosis.

BACKGROUND: Measurement of past sun exposure through recall by adults has the potential for measurement error. We aimed to investigate aspects of validity and reliability of self-reported past sun exposure. METHODS: A population-based case-control study was conducted in Tasmania on 136 cases with multiple sclerosis and 272 age- and sex-matched community controls. Repeat interviews on 52 cases and 52 controls were done on average 11 weeks after the initial interview. Sun exposure was assessed by questionnaire and lifetime calendar. Other measurements included serum 25-hydroxyvitamin D, actinic damage, and skin phenotype. RESULTS: There was an association between recent sun exposure and serum vitamin D (time in the sun: r = 0.22, P < 0.01; activities outside: r = 0.31, P < 0.01 for controls) and between lifetime sun exposure and actinic damage [correlation between 0.34 (P < 0.01) and 0.17 (P = 0.01) for controls]. The test-retest weighted kappa statistic of self-reported sun exposure ranged from 0.43 to 0.74. Recall of childhood/adolescent sun exposure by standardized questioning was no less reproducible than recall of recent adult sun exposure and no less reliable when made with the calendar method. Comparing the questionnaire and calendar method, the measures of childhood/adolescent sun exposure had a similar predictive validity for multiple sclerosis. CONCLUSIONS: The results of this study provide further evidence that adults are able to recall past sun exposure with shown validity and reliability and present information about the possible reasons for the good reliability of recalled sun exposure measures.

UVR, vitamin D and three autoimmune diseases--multiple sclerosis, type 1 diabetes, rheumatoid arthritis.

We review the evidence indicating a possible beneficial role for UVR on three Th1-mediated autoimmune diseases: multiple sclerosis, type 1 diabetes and rheumatoid arthritis in relation to recent developments in photoimmunology. Recent work suggests that UVR exposure may be one factor that can attenuate the autoimmune activity leading to these three diseases through several pathways involving UVB and UVA irradiation, UVR-derived vitamin D synthesis and other routes such as alpha-melanocyte-stimulating hormone, calcitonin gene related peptide and melatonin. Ecological features, particularly a gradient of increasing prevalence of multiple sclerosis and type 1 diabetes with higher latitude, provide some support for a beneficial role of UVR. Analytical studies provide additional support, particularly as low vitamin D has been prospectively associated with disease onset for all three diseases, but are not definitive. Randomized controlled trial data are required. Further, we discuss how associated genetic studies may assist the accumulation of evidence with regard to the possible causal role of low UVR exposure and/or low vitamin D status in the development of these diseases.