Vitamin D and multiple sclerosis: epidemiological studies on environmental and genetic risk factors

Background: Multiple sclerosis (MS) is an autoimmune inflammatory neurological disease with complex aetiology where the causes are not completely known. The main aim of this thesis was to investigate the influence of vitamin D on the risk of developing MS. Methods: The papers in this thesis are based on data from a nationwide population-based case–control study, the Epidemiological Investigation of Multiple Sclerosis (EIMS) study. The source population for the EIMS study is the Swedish population, aged 16–70 years, in defined areas of Sweden. The cases are diagnosed at neurological centres according to the McDonalds criteria, and included in the study within 2 years after diagnosis, and the controls are selected randomly from the population register and matched according to sex and age and residential area at the time of diagnosis of the case. All study participants are invited to respond to an extensive questionnaire regarding environmental and lifestyle factors and to give blood samples. The response proportion has been 91% for the cases and 70% for the controls for the questionnaire and 94% and 57% for the blood samples, respectively. The fourth paper in this thesis is based on data from the EIMS study as well as data from another Swedish case–control study, the Genes and Environment in Multiple Sclerosis (GEMS) study, and the American Kaiser Permanente Medical Plan Northern California (KPNC) study. In these studies, prevalent MS cases aged 18 years and above (and white non-hispanic individuals for the KPNC study), with a verified diagnosis according to McDonalds criteria or International Classification of Diseases (ninth revision), were invited to participate and exposure information was collected through questionnaires and blood sampling. Results: Low sunlight exposure was associated with increased MS risk, where self-reported no voluntary sun exposure was associated with a 60% increased risk of developing MS compared to daily sun exposure. Low vitamin D levels were also associated with increased MS risk (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.2–1.7), with no interaction with HLA-DRB1*15. High fatty fish intake, i.e. at least once a week, which is a source of vitamin D, was significantly associated with decreased MS risk (OR 0.82, 95% CI 0.68–0.98). To investigate the timing of the exposure of vitamin D we evaluated the association between vitamin D levels in blood samples taken at birth and later risk of developing MS and did not find any sign of an association. Finally, we investigated whether or not the association seen in our studies between vitamin D deficiency and MS risk was a causal association. We calculated a genetic risk score for vitamin D levels based on three genetic polymorphisms, where a higher score corresponded to higher vitamin D levels. We found that a higher score was associated with decreased MS risk (OR 0.85, 95% CI 0.76–0.94). Conclusion: Vitamin D deficiency seems to be a causal risk factor for MS, but the susceptibility period does not appear to be during the neonatal stage. Oral vitamin D intake may be protective and sunlight exposure may impact MS risk with no influence from HLA- DRB1*15 status

Recognising the small Ree groups in their natural representations

We present Las Vegas algorithms for constructive recognition and constructive membership testing of the Ree groups 2G_2(q) = Ree(q), where q = 3^{2m + 1} for some m > 0, in their natural representations of degree 7. The input is a generating set X. The constructive recognition algorithm is polynomial time given a discrete logarithm oracle. The constructive membership testing consists of a pre-processing step, that only needs to be executed once for a given X, and a main step. The latter is polynomial time, and the former is polynomial time given a discrete logarithm oracle. Implementations of the algorithms are available for the computer algebra system MAGMA

När det händer sådana saker, blir man förvirrad...

”Pain itself poses an obdurate resistance to cultural categories. It is an experience that simply cannot be avoided, en experience that sets limits to the meanings given it by cultural beliefs, discourses, or practices. Something is at stake, frequently desperately so, in the life of pain patients. Pain can be a massive threat to the legitimacy of the everyday world. Viewed in these terms, the anthropological study of chronic pain addresses the sources, varieties, and consequences of human suffering.” (Kleinman med fler, 1994. sid. 7)Oförklarade kroppsliga besvär innebär en osäkerhet för såväl patient som behandlare. En kvinnlig turkiskfödd patients erfarenheter av och perspektiv på sin sjukdom presenteras. Utifrån detta fall och utifrån en kvalitativ avhandling utforskande sjukdomsförståelse diskuteras min osäkerhet inför de teoretiska begreppen ’somatisering’ och ’explanatory models’ (förklaringsmodeller) och behandlares osäkerhet vid svårigheter att tolka patienters kommunikation. Avslutningsvis diskuteras behovet av klinisk metodutveckling i mångkulturella vårdmiljöer. Osäkerhet i den kliniska vardagen kan fungera som en utgångspunkt för att identifiera behov av kunskapsutveckling

The Product Replacement Prospector

AbstractWe present a heuristic extension to the product replacement algorithm, called the Prospector. The aim is to find hopefully good quality ‘random’ elements with short straight line programs in the given generators. This is achieved by saving the random state at certain points and later restoring it. Statistical tests are employed in order to determine when to save the state. We also give evidence for the surprisingly good effect of using an accelerator. The Prospector has been implemented in Magma, and experimental evidence is provided which indicates that it is a very practical method

Recognising the Suzuki groups in their natural representations

Under the assumption of a certain conjecture, for which there exists strong experimental evidence, we produce an efficient algorithm for constructive membership testing in the Suzuki groups Sz(q), where q = 2^{2m + 1} for some m > 0, in their natural representations of degree 4. It is a Las Vegas algorithm with running time O{log(q)} field operations, and a preprocessing step with running time O{log(q) loglog(q)} field operations. The latter step needs an oracle for the discrete logarithm problem in GF(q). We also produce a recognition algorithm for Sz(q) = . This is a Las Vegas algorithm with running time O{|X|^2} field operations. Finally, we give a Las Vegas algorithm that, given ^h = Sz(q) for some h in GL(4, q), finds some g such that ^g = Sz(q). The running time is O{log(q) loglog(q) + |X|} field operations. Implementations of the algorithms are available for the computer system MAGMA

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk.

ObjectiveWe sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.MethodsWe conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.ResultsFindings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p = 0.04, 95% confidence interval (CI): 0.64-0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p = 0.03, 95% CI: 0.76-0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p = 0.003, 95% CI: 0.76-0.94). No association was observed for age at onset or disease severity.ConclusionsThese results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors