Obesity and Multiple Sclerosis: A Mendelian Randomization Study.

BACKGROUND: Observational studies have reported an association between obesity, as measured by elevated body mass index (BMI), in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS. METHODS AND FINDINGS: Employing a two-sample MR approach, we used summary statistics from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the International MS Genetics Consortium (IMSGC), the largest genome-wide association studies for BMI and MS, respectively (GIANT: n = 322,105; IMSGC: n = 14,498 cases and 24,091 controls). Seventy single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10-8) for BMI in GIANT (n = 322,105) and were investigated for their association with MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI, and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m2) increased odds of MS by 41% (odds ratio [OR]: 1.41, 95% CI 1.20-1.66, p = 2.7 x 10-5, I2 = 0%, 95% CI 0-29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. The main study limitations are that, while these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely. CONCLUSION: Genetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity.National Institute for Health Research Cambridge Biomedical Research CentreThis is the final version of the article. It first appeared from Public Library of Science via http://dx.doi.org/10.1371/journal.pmed.1002053

Large differences in adiponectin levels have no clear effect on multiple sclerosis risk: A Mendelian randomization study.

BACKGROUND: Mendelian randomization (MR) studies have demonstrated strong support for an association between genetically increased body mass index and risk of multiple sclerosis (MS). The adipokine adiponectin may be a potential mechanism linking body mass to risk of MS. OBJECTIVE: To evaluate whether genetically increased adiponectin levels influence risk of MS. METHODS: Using genome-wide significant single nucleotide polymorphisms (SNPs) for adiponectin, we undertook an MR study to estimate the effect of adiponectin on MS. This method prevents bias due to reverse causation and minimizes bias due to confounding. Sensitivity analyses were performed to evaluate the assumptions of MR. RESULTS: MR analyses did not support a role for genetically elevated adiponectin in risk of MS (odds ratio (OR) = 0.93 per unit increase in natural-log-transformed adiponectin, equivalent to a two-standard deviation increase in adiponectin on the absolute scale; 95% confidence interval (CI) = 0.66-1.33; p = 0.61). Further MR analysis suggested that genetic variation at the adiponectin gene, which influences adiponectin level, does not impact MS risk. Sensitivity analyses, including MR-Egger regression, suggested no bias due to pleiotropy. CONCLUSION: Lifelong genetically increased adiponectin levels in humans have no clear effect on risk of MS. Other biological factors driving the association between body mass and MS should be investigated

Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease: A Mendelian randomization study

Abstract: Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11–1.34, P-value = 6 × 10−5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05–1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials

Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease: A Mendelian randomization study

Abstract: Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11–1.34, P-value = 6 × 10−5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05–1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials

Systematic evidence for quasifission in 9Be-, 12C-, and 16O-induced reactions forming 258, 260No

Background: Cross sections for the formation of superheavy elements (SHE) by heavy ion fusion are suppressed by the competing quasifission process. This results in a fissionlike decay after capture but before formation of a compact compound nucleus. Fast quasifission is evident from very mass-asymmetric fission, focused in angle. In contrast, slow quasifission shows no significant mass-angle correlation, and a mass distribution peaked at symmetry. However, it shows angular distributions more anisotropic than those calculated for fission following fusion. Following fusion, low excitation energies should increase SHE survival through reduced competition from fission. However, in reactions with deformed actinide target nuclei, subbarrier fusion is highly suppressed by both fast and slow quasifission

Using Mendelian randomization to elucidate the role of vitamin D in multiple sclerosis

Background: Observational studies have long reported an association between decreased vitamin D and increased risk of multiple sclerosis (MS). However since it is difficult to fully protect these approaches from confounding and reverse causation, it remains unclear whether vitamin D is a causal risk factor in MS etiology. Objectives: To review the current literature of the association between vitamin D and MS and discuss the limitations of these previous approaches. Next, to introduce Mendelian randomization (MR) and apply its principles to investigate whether the genetic determinants of vitamin D are associated with MS susceptibility. Methods: PubMed was used to search for relevant ecological, observational and randomized controlled trials. For our MR analysis, we first selected single nucleotide polymorphisms (SNPs) that achieved genome-wide significant (p-value < 5 x10-8) for 25-hydroxyvitamin D (25OHD), the clinical determinant of vitamin D status, in the SUNLIGHT consortium (N= 33,996). We then obtained effect sizes for these SNPs upon MS in the International Multiple Sclerosis Genetics Consortium (IMSGC), the largest genome-wide association study for MS (including up to 14,498 cases and 24,091 controls). MR estimates were obtained by weighting each SNP's effect on MS by its effect on 25OHD, with estimates pooled to provide a summary measure of the effect of genetically lowered vitamin D upon risk of MS.Results: Results of our MR analysis using four vitamin D associated SNPs, demonstrated that a 1 standard deviation decrease in natural log 25OHD increased odds of MS by 2 fold (OR=2.02, 95% CI: 1.7–2.5; p = 7.7 × 10−12; I2 = 63%, 95% CI: 0%–88%). Conclusions: Using MR, our findings support vitamin D as a causal risk factor for MS, substantiating conclusions first suggested by observational analyses. This provides rationale to promote vitamin D awareness among individual at risk for MS. Whether vitamin D supplementation can prevent MS warrants further investigation by long-term clinical trials.Contexte: Des études observationelles rapportent depuis longtemps une association entre la baisse du niveau de vitamine D et l'augmentation du risque de sclérose en plaques (SP). Or, puisqu'il est difficile de complètement protéger ces approches de l'effet des facteurs de confusion et de la rétrocausalité, il reste toujours à déterminer si le niveau de vitamine D est réellement un facteur de risque causal dans l'étiologie de la SP.Objectifs: Passer en revue les publications portant sur l'association entre la vitamine D et la SP et discuter des limites des approches précédentes. Ensuite, introduire la randomisation mendélienne (RM) et appliquer ses principes pour évaluer si les déterminants génétiques de la vitamine D sont associés à la prédisposition à la SP. Méthodes: PubMed a été utilisé pour identifier les études randomisées, observationelles et écologiques pertinentes. Pour notre analyse de RM, nous avons d'abord sélectionné les polymorphismes nucléotidiques (SNP, single-nucleotide polymorphism) qui étaient significatifs au niveau du génome (valeur-p < 5 x10-8) pour la 25-hydroxyvitamine D (25OHD), le déterminant clinique du niveau de vitamine D, dans l'étude du consortium SUNLIGHT (N = 33,996). Nous avons ensuite obtenu les tailles d'effet des SNPs sur la SP pour l'étude du International Multiple Sclerosis Genetics Consortium (IMSGC), la plus importante étude d'association pangénomique portant sur la SP (incluant 14,498 cas et 24,091 témoins). Les estimés de l'étude de RM ont ensuite été obtenus en pondérant l'effet de chaque SNP sur la SP par son effet sur la 25OHD, les estimés étant finalement groupés afin d'obtenir une mesure conjointe de l'effet sur le risque de SP d'un niveau génétiquement bas de vitamine D.Résultats: Les résultats de notre analyse de RM utilisant quatre SNPs associés à la vitamine D démontrent qu'une baisse du niveau de 25OHD équivalant à une erreur type (sur l'échelle logarithmique) double la cote de la SP (OR=2.02, 95% CI: 1.7–2.5; p = 7.7 ×10−12; I2 = 63%, 95% CI: 0%–88%). Conclusions: En utilisant la RM, nos conclusions supportent l'hypothèse de la vitamine D comme facteur de risque causal pour la SP, appuyant les conclusions d'abord suggérées par les études observationelles. Elles supportent aussi la promotion de la vitamine D chez les individus à risque de SP. Toutefois, des études randomisées de longue haleine sont nécessaires pour déterminer si les suppléments de vitamine D peuvent prévenir la SP

Genotype calls from Rare Variant Sanger Sequencing in 1,998 Individuals

<p>Available genotype calls from rare variant sanger sequencing performed on 1,998 individuals.</p> <p> </p> <p>From published paper: <em>The Empirical Power of Rare Variant Association Methods: Results from Sanger Sequencing in 1,998 Individuals</em>. Martin Ladouceur, Zari Dastani, Yurii S. Aulchenko, Celia M. T. Greenwood, J. Brent Richards. Published online February 2nd 2012.</p> <p>DOI: 10.1371/journal.pgen.1002496</p> <p> </p

Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease: A Mendelian randomization study.

Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11-1.34, P-value = 6 × 10-5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05-1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials