Characterization of complex groundwater flows in the environment of singular buildings by combining hydrogeological and non-destructive geophysical (ground-penetrating radar) techniques: Punta Begona Galleries (Getxo, Spain)

[EN] Locating and quantifying groundwater flow in many built-up areas are a priority with regard to its complete restoration. In this work, a hydrogeological survey of the surroundings of the Punta Begona Galleries (Getxo, Bizkaia), built on a coastal cliff, was completed by using ground penetrating radar (GPR) testing. Thus, the preliminary characterization of soils and rocks in accessible areas of the cliff was first improved by hydrogeological information gathered from a single survey borehole, including permeability measurements by low pressure injection tests (LPTs) and continuous water level monitoring. As a complementary method, the non-destructive GPR technique was performed during both dry and wet hydrological periods and in tandem with the injection tests, providing more complete spatial and temporal images of water flows. Specifically, GPR allows mapping of flow paths in soils and assessing the continuity of fractures in rock masses. Altogether, this complementary approach provides greater knowledge of complex underground flow dynamics in built environments, thus making it easier to make decisions for their managementCity Council of Getxo, Grant/Award Number: OTRI2016-0738; University of the Basque CountryUriarte, JA.; Damas Molla, L.; Sagarna, M.; Aranburu, A.; García García, F.; Antiguedad, I.; Morales, T. (2020). Characterization of complex groundwater flows in the environment of singular buildings by combining hydrogeological and non-destructive geophysical (ground-penetrating radar) techniques: Punta Begona Galleries (Getxo, Spain). Hydrological Processes. 34(4):1004-1015. https://doi.org/10.1002/hyp.13635S1004101534

Assessing the hydrological response from an ensemble of CMIP5 climate projections in the transition zone of the Atlantic region (Bay of Biscay)

The climate changes projected for the 21st century will have consequences on the hydrological response of catchments. These changes, and their consequences, are most uncertain in the transition zones. The study area, in the Bay of Biscay, is located in the transition zone of the European Atlantic region, where hydrological impact of climate change was scarcely studied. In order to address this scarcity, the hydrological impacts of climate change on river discharge were assessed. To do so, a hydrological modelling was carried out considering 16 climate scenarios that include 5 General Circulation Models (GCM) from the 5th report of the Coupled Model Intercomparison Project (CMIP5), 2 statistical downscaling methods and 2 Representative Concentration Pathways. Projections for future discharge (2011-2100) were divided into three 30-year horizons (2030s, 2060s and 2090s) and a comparison was made between these time horizons and the baseline (1961-2000). The results show that the downscaling method used resulted in a higher source of uncertainty than GCM itself. In addition, the uncertainties inherent to the methods used at all the levels do not affect the results equally along the year. In spite of those uncertainties, general trends for the 2090s predict seasonal discharge decreases by around -17% in autumn, -16% in spring, -11% in winter and -7% in summer. These results are in line with those predicted for the Atlantic region (France and the Iberian Peninsula). Trends for extreme flows were also analysed: the most significant show an increase in the duration (days) of low flows. From an environmental point of view, and considering the need to meet the objectives established by the Water Framework Directive (WFD), this will be a major challenge for the future planning on water management

Evaluation of riparian groundwaters quality using microalgal response to pollutants

Society of Environmental Toxicology and Chemistry (SETAC Europe) 28th Annual Meeting, Responsible and Innovative Research for Environmental Quality, 13−17 May 2018, Rome, Italy.-- 1 pageContamination of ecosystems by pesticides, pharmaceuticals and trace metals becomes a major environmental problem. Freshwater algae are well known bio-indicators of river pollution but diatom indices do not allow to evaluate the specific effects of the contaminants. Their sensitivity to pesticides differ markedly among microalgae species and therefore the toxicity data for multiple species need to be efficiently obtained. In the present work, we measured the growth of the three lotic dominant species Desmodesmus subspicatus, Nitzschia palea and Navicula pelliculosa by an automated fluorometric microplate assay to evaluate the groundwater and river quality in four riparian wetlands in the south-west of Europe(Monbéqui (France), Saragossa (Spain), Bidasoa (Spain) and Toledo (Spain)). Four campaigns of water sampling were realized during contrasted hydrological conditions under different pedo-climatic conditions in agricultural area. Pesticides, pharmaceuticalsand metals concentration were measured by HPLC-MS or ICP-MS. PCA, ANOVA and co-inertia analysis results showed that algal growth was different between freshwater and groundwater. As expected, the green alga was sensitive to alkalinity, SO4, O2and pH whereas diatoms were positively sensitive to silica concentration and dissolved organic carbon (DOC). Besides, the green alga responded positively to the metals Co and Ni and negatively to S-triazines, terbutylazine and their metabolites. At last, the pharmaceuticals benzoylecgonine and carbamazepine/irbesartan/valsartan induced growth stimulation of N. paleaand N. pelliculosa, respectively. Same records for pharmaceuticals were observed for the other three sites, excepted Bidasoa. Both extensive sampling and data analysis makes our approach a new useful bio-indicator for preliminary investigation of groundwater quality in order to predict the best location of quality water for human consumption (ATTENAGUA project)Peer Reviewe

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured byATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have \u3e85% loss of \u27pore\u27 function of the P2X7 receptor measured byATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory \u27pore\u27 function

Genome-wide significant association with seven novel multiple sclerosis risk loci

Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5x10(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03x10(-12)), CD28 (rs6435203, p=1.35x10(-9)), LPP (rs4686953, p=3.35x10(-8)), ETS1 (rs3809006, p=7.74x10(-9)), DLEU1 (rs806349, p=8.14x10(-12)), LPIN3 (rs6072343, p=7.16x10(-12)) and IFNGR2 (rs9808753, p=4.40x10(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases

Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial

Background Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis.Methods We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 1858 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov, number NCT01864148.Findings Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0.89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment.Interpretation Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

reserved328Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS.Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18-60 years) with SPMS and an Expanded Disability Status Scale score of 3.0-6.5 were randomly assigned (2: 1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials. gov, number NCT01665144.Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16.8 years (SD 8.3), and the mean time since conversion to SPMS was 3.8 years (SD 3.5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0.79, 95% CI 0.65-0.95; relative risk reduction 21%; p=0.013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.mixedKappos L.; Bar-Or A.; Cree B.A.C.; Fox R.J.; Giovannoni G.; Gold R.; Vermersch P.; Arnold D.L.; Arnould S.; Scherz T.; Wolf C.; Wallstrom E.; Dahlke F.; Achiron A.; Achtnichts L.; Agan K.; Akman-Demir G.; Allen A.B.; Antel J.P.; Antiguedad A.R.; Apperson M.; Applebee A.M.; Ayuso G.I.; Baba M.; Bajenaru O.; Balasa R.; Balci B.P.; Barnett M.; Bass A.; Becker V.U.; Bejinariu M.; Bergh F.T.; Bergmann A.; Bernitsas E.; Berthele A.; Bhan V.; Bischof F.; Bjork R.J.; Blevins G.; Boehringer M.; Boerner T.; Bonek R.; Bowen J.D.; Bowling A.; Boyko A.N.; Boz C.; Bracknies V.; Braune S.; Brescia Morra V.; Brochet B.; Brola W.; Brownstone P.K.; Brozman M.; Brunet D.; Buraga I.; Burnett M.; Buttmann M.; Butzkueven H.; Cahill J.; Calkwood J.C.; Camu W.; Cascione M.; Castelnovo G.; Centonze D.; Cerqueira J.; Chan A.; Cimprichova A.; Cohan S.; Comi G.; Conway J.; Cooper J.A.; Corboy J.; Correale J.; Costell B.; Cottrell D.A.; Coyle P.K.; Craner M.; Cui L.; Cunha L.; Czlonkowska A.; da Silva A.M.; de Sa J.; de Seze J.; Debouverie M.; Debruyne J.; Decoo D.; Defer G.; Derfuss T.; Deri N.H.; Dihenia B.; Dioszeghy P.; Donath V.; Dubois B.; Duddy M.; Duquette P.; Edan G.; Efendi H.; Elias S.; Emrich P.J.; Estruch B.C.; Evdoshenko E.P.; Faiss J.; Fedyanin A.S.; Feneberg W.; Fermont J.; Fernandez O.F.; Ferrer F.C.; Fink K.; Ford H.; Ford C.; Francia A.; Freedman M.; Frishberg B.; Galgani S.; Garmany G.P.; Gehring K.; Gitt J.; Gobbi C.; Goldstick L.P.; Gonzalez R.A.; Grandmaison F.; Grigoriadis N.; Grigorova O.; Grimaldi L.M.E.; Gross J.; Gross-Paju K.; Gudesblatt M.; Guillaume D.; Haas J.; Hancinova V.; Hancu A.; Hardiman O.; Harmjanz A.; Heidenreich F.R.; Hengstman G.J.D.; Herbert J.; Herring M.; Hodgkinson S.; Hoffmann O.M.; Hofmann W.E.; Honeycutt W.D.; Hua L.H.; Huang D.; Huang Y.; Huang D.; Hupperts R.; Imre P.; Jacobs A.K.; Jakab G.; Jasinska E.; Kaida K.; Kalnina J.; Kaprelyan A.; Karelis G.; Karussis D.; Katz A.; Khabirov F.A.; Khatri B.; Kimura T.; Kister I.; Kizlaitiene R.; Klimova E.; Koehler J.; Komatineni A.; Kornhuber A.; Kovacs K.; Koves A.; Kozubski W.; Krastev G.; Krupp L.B.; Kurca E.; Lassek C.; Laureys G.; Lee L.; Lensch E.; Leutmezer F.; Li H.; Linker R.A.; Linnebank M.; Liskova P.; Llanera C.; Lu J.; Lutterotti A.; Lycke J.; Macdonell R.; Maciejowski M.; Maeurer M.; Magzhanov R.V.; Maida E.-M.; Malciene L.; Mao-Draayer Y.; Marfia G.A.; Markowitz C.; Mastorodimos V.; Matyas K.; Meca-Lallana J.; Merino J.A.G.; Mihetiu I.G.; Milanov I.; Miller A.E.; Millers A.; Mirabella M.; Mizuno M.; Montalban X.; Montoya L.; Mori M.; Mueller S.; Nakahara J.; Nakatsuji Y.; Newsome S.; Nicholas R.; Nielsen A.S.; Nikfekr E.; Nocentini U.; Nohara C.; Nomura K.; Odinak M.M.; Olsson T.; van Oosten B.W.; Oreja-Guevara C.; Oschmann P.; Overell J.; Pachner A.; Panczel G.; Pandolfo M.; Papeix C.; Patrucco L.; Pelletier J.; Piedrabuena R.; Pless M.; Polzer U.; Pozsegovits K.; Rastenyte D.; Rauer S.; Reifschneider G.; Rey R.; Rizvi S.A.; Robertson D.; Rodriguez J.M.; Rog D.; Roshanisefat H.; Rowe V.; Rozsa C.; Rubin S.; Rusek S.; Sacca F.; Saida T.; Salgado A.V.; Sanchez V.E.F.; Sanders K.; Satori M.; Sazonov D.V.; Scarpini E.A.; Schlegel E.; Schluep M.; Schmidt S.; Scholz E.; Schrijver H.M.; Schwab M.; Schwartz R.; Scott J.; Selmaj K.; Shafer S.; Sharrack B.; Shchukin I.A.; Shimizu Y.; Shotekov P.; Siever A.; Sigel K.-O.; Silliman S.; Simo M.; Simu M.; Sinay V.; Siquier A.E.; Siva A.; Skoda O.; Solomon A.; Stangel M.; Stefoski D.; Steingo B.; Stolyarov I.D.; Stourac P.; Strassburger-Krogias K.; Strauss E.; Stuve O.; Tarnev I.; Tavernarakis A.; Tello C.R.; Terzi M.; Ticha V.; Ticmeanu M.; Tiel-Wilck K.; Toomsoo T.; Tubridy N.; Tullman M.J.; Tumani H.; Turcani P.; Turner B.; Uccelli A.; Urtaza F.J.O.; Vachova M.; Valikovics A.; Walter S.; Van Wijmeersch B.; Vanopdenbosch L.; Weber J.R.; Weiss S.; Weissert R.; Vermersch P.; West T.; Wiendl H.; Wiertlewski S.; Wildemann B.; Willekens B.; Visser L.H.; Vorobeychik G.; Xu X.; Yamamura T.; Yang Y.N.; Yelamos S.M.; Yeung M.; Zacharias A.; Zelkowitz M.; Zettl U.; Zhang M.; Zhou H.; Zieman U.; Ziemssen T.Kappos, L.; Bar-Or, A.; Cree, B. A. C.; Fox, R. J.; Giovannoni, G.; Gold, R.; Vermersch, P.; Arnold, D. L.; Arnould, S.; Scherz, T.; Wolf, C.; Wallstrom, E.; Dahlke, F.; Achiron, A.; Achtnichts, L.; Agan, K.; Akman-Demir, G.; Allen, A. B.; Antel, J. P.; Antiguedad, A. R.; Apperson, M.; Applebee, A. M.; Ayuso, G. I.; Baba, M.; Bajenaru, O.; Balasa, R.; Balci, B. P.; Barnett, M.; Bass, A.; Becker, V. U.; Bejinariu, M.; Bergh, F. T.; Bergmann, A.; Bernitsas, E.; Berthele, A.; Bhan, V.; Bischof, F.; Bjork, R. J.; Blevins, G.; Boehringer, M.; Boerner, T.; Bonek, R.; Bowen, J. D.; Bowling, A.; Boyko, A. N.; Boz, C.; Bracknies, V.; Braune, S.; Brescia Morra, V.; Brochet, B.; Brola, W.; Brownstone, P. K.; Brozman, M.; Brunet, D.; Buraga, I.; Burnett, M.; Buttmann, M.; Butzkueven, H.; Cahill, J.; Calkwood, J. C.; Camu, W.; Cascione, M.; Castelnovo, G.; Centonze, D.; Cerqueira, J.; Chan, A.; Cimprichova, A.; Cohan, S.; Comi, G.; Conway, J.; Cooper, J. A.; Corboy, J.; Correale, J.; Costell, B.; Cottrell, D. A.; Coyle, P. K.; Craner, M.; Cui, L.; Cunha, L.; Czlonkowska, A.; da Silva, A. M.; de Sa, J.; de Seze, J.; Debouverie, M.; Debruyne, J.; Decoo, D.; Defer, G.; Derfuss, T.; Deri, N. H.; Dihenia, B.; Dioszeghy, P.; Donath, V.; Dubois, B.; Duddy, M.; Duquette, P.; Edan, G.; Efendi, H.; Elias, S.; Emrich, P. J.; Estruch, B. C.; Evdoshenko, E. P.; Faiss, J.; Fedyanin, A. S.; Feneberg, W.; Fermont, J.; Fernandez, O. F.; Ferrer, F. C.; Fink, K.; Ford, H.; Ford, C.; Francia, A.; Freedman, M.; Frishberg, B.; Galgani, S.; Garmany, G. P.; Gehring, K.; Gitt, J.; Gobbi, C.; Goldstick, L. P.; Gonzalez, R. A.; Grandmaison, F.; Grigoriadis, N.; Grigorova, O.; Grimaldi, L. M. E.; Gross, J.; Gross-Paju, K.; Gudesblatt, M.; Guillaume, D.; Haas, J.; Hancinova, V.; Hancu, A.; Hardiman, O.; Harmjanz, A.; Heidenreich, F. R.; Hengstman, G. J. D.; Herbert, J.; Herring, M.; Hodgkinson, S.; Hoffmann, O. M.; Hofmann, W. E.; Honeycutt, W. D.; Hua, L. H.; Huang, D.; Huang, Y.; Huang, D.; Hupperts, R.; Imre, P.; Jacobs, A. K.; Jakab, G.; Jasinska, E.; Kaida, K.; Kalnina, J.; Kaprelyan, A.; Karelis, G.; Karussis, D.; Katz, A.; Khabirov, F. A.; Khatri, B.; Kimura, T.; Kister, I.; Kizlaitiene, R.; Klimova, E.; Koehler, J.; Komatineni, A.; Kornhuber, A.; Kovacs, K.; Koves, A.; Kozubski, W.; Krastev, G.; Krupp, L. B.; Kurca, E.; Lassek, C.; Laureys, G.; Lee, L.; Lensch, E.; Leutmezer, F.; Li, H.; Linker, R. A.; Linnebank, M.; Liskova, P.; Llanera, C.; Lu, J.; Lutterotti, A.; Lycke, J.; Macdonell, R.; Maciejowski, M.; Maeurer, M.; Magzhanov, R. V.; Maida, E. -M.; Malciene, L.; Mao-Draayer, Y.; Marfia, G. A.; Markowitz, C.; Mastorodimos, V.; Matyas, K.; Meca-Lallana, J.; Merino, J. A. G.; Mihetiu, I. G.; Milanov, I.; Miller, A. E.; Millers, A.; Mirabella, M.; Mizuno, M.; Montalban, X.; Montoya, L.; Mori, M.; Mueller, S.; Nakahara, J.; Nakatsuji, Y.; Newsome, S.; Nicholas, R.; Nielsen, A. S.; Nikfekr, E.; Nocentini, U.; Nohara, C.; Nomura, K.; Odinak, M. M.; Olsson, T.; van Oosten, B. W.; Oreja-Guevara, C.; Oschmann, P.; Overell, J.; Pachner, A.; Panczel, G.; Pandolfo, M.; Papeix, C.; Patrucco, L.; Pelletier, J.; Piedrabuena, R.; Pless, M.; Polzer, U.; Pozsegovits, K.; Rastenyte, D.; Rauer, S.; Reifschneider, G.; Rey, R.; Rizvi, S. A.; Robertson, D.; Rodriguez, J. M.; Rog, D.; Roshanisefat, H.; Rowe, V.; Rozsa, C.; Rubin, S.; Rusek, S.; Sacca, F.; Saida, T.; Salgado, A. V.; Sanchez, V. E. F.; Sanders, K.; Satori, M.; Sazonov, D. V.; Scarpini, E. A.; Schlegel, E.; Schluep, M.; Schmidt, S.; Scholz, E.; Schrijver, H. M.; Schwab, M.; Schwartz, R.; Scott, J.; Selmaj, K.; Shafer, S.; Sharrack, B.; Shchukin, I. A.; Shimizu, Y.; Shotekov, P.; Siever, A.; Sigel, K. -O.; Silliman, S.; Simo, M.; Simu, M.; Sinay, V.; Siquier, A. E.; Siva, A.; Skoda, O.; Solomon, A.; Stangel, M.; Stefoski, D.; Steingo, B.; Stolyarov, I. D.; Stourac, P.; Strassburger-Krogias, K.; Strauss, E.; Stuve, O.; Tarnev, I.; Tavernarakis, A.; Tello, C. R.; Terzi, M.; Ticha, V.; Ticmeanu, M.; Tiel-Wilck, K.; Toomsoo, T.; Tubridy, N.; Tullman, M. J.; Tumani, H.; Turcani, P.; Turner, B.; Uccelli, A.; Urtaza, F. J. O.; Vachova, M.; Valikovics, A.; Walter, S.; Van Wijmeersch, B.; Vanopdenbosch, L.; Weber, J. R.; Weiss, S.; Weissert, R.; Vermersch, P.; West, T.; Wiendl, H.; Wiertlewski, S.; Wildemann, B.; Willekens, B.; Visser, L. H.; Vorobeychik, G.; Xu, X.; Yamamura, T.; Yang, Y. N.; Yelamos, S. M.; Yeung, M.; Zacharias, A.; Zelkowitz, M.; Zettl, U.; Zhang, M.; Zhou, H.; Zieman, U.; Ziemssen, T

Closing the case of APOE in multiple sclerosis: no association with disease risk in over 29 000 subjects

Background Single nucleotide polymorphisms (SNPs) rs429358 (epsilon 4) and rs7412 (epsilon 2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently