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Background: Inter-individual differences in treatment response are marked in multiple sclerosis (MS). This is true for Natalizumab (NTZ), to which a subset of patients displays sub-optimal treatment response. We conducted a multi-centric genome-wide association study (GWAS), with additional pathway and network analysis to identify genetic predictors of response to NTZ., Methods: MS patients from three different centers were included. Response to NTZ was dichotomized, nominating responders (R) relapse-free patients and non-responders (NR) all the others, over a follow-up of 4 years. Association analysis on ~ 4.7 M imputed autosomal common single-nucleotide polymorphisms (SNPs) was performed fitting logistic regression models, adjusted for baseline covariates, followed by meta-analysis at SNP and gene level. Finally, these signals were projected onto STRING interactome, to elicit modules and hub genes linked to response., Results: Overall, 1834 patients were included: 119 from Italy (R = 94, NR = 25), 81 from Germany (R = 61, NR = 20), and 1634 from Sweden (R = 1349, NR = 285). The top-associated variant was rs11132400 T (p = 1.33 × 10 -6 , OR = 0.58), affecting expression of several genes in the locus, like KLKB1. The interactome analysis implicated a module of 135 genes, with over-representation of terms like canonical WNT signaling pathway (p adjust  = 7.08 × 10 -6 ). Response-associated genes like GRB2 and LRP6, already implicated in MS pathogenesis, were topologically prioritized within the module., Conclusion: This GWAS, the largest pharmacogenomic study of response to NTZ, suggested MS-implicated genes and Wnt/β-catenin signaling pathway, an essential component for blood-brain barrier formation and maintenance, to be related to treatment response., Competing Interests: Declarations Competing interests F. Clarelli, A. Corona, K. Pääkkönen, M. Sorosina, A. Zollo, F. Piehl, T. Olsson, P. Stridh, M. Jagodic, B. Hemmer, C. Gasperi, A. Harroud, K. Shchetynsky, A. Mingione, E. Mascia, K. Misra, A. Giordano, M.L. Terzi Mazzieri, A. Priori, J. Saarela, I. Kockum, M. Filippi, F. Esposito, and F. Martinelli Boneschi have no competing interests to declare that are relevant to the topic of the present study. T. Olsson has received honoraria from Biogen, Merck, Novartis, and Sanofi for lectures/advisory Boards, and unrestricted MS research grants from the same companies. B. Hemmer has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon, and TG therapeutics; his institution received research grants from Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. He is associated with DIFUTURE (Data Integration for Future Medicine) [BMBF 01ZZ1804[A-I]]. C. Gasperi received funding from the German Federal Ministry of Education and Research (BMBF—161L0216), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation—GA 2913/3–1, project number 513308106), and the Hertie Foundation (P1200018). A. Harroud has received consultancy fees from Biogen and Pfizer, and received compensation for serving on a scientific advisor board for Amgen. A. Priori is the founder and the chair of the scientific advisory board of Newronika SpA, Milan Italy. M. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate Editor of Radiology, and Associate Editor of Neurological Sciences. He received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, and Sanofi-Genzyme, and he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). F. Esposito received consulting and speaking fees from Novartis and Sanofi Genzyme. F. Martinelli Boneschi has received compensation for consulting services and/or speaking activities from Teva Pharmaceutical Industries, Sanofi Genzyme, Merck-Serono, Biogen Idec, Roche, Medday, and Excemed, and received research support from Merck, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and Fondazione Cariplo., (© 2024. The Author(s).)

Identified in 1998, Ljungan virus (LV; Picornaviridae) causes type 1 diabetes-like symptoms and myocarditis in bank voles (Myodes glareolus) from Sweden and Denmark, and may be a zoonotic agent of several important diseases (e.g., intrauterine fetal death, type 1 diabetes, Guillain-Barré syndrome, and myocarditis). Using a real-time reverse transcriptase-polymerase chain reaction assay and sequence analysis, we detected LV in bank voles, and for the first time, in yellow-necked mice (Apodemus flavicollis) collected during 2006 from a site in northern Italy. The global distribution of LV and its role as a mammalian pathogen deserve further attention.

Interferon regulatory factor-1 (IRF-1) is a transcriptional inducer of the interferon-beta (IFN-beta) gene and other interferon-stimulated genes. A GT repeat polymorphism in the 7th intron of the IRF-1 gene was used as a marker to test for association with multiple sclerosis (MS) in a case-control study including individuals from Germany, Northern Italy and Sweden. In none of these populations, did we find any significant allelic association with disease. This lack of association was confirmed by testing transmission disequilibrium of individual IRF1 alleles in a representative sample of Sardinian simplex MS families. No deviation of the expected 50% transmission rates was seen. Therefore, our work does not provide evidence in favor of IRF1 being a candidate for conferring genetic susceptibility to, or protection against, MS in Europe.

An intronic dinucleotide polymorphism in the IFN-gamma gene (IFNG) was used as a marker for testing association with multiple sclerosis (MS). Disease association was analyzed in case-control sets sampled from four geographically separate European populations (Germany, Northern Italy, Sardinia, and Sweden). Only in the Swedish was a weak disease association of the IFNG allele pattern found, mainly due to a higher frequency of IFNG allele I1 in MS patients. No evidence for association was found in the German or Northern Italian populations. These results contrast with the situation in Sardinia. We have recently reported transmission disequilibrium of IFNG allele I2 in Sardinian MS siblings not carrying the predisposing DRB1 *03 or *04 alleles (Ann. Neurol. 44, 841-842, 1998). Further analysis now shows that I2 is significantly more often transmitted to DRB1 *03-/*04- males, than to DRB1 *03-/*04- females. The odds ratio (OR) for IFNG-associated susceptibility to MS in the total Sardinian DRB1*03-/*04- group was 1.88 for I2 heterozygotes but amounted to 8.235 for I2 homozygotes, suggestive of a recessive mode of inheritance. Score test-based statistics pointed to an I2 allele dosage effect acting in susceptibility. Comparison of the IFNG allele frequencies in seven European populations (Northern Finnish, Southern Finnish, Swedish, Danish, German, Italian, and Sardinian) revealed a highly different distribution pattern. We introduced latitude as a score variable in order to test for trend in binomial proportions. This test statistic showed that for both most common alleles, I1 and I2 (compiled allele frequency about 85%), a significant opposite north-to-south trend is seen throughout Europe. This effect is primarily due to the extreme values found in the outlier populations of Finland and Sardinia. Our findings are discussed with respect to recent literature pertinent to the role of the IFNG chromosome region in autoimmune diseases.