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N Engl J Med. 2017 Apr 27;376(17):1615-1626. doi: 10.1056/NEJMoa1610528.

Overexpression of the Cytokine BAFF and Autoimmunity Risk.

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From Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (M.S., V.O., M.L.I., M. Pitzalis, M. Pala, C.S., V.F., M.F., M. Deiana, I.A., E.P., A. Mulas, M.G.P., M. Lobina, S.L., Mara Marongiu, V.S., Michele Marongiu, G.S., F.B., A. Maschio, F.D., M. Dei, F.V., S.O., A.A., M.B.W., A. Meloni, S. Sanna, E.F., M.Z., F.C.), Center for Advanced Studies, Research, and Development in Sardinia, Parco Scientifico e Tecnologico della Sardegna (I.Z., M.F., R.C., G. Cuccuru), Struttura Complessa Disciplina di Ematologia e Centro Trapianto Cellule Staminali Emopoietiche Wilma Deplano, Ospedale Oncologico di Riferimento Regionale Armando Businco (M. Pani), Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università di Cagliari (E.C., J.F., G. Coghe, L.L., G. Fenu), Azienda Ospedaliera Brotzu, S.C. Neurologia (P.F., M. Melis), Division of Rheumatology, University and University Hospital of Cagliari (M. Piga, A. Mathieu), Department of Medical Sciences M. Aresu, University of Cagliari (D.F., S.D.G., M.G.M.), Azienda Ospedaliera Brotzu, U.S. Gastroenterologia Pediatrica Ospedale Pediatrico Microcitemico A. Cao (M.C.), and Nephrology, Dialysis, and Transplantation Unit, Giuseppe Brotzu Hospital (A.P.), Cagliari, Dipartimento di Scienze Biomediche, Università degli Studi di Sassari (M.F., F.P., F.C.), Unit of Neurology, Department of Clinical and Experimental Medicine, University of Sassari (G. Farina, G.R.), and Servizio Trasfusionale (M.A.S.) and Clinica Medica (A.D.), Azienda Ospedaliero Universitaria di Sassari, Sassari, Neurology B, Department of Neurological, Biomedical, and Movement Sciences, University of Verona, Verona (G. Farina), Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont, Novara (N.B., S.D.), SC Neurologia, Dipartimento di Scienze Mediche, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo (M. Leone), Don C. Gnocchi Foundation IRCCS (F.R.G.), and Referral Center for Systemic Autoimmune Diseases Fondazione IRCCS Cá Granda Ospedale Maggiore Policlinico and University of Milan (M. Marchini), Milan, and Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche e Ospedali Riuniti, Ancona (M.G.D.) - all in Italy; Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore (M.L.I., M.G., D.S.); the Department of Clinical Neurosciences (M.B., S. Sawcer) and JDRF-Wellcome Trust Diabetes and Inflammation Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Institute for Medical Research (J.A.T.), University of Cambridge, Cambridge, United Kingdom; Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital Solna (I.K., I.L.B., T.O., J.H.), Institute of Environmental Medicine (L.A.) and Institute of Environmental Medicine, Unit of Immunology and Chronic Disease (M.E.A.R.), Karolinska Institute, and Center for Occupational and Environmental Medicine, Stockholm County Council (L.A.), Stockholm; Department of Functional Biology, University of Oviedo, Oviedo (A.S.), Rheumatology Department, Hospital Universitario 12 de Octubre, Madrid (P.E.C.), Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Seville (M.J.C.-P.), Laboratorio de Investigacion 10 and Rheumatology Unit, Instituto de Investigacion Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela (A.G.), and Centro de Genómica e Investigación Oncológica, Pfizer-Universidad de Granada-Junta de Andalucía, Granada (M.E.A.R.) - all in Spain; Department of Human Genetics, University of Chicago, Chicago (J.H.M., J.N.); Centro Hospitalar do Porto-Hospital Santo Antonio and Unit for Multidisciplinary Research in Biomedicine-Unidade Multidisciplinar de Investigação Biomédica, Porto, Portugal (B.M.S.); Departments of Pathology and Genetics, Stanford University, Stanford, CA (S.B.M.); and Center for Statistical Genetics, University of Michigan, Ann Arbor (G.R.A.).



Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways.


Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated.


A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria.


A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).

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