Carlo Sidore1, Valeria Orrù1, Eleonora Cocco2, Maristella Steri1, Jamie Rj Inshaw3, Maristella Pitzalis1, Antonella Mulas1, Stuart McGurnaghan4, Jessica Frau2, Eleonora Porcu5, Fabio Busonero1, Mariano Dei1, Sandra Lai1, Gabriella Sole1, Francesca Virdis1, Valentina Serra1, Fausto Poddie6, Alessandro Delitala7, Michele Marongiu1, Francesca Deidda1, Mauro Pala1, Matteo Floris6, Marco Masala1, Suna Onengut-Gumuscu8, Catherine C Robertson8, Lidia Leoni9, Annapaola Frongia10, Maria Rossella Ricciardi11, Margherita Chessa12, Nazario Olla1, Mario Lovicu1, Annalisa Loizedda1, Andrea Maschio1, Luisa Mereu13, Paola Ferrigno14, Nicolo Curreli1, Lenuta Balaci1, Francesco Loi1, Liana Ap Ferreli1, Maria Grazia Pilia1, Antonello Pani15, Maria Giovanna Marrosu2, Goncalo R Abecasis16, Stephen S Rich8, Helen Colhoun4, John A Todd3, David Schlessinger17, Edoardo Fiorillo1, Francesco Cucca18, Magdalena Zoledziewska1. 1. Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Monserrato, Italy. 2. Department of Medical Sciences and Public health, Multiple Sclerosis Centre, University of Cagliari, Cagliari, Italy. 3. JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Oxford, UK/Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, Oxford, UK. 4. Diabetes Medical Informatics and Epidemiology, The University of Edinburgh, Edinburgh, Scotland. 5. Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland/Swiss Institute of Bioinformatics, Lausanne, Switzerland. 6. Department of Biomedical Sciences, University of Sassari, Sassari, Italy. 7. Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Monserrato, Italy/Department of Surgical, Medical and Experimental Sciences, University of Sassari, Sassari, Italy. 8. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. 9. Center for Advanced Studies, Research and Development in Sardinia (CRS4), Parco Scientifico e Tecnologico della Sardegna, Pula, Italy. 10. Unit of Paediatric Diabetes, Brotzu Hospital, Cagliari, Italy. 11. Diabetologia Pediatrica, Azienda Ospedaliera G. Brotzu, Cagliari, Italy. 12. Struttura Complessa di Pediatria, Azienda Ospedaliera G. Brotzu, Cagliari, Italy. 13. Unità Operativa di Pediatria, Ospedale San Martino di Oristano, Oristano, Italy. 14. Reparto di Neurologia, Azienda Ospedaliera G. Brotzu, Cagliari, Italy. 15. Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Monserrato, Italy/Struttura Complessa di Nefrologia e Dialisi, Azienda Ospedaliera G. Brotzu, Cagliari, Italy. 16. Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA. 17. Laboratory of Genetics and Genomics, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD, USA. 18. Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Monserrato, Italy/Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
Abstract
BACKGROUND: Defective alleles within the PRF1 gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines-cytokine storm. OBJECTIVE: The aim of this study was to determine the function of hypomorph PRF1:p.A91V g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D). METHODS: We cross-compare the association data for PRF1:p.A91V mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians. RESULTS: We report that PRF1:p.A91V, is associated with increase of lymphocyte levels, especially within the cytotoxic memory T-cells, at general population level with reduced interleukin 7 receptor expression on these cells. The minor allele increased risk of MS, in 2903 cases and 2880 controls from Sardinia p = 2.06 × 10-4, odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D p = 1.04 × 10-5, OR = 0.82. CONCLUSION: Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis.
BACKGROUND: Defective alleles within the PRF1 gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines-cytokine storm. OBJECTIVE: The aim of this study was to determine the function of hypomorph PRF1:p.A91V g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D). METHODS: We cross-compare the association data for PRF1:p.A91V mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians. RESULTS: We report that PRF1:p.A91V, is associated with increase of lymphocyte levels, especially within the cytotoxic memory T-cells, at general population level with reduced interleukin 7 receptor expression on these cells. The minor allele increased risk of MS, in 2903 cases and 2880 controls from Sardinia p = 2.06 × 10-4, odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D p = 1.04 × 10-5, OR = 0.82. CONCLUSION: Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis.
Authors: M Clementi; P Forabosco; A Amadori; R Zamarchi; G De Silvestro; E Di Gianantonio; L Chieco-Bianchi; R Tenconi Journal: Hum Genet Date: 1999-10 Impact factor: 4.132
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Authors: Jeffrey C Barrett; David G Clayton; Patrick Concannon; Beena Akolkar; Jason D Cooper; Henry A Erlich; Cécile Julier; Grant Morahan; Jørn Nerup; Concepcion Nierras; Vincent Plagnol; Flemming Pociot; Helen Schuilenburg; Deborah J Smyth; Helen Stevens; John A Todd; Neil M Walker; Stephen S Rich Journal: Nat Genet Date: 2009-05-10 Impact factor: 38.330