Variants Within the Immunoregulatory CBLB Gene Are Associated with Multiple Sclerosis

Overview

Journal Nat Genet

Specialty Genetics

Date 2010 May 11

PMID 20453840

Citations 98

Authors

Serena Sanna

Maristella Pitzalis

Magdalena Zoledziewska

Ilenia Zara

Carlo Sidore

Raffaele Murru

Michael B Whalen

Fabio Busonero

Andrea Maschio

Gianna Costa

Maria Cristina Melis

Francesca Deidda

Fausto Poddie

Laura Morelli

Gabriele Farina

Yun Li

Mariano Dei

Sandra Lai

Antonella Mulas

Gianmauro Cuccuru

Eleonora Porcu

Liming Liang

Patrizia Zavattari

Loredana Moi

Elisa Deriu

M Francesca Urru

Michele Bajorek

Maria Anna Satta

Eleonora Cocco

Paola Ferrigno

Stefano Sotgiu

Maura Pugliatti

Sebastiano Traccis

Andrea Angius

Maurizio Melis

Giulio Rosati

Goncalo R Abecasis

Manuela Uda

Maria Giovanna Marrosu

David Schlessinger

Francesco Cucca

Affiliations

Soon will be listed here.

Abstract

A genome-wide association scan of approximately 6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 x 10(-10), OR = 1.40). CBLB encodes a negative regulator of adaptive immune responses, and mice lacking the ortholog are prone to experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis.

Citing Articles

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References

Schmitz M . Activation of T cells: releasing the brakes by proteolytic elimination of Cbl-b. Sci Signal. 2009; 2(76):pe38. DOI: 10.1126/scisignal.276pe38. View

Pugliatti M, Rosati G, Carton H, Riise T, Drulovic J, Vecsei L . The epidemiology of multiple sclerosis in Europe. Eur J Neurol. 2006; 13(7):700-22. DOI: 10.1111/j.1468-1331.2006.01342.x. View

Dixon A, Liang L, Moffatt M, Chen W, Heath S, Wong K . A genome-wide association study of global gene expression. Nat Genet. 2007; 39(10):1202-7. DOI: 10.1038/ng2109. View

Loeser S, Penninger J . Regulation of peripheral T cell tolerance by the E3 ubiquitin ligase Cbl-b. Semin Immunol. 2007; 19(3):206-14. DOI: 10.1016/j.smim.2007.02.004. View

Chiang Y, Kole H, Brown K, Naramura M, Fukuhara S, Hu R . Cbl-b regulates the CD28 dependence of T-cell activation. Nature. 2000; 403(6766):216-20. DOI: 10.1038/35003235. View

. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet. 2009; 41(7):824-8. DOI: 10.1038/ng.396. View

Yokoi N, Komeda K, Wang H, Yano H, Kitada K, Saitoh Y . Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet. 2002; 31(4):391-4. DOI: 10.1038/ng927. View

Kojo S, Elly C, Harada Y, Langdon W, Kronenberg M, Liu Y . Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1. Proc Natl Acad Sci U S A. 2009; 106(42):17847-51. PMC: 2764888. DOI: 10.1073/pnas.0904078106. View

Li Y, Willer C, Sanna S, Abecasis G . Genotype imputation. Annu Rev Genomics Hum Genet. 2009; 10:387-406. PMC: 2925172. DOI: 10.1146/annurev.genom.9.081307.164242. View

10.

Jeon M, Atfield A, Venuprasad K, Krawczyk C, Sarao R, Elly C . Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity. 2004; 21(2):167-77. DOI: 10.1016/j.immuni.2004.07.013. View

11.

De Jager P, Jia X, Wang J, de Bakker P, Ottoboni L, Aggarwal N . Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet. 2009; 41(7):776-82. PMC: 2757648. DOI: 10.1038/ng.401. View

12.

Qiao G, Lei M, Li Z, Sun Y, Minto A, Fu Y . Negative regulation of CD40-mediated B cell responses by E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-B. J Immunol. 2007; 179(7):4473-9. DOI: 10.4049/jimmunol.179.7.4473. View

13.

Hafler D, Compston A, Sawcer S, Lander E, Daly M, De Jager P . Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med. 2007; 357(9):851-62. DOI: 10.1056/NEJMoa073493. View

14.

Marrosu M, Murru R, Murru M, Costa G, Zavattari P, Whalen M . Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. Hum Mol Genet. 2001; 10(25):2907-16. DOI: 10.1093/hmg/10.25.2907. View

15.

Bachmaier K, Krawczyk C, Kozieradzki I, Kong Y, Sasaki T, Mariathasan S . Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature. 2000; 403(6766):211-6. DOI: 10.1038/35003228. View