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Variations of the perforin gene in patients with multiple sclerosis

Genes & Immunity volume 9, pages 438–444 (2008)Cite this article

Abstract

Perforin is involved in cell-mediated cytotoxicity and mutations of its gene (PRF1) cause familial hemophagocytic lymphohistiocytosis (FLH2). PRF1 sequencing in 190 patients with multiple sclerosis and 268 controls detected two FLH2-associated variations (A91V, N252S) in both groups and six novel mutations (C999T, G1065A, G1428A, A1620G, G719A, C1069T) in patients. All together, carriers of these variations were more frequent in patients than in controls (phenotype frequency: 17 vs 9%, P=0.0166; odds ratio (OR)=2.06, 95% confidence interval (CI): 1.13–3.77). Although A91V was the most frequent variation and displayed a trend of association with multiple sclerosis (MS) in the first population of patients and controls (frequency of the 91V allele: 0.076 vs 0.043, P=0.044), we used it as a marker to confirm PRF1 involvement in MS and assessed its frequency in a second population of 966 patients and 1520 controls. Frequency of the 91V allele was significantly higher in patients than in controls also in the second population (0.075 vs 0.058%, P=0.019). In the combined cohorts of 1156 patients and 1788 controls, presence of the 91V allele in single or double dose conferred an OR=1.38 (95% CI=1.10–1.74). These data suggest that A91V and possibly other perforin variations indicate susceptibility to MS.

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Acknowledgements

This work was partially supported by FISM grant 2005/R/10 (Genoa), Telethon grant E1170 (Rome), AIRC (Milan), PRIN Project (MIUR, Rome), Compagnia di San Paolo (Turin), Fondazione Cassa di Risparmio di Cuneo (Cuneo), Regione Piemonte (Ricerca Sanitaria Finalizzata Project and Ricerca Sanitaria Applicata-CIPE Project), Associazione ‘Amici di Jean’ (Turin), Fondazione Lagrange (Turin) and Centro Dino Ferrari (Milan).

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  1. G Cappellano and E Orilieri: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases, A Avogadro University of Eastern Piedmont, Novara, Italy

    G Cappellano, E Orilieri, A Chiocchetti, S Bocca, E Boggio, I S Bernardone, R Clementi, N Barizzone, S D'Alfonso, L Corrado, M Leone, F Monaco & U Dianzani

  2. Department of Neurology, A Avogadro University of Eastern Piedmont, Novara, Italy

    C Comi, M Leone & F Monaco

  3. Neurorehabilitation Center, ML Novarese, Moncrivello, Italy

    C Comi

  4. Division of Pediatric Hematology/Oncology, Laboratory of Transplant Immunology, IRCCS Policlinico San Matteo, Pavia, Italy

    A Cometa

  5. Department of Neurological Sciences, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy

    D Galimberti & E Scarpini

  6. Laboratory of Molecular Medicine and Biotechnology, Don C Gnocchi Foundation ONLUS, IRCCS, Milan, Italy

    F R Guerini

  7. Multiple Sclerosis Unit, Don C Gnocchi Foundation ONLUS, IRCCS, Milan, Italy

    D Caputo

  8. Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy

    D Paolicelli & M Trojano

  9. Neurological Center of Experimental Therapy, University of Rome, La Sapienza, S Andrea Hospital, Rome, Italy

    L Figà-Talamanca & M Salvetti

  10. Neurology Division, S Croce e Carle Hospital, Cuneo, Italy

    F Perla

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Cappellano, G., Orilieri, E., Comi, C. et al. Variations of the perforin gene in patients with multiple sclerosis. Genes Immun 9, 438–444 (2008). https://doi.org/10.1038/gene.2008.35

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