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Association of HLA class I markers with multiple sclerosis in the Italian and UK population: evidence of two independent protective effects
  1. Laura Bergamaschi1,
  2. Maria Ban2,
  3. Nadia Barizzone1,
  4. Maurizio Leone3,
  5. Daniela Ferrante4,
  6. Maria Edvige Fasano5,
  7. Franca R Guerini6,
  8. Lucia Corrado1,
  9. Paola Naldi3,
  10. Ennia Dametto5,
  11. Cristina Agliardi6,
  12. Marco Salvetti7,
  13. Rosella Mechelli7,
  14. Daniela Galimberti8,
  15. Elio Scarpini8,
  16. Paola Cavalla9,
  17. Valeria Bargiggia10,
  18. Domenico Caputo11,
  19. Susanna Cordera12,
  20. Francesco Monaco13,
  21. Patricia Momigliano-Richiardi1,
  22. Sandra D'Alfonso1
  1. 1Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy
  2. 2Department of Clinical Neuroscience, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
  3. 3Department of Neurology, A.O.U. Maggiore della Carità, IRCAD, Novara, Italy
  4. 4Department of Medical Sciences, Unit of Medical Statistics and Cancer Epidemiology, University of Eastern Piedmont and CPO Piemonte, Novara, Italy
  5. 5SCDU Transplantation Immunology, A.O.U. S. Giovanni Battista di Torino, Turin, Italy
  6. 6Laboratory of Molecular Medicine and Biotechnologies, Don C. Gnocchi Foundation IRCCS, S. Maria Nascente, Milan, Italy
  7. 7Neurology and Center for Experimental Neurological Therapy (CENTERS), Università La Sapienza, Rome, Italy
  8. 8Department of Neurological Sciences, University of Milan, Dino Ferrari Center, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
  9. 9Multiple Sclerosis Center, A.O.U. S. Giovanni Battista di Torino, Department of Neurosciences, University of Turin, Turin, Italy
  10. 10Multiple Sclerosis Center, Neurological Institute C. Mondino, IRCCS, Pavia, Italy
  11. 11Multiple Sclerosis Unit, Don C. Gnocchi Foundation, IRCCS, S. Maria Nascente, Milan, Italy
  12. 12Neurology, Ospedale Umberto Parini, Aosta, Italy
  13. 13Department of Neurology, A.O.U. Maggiore della Carità Novara, and Department of Clinical and Experimental Medicine, University of Eastern Piedmont, Novara, Italy
  1. Correspondence to Professor Sandra D'Alfonso, Department of Medical Sciences, Eastern Piedmont University, Via Solaroli 17, Novara 28100, Italy; dalfonso{at}


Background The association of HLA A*02 with multiple sclerosis (MS) was recently confirmed by the authors, and it was observed that the combined presence of HLA Cw*05 significantly enhanced (threefold) the protective effect of HLA A*02.

Objectives and methods Since A*02-Cw*05 is carried by two HLA extended haplotypes characterised by the B*4402 and B*1801 alleles, respectively, the association analysis was extended to HLA B*44 and B*18 in an Italian sample (1445 MS cases and 973 controls) and these associations were verified in a UK cohort (721 MS cases, 408 controls and 480 family trios).

Results A strong protective effect, independent of DR15, of the A*02-Cw*05 combination carrying B*44 (OR 0.27, p=3.3×10-5) was seen in the Italian samples and confirmed in UK family trios (OR 0.33, p=5.5×10-4) and in a combined cohort of UK families and case–controls (OR 0.53, p=0.044). This protective effect was significantly stronger than that mediated by A*02 alone. Logistic regression showed that A*02-Cw*05 maintained a significant protection when adjusted for B alleles (Italy: OR 0.38, p=6.5×10-7; UK: OR 0.60, p=0.0029), indicating that it was not secondary to linkage disequilibrium with B*44. Different from A*02, the other HLA class I tested markers individually showed no significant (Cw*05, B*18) or a modest (B*44) protection when adjusted for the remaining markers.

Conclusions This study identified at least two independent protective effects which are tagged by A*02–Cw*05 and A*02, respectively. Further studies are needed to elucidate whether this protective effect is due to the presence of an unanalysed factor characterising the HLA extended haplotype(s) carrying A*02 and Cw*05 or to a direct interaction between these alleles.

  • Multiple sclerosis
  • HLA class I markers
  • haplotypes
  • genetic association
  • molecular genetics
  • immunology (including allergy)
  • multiple sclerosis
  • neurosciences

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  • Funding NB and LC were supported by a fellowship from FISM (2003/B/2, 2009/B/1). LB was supported by a PhD Lagrange Fellowship.

  • Competing interests None to declare.

  • Ethics approval This study was conducted with the approval of the local ethics committee of the different clinical centres.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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