Association of HLA class I markers with Multiple Sclerosis in the Italian and UK population: evidence of two independent protective effects

Laura Bergamaschi (1) , Maria Ban (2) , Nadia Barizzone (3) , Maurizio Leone (4) , Maria Edvige Fasano (5) , Franca R Guerini (6) , Lucia Corrado (4) , Paola Naldi (4) , Ennia Dametto (5) , Cristina Agliardi (6) , Marco Salvetti (7) , Rosella Mechelli (7) , Daniela Galimberti (8) , Elio Scarpini (8) , Paola Cavalla (9) , Valeria Bargiggia (10) , Domenico Caputo (11) , Susanna Cordera (12) , Francesco Monaco (13) , Patricia Momigliano-Richiardi (4) , Sandra d'Alfonso (4)

1 University of eastern piedmont of Novara
2 Addenbrooke's Hospital
3 University of Eastern Piedmont, Department of Medical Sciences, IRCAD, Novara
4 Department of Neurology, A.O.U. Maggiore della Carità, and IRCAD, Novara
5 Transplantation Immunology, A.O.U. S. Giovanni Battista di Torino
6 Laboratory of Molecular Medicine and Biotechnologies, Don C. Gnocchi Foundation IRCCS, Milan
7 Neurology and Center for Experimental Neurological Therapy (CENTERS), Università La Sapienza, Rome
8 Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico
9 UNITO - Università degli studi di Torino = University of Turin
10 9Multiple Sclerosis Center, Neurological Institute C. Mondino, IRCCS, Pavia
11 Sclerosis Unit, Don C. Gnocchi Foundation, IRCCS, S. Maria Nascente, Milan
12 Neurology, Ospedale Umberto Parini, Aosta
13 Department of Neurology, Ospedale Maggiore, University of Eastern Piedmont,Novara

Background: We recently confirmed the association with Multiple Sclerosis (MS) of HLA-A*02 and observed that the combined presence of HLA-Cw*05 significantly enhanced (3-fold) the protective effect of HLA A*02. Objectives and Methods: Since A*02-Cw*05 is carried by two HLA extended haplotypes characterized by the B*4402 and B*1801 alleles, respectively, we extended the association analysis to HLA-B*44 and -B*18 in our Italian sample (1445 MS cases and 973 controls) and verified these associations 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=3.3x10-5), was seen in the Italian samples and confirmed in UK family trios (OR=0.33 p=5.5x10-4) 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=6.5x10-7; UK: OR=0.60 p=0.0029) indicating that it was not secondary to linkage disequilibrium with B*44. At difference 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: We 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 unanalyzed factor characterizing the HLA extended haplotype/s carrying A*02 and Cw*05 or to a direct interaction between these alleles

Mots clés: Molecular genetics; Immunology (including allergy); Multiple sclerosis; Neurosciences

Laura Bergamaschi, Maria Ban, Nadia Barizzone, Maurizio Leone, Maria Edvige Fasano, et al.. Association of HLA class I markers with Multiple Sclerosis in the Italian and UK population: evidence of two independent protective effects. Journal of Medical Genetics, 2011, 48 (7), pp.485. ⟨10.1136/jmg.2010.080721⟩. ⟨hal-00616879⟩