title: Association of HLA class I markers with multiple sclerosis in the Italian and UK population: evidence of two independent protective effects.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors: Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy.
authors: Laura
authors: L
authors: Bergamaschi
authors: Maria
authors: M
authors: Ban
authors: Nadia
authors: N
authors: Barizzone
authors: Maurizio
authors: M
authors: Leone
authors: Daniela
authors: D
authors: Ferrante
authors: Maria Edvige
authors: ME
authors: Fasano
authors: Franca R
authors: FR
authors: Guerini
authors: Lucia
authors: L
authors: Corrado
authors: Paola
authors: P
authors: Naldi
authors: Ennia
authors: E
authors: Dametto
authors: Cristina
authors: C
authors: Agliardi
authors: Marco
authors: M
authors: Salvetti
authors: Rosella
authors: R
authors: Mechelli
authors: Daniela
authors: D
authors: Galimberti
authors: Elio
authors: E
authors: Scarpini
authors: Paola
authors: P
authors: Cavalla
authors: Valeria
authors: V
authors: Bargiggia
authors: Domenico
authors: D
authors: Caputo
authors: Susanna
authors: S
authors: Cordera
authors: Francesco
authors: F
authors: Monaco
authors: Patricia
authors: P
authors: Momigliano-Richiardi
authors: Sandra
authors: S
authors: D'Alfonso
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D023061:Gene Order; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D006113:United Kingdom; D055815:Young Adult
chemical_list: D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I