The role of HLA genes in familial spondyloarthropathy: a comprehensive study of 70 multiplex families.
OBJECTIVE
To investigate whether HLA alleles, other than HLA-B27, influence predisposition to spondyloarthropathy (SpA) in multiplex families.


METHODS
Seventy French families with at least two affected SpA members were recruited. Patients, and their first degree relatives were typed for HLA-A, B, C, and DR, and extended HLA haplotypes were determined. The distribution of HLA-A, C, and DR alleles carried on HLA-B27+ haplotypes in SpA families was compared with the distribution of these alleles among HLA-B27+ haplotypes in the French general population. Contribution to SpA susceptibility of HLA-A, B, C, and DR alleles, other than HLA-B27, was tested by transmission disequilibrium test. The contribution of HLA alleles to specific presentation features of SpA was examined.


RESULTS
Frequencies of HLA-A, C, and DR alleles carried on HLA-B27+ haplotypes from SpA families were comparable with those seen in the French population, except for DR13 which was overrepresented among patients (pcorr<0.001). Most interestingly, the HLA-DR4 allele was transmitted in excess to patients with SpA, independently of linkage to HLA-B27 (pcorr=0.05), and in a direction opposite to that for HLA-B27+ unaffected siblings (pcorr=0.01). Finally, the distribution of HLA alleles was not related to the presentation feature of SpA.


CONCLUSIONS
HLA predisposition to familial SpA appears not to be limited to HLA-B27, but some HLA-DR alleles also have a significant influence. In particular, HLA-DR4 contributes significantly to a genetic predisposition to SpA, which may have implications in our understanding of SpA pathogenesis.
Said-Nahal
R
R
Rheumatology Division, Cochin Hospital, AP-HP, Université René Descartes, Paris, France.
Miceli-Richard
C
C
Gautreau
C
C
Tamouza
R
R
Borot
N
N
Porcher
R
R
Charron
D
D
Dougados
M
M
Breban
M
M
D000328:Adult; D000483:Alleles; D016010:Binomial Distribution; D016009:Chi-Square Distribution; D016001:Confidence Intervals; D005260:Female; D005602:France; D006680:HLA Antigens / Q000235:genetics*; D015234:HLA-A Antigens / Q000235:genetics; D015796:HLA-B27 Antigen / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D015804:HLA-DR4 Antigen / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010375:Pedigree; D025242:Spondylarthropathies / Q000235:genetics*
D006680:HLA Antigens; D015234:HLA-A Antigens; D015796:HLA-B27 Antigen; D015236:HLA-C Antigens; D015804:HLA-DR4 Antigen