B4.6 GENETIC ANALYSIS OF HLA-DR/-DQ/NOTCH4/-B IN ALOPECIA AREATA REVEALS MORE THAN ONE SUSCEPTIBILITY HAPLOTYPE WITHIN THE MHC REGION

D. Wengraf, A. Cox,  M.J. Cork, D.J. Gawkrodger, M.P. Birch, A.G. Messenger, A.J.G. McDonagh, R. Tazi-Ahnini

Division of Genomic Medicine, Royal Hallamshire Hospital, University of Sheffield, Sheffield S10 2RX, UK. Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF

The most robust genetic associations reported for alopecia areata have been with loci of the major histocompatability complex, but the pathogenetic significance of the MHC genes studied to date remains uncertain.  Linkage disequilibrium makes genetic analysis particularly difficult in this region of the genome. To refine the MHC associations in alopecia areata, we have performed a wider analysis than previous studies, examining variation at the HLA-B, HLA-DQ, HLA-DR and NOTCH4 loci together in 398 patients and 432 healthy controls.

HLA-B alleles showed the strongest genetic association (p<4x10^-12) with alopecia areata both overall and on subdividing the patients by disease severity. HLAB*35, in particular was associated with disease while B8 appeared to be protective against alopecia areata. We confirmed previous studies showing strong HLA-DQ associations (p<0.001), especially with DQ*03. Other HLA-DQ alleles especially DQ*04, *05 and *06 appeared to be protective. There was also a differential association with NOTCH4 (+1297) according to severity of the disease (patchy alopecia areata vs alopecia universalis). Haplotype analysis indicated that the disease-associated HLA-DQ and -DR alleles are not carried on the same haplotype as HLA-B alleles and there appears to be a breakpoint between disease-associated haplotypes carrying the HLA-DQ-DR components and those carrying the HLA-B genes located within the sequence of NOTCH4 itself. In addition, we identified haplotype blocks containing NOTCH4 (+1297) and (+3063) SNPs and HLA-B, in which B*35 and B8 are susceptibility and protective alleles for disease respectively.

These data demonstrate that there is more than one susceptibility haplotype for alopecia areata within the MHC. In addition, these haplotypes appear to be important in determining disease severity.