O#14   The MHC in Alopecia Areata : Novel Association with non-HLA Gene Notch 4

A.J.G. McDonagh, M.J. Cork, A.G. Messenger, D.J. Gawkrodger, A.G. Wilson, R. Tazi-Ahnini. Dept of Dermatology & Div. of Genomic Medicine, Royal Hallamshire Hospital, University of Sheffield, Sheffield, UK

Alopecia areata (AA) is a disorder primarily affecting hair and nails in which associated autoimmune or atopic disease is common. Genetically, it is a complex trait with a possible role in the pathogenesis for genes of the MHC, the interleukin-1 cluster and the chromosome 21q22 region. Several studies have shown association with the HLA class II region in AA, the strongest being with HLA-DRQB1*0302 and DRB1*04 alleles. Whether these contribute pathogenetically or show association through linkage disequilibrium with nearby disease genes is unknown. Notch 4 is located approximately 350 kb telomeric to HLA DRB1 locus and Notch pathway signalling is a direct determinant of keratinocyte growth arrest and entry into differentiation. A possible role for Notch in hair growth was indicated by transgenic mouse findings that Notch activation in hair cortex leads to aberrant differentiation of adjacent hair-shaft layers. We have therefore examined Notch 4 as a candidate gene for AA.
The allelic distribution of two exonic Notch 4 polymorphisms (+1297 and +3063) was analysed in 56 AA patients and 211 ethnically matched healthy control subjects. No association was found between disease overall or any subtype and the Notch 4+1297 variant. However, there was a strong association of AA with the Notch 4+3063 polymorphism (OR 1.97 [95% ci 1.22, 3.20]; p=0.0055). This effect was most pronounced in mild disease (patchy AA) (OR 2.40 [1.12, 5.15]; p=0.0212). Moreover, the rare allele of the Notch 4 +3063 is less frequent in patients with disease of late onset (0.20 patients vs 0.34 controls). This allele seems to decrease the risk developing AA late in life. This association of Notch 4 with AA reopens the question of what role is played by HLA genes in the pathogenesis.