Structure and polymorphism of the human gene for the interferon-induced p78 protein (MX1): evidence of association with alopecia areata in the Down syndrome region

Alopecia areata (AA) is a chronic inflammatory disease characterised by pat chy hair loss with T cell infiltration of hair follicles. AA occurs in appr oximately 0.1% of the general population, but this is increased to 9% in Do wn syndrome (DS). DS is associated with an additional copy (full or partial ) of chromosome 21, and the DS region may potentially include genes involve d in the pathogenesis of AA. MX1 is the gene encoding the interferon-induce d p78 protein (MxA). MxA protein confers resistance to influenza viruses, a nd we have previously shown that MxA protein is strongly expressed in lesio nal anagen hair bulbs from patients with AA bur not in normal follicles. We therefore studied the possible involvement of MX1 in the pathogenesis of A A. To establish markers in the MX1 region which could be screened by PCR-ba sed methods, we defined the human MX1 exon/intron organisation and screened the exons and the introns by conformation-sensitive gel electrophoresis. W e found that the MX1 gene contains 17 exons extending over 33 kb. The size and sequence of the region from exon 6 to exon 16 are highly conserved betw een human and mouse. Screening of 4747 bp within the MX1 gene revealed four single nucleotide polymorphisms in intron 6. These polymorphisms are conce ntrated within 147 bp and show strong linkage disequilibrium. In a case-con trol association study for the MX1 (+9959) polymorphism in 165 AA patients and 510 controls we found a significant association of this marker with AA (odds ratio 1.79, 95% CI 1.21-2.66, chi(2)=8.464, P=0.0036). The risk of di sease was greater for patchy AA (mild disease) and with early age at onset (odds ratio 2.34, 95% CI 1.24-4.43, P=0.0072), providing new evidence of ge netic heterogeneity in AA. Our demonstration of genetic association between the MX1 gene and disease supports the hypothesis that this is a new candid ate gene in AA.