Comparative association analysis reveals that corneodesmosin is more closely associated with psoriasis than HLA-Cw*0602-B*5701 in German families

HLA antigens are associated with psoriasis vulgaris across populations with different ethnic background, We have previously shown that in Caucasians t his association is primarily based on the class I alleles of the extended H LA haplotype 57.1 (EH57.1/I), HLA-Cw6-HLA-B57, However, it remained unclear whether HLA-Cw6 itself or a closely linked locus predisposes to the diseas e. An interesting candidate for this presumed locus is corneodesmosin, whic h is exclusively synthesized in keratinocytes. The corneodesmosin gene locu s (CDSN) is only 160 kb telomeric to HLA-C and tightly associated with psor iasis. in order to find out whether EH57.1/I or a corneodesmosin variant ar e the susceptibility determinants on 6p, HLA class I alleles and single-nuc leotide polymorphisms (SNPs) of corneodesmosin were investigated at the seq uence level and analyzed by comparative association tests. Transmission dis equilibrium tests (TDT) were performed in 52 nuclear families, of which 36 were fully informative for a joint comparison of HLA and CDSN with regard t o association to psoriasis, The extended TDT according to Wilson was employ ed to test for locus interaction. Using the HLA haplotype EH57.1/I and the CDSN haplotype formed by three intragenic variant sites at nt=619 (T), 1236 (T), and 1243 (C), we obtained the best resolution of parental transmissio n to index cases in the trio families. On direct comparison of the contribu tions of the HLA and the CDSN haplotypes, there was a markedly stronger ass ociation of the corneodesmosin TTC haplotype, which is not apparent in sing le locus analysis. We show furthermore that there is no higher order intera ction between psoriasis, HLA, and CDSN. This lack of three-locus interactio n is suggestive of two independent genetic contributions to psoriasis withi n the major histocompatibility complex (MHC).