PERB11 (MIC): a polymorphic MHC gene is expressed in skin and single nucleotide polymorphisms are associated with psoriasis

Abstract

The susceptibility genes for psoriasis remain to be identified. At least one of these must be in the major histocompatibility complex (MHC) to explain associations with alleles at human leucocyte antigen (HLA)-A, -B, -C, -DR, -DQ and C4. In fact, most of these alleles are components of just two ancestral haplotypes (AHs) designated 13.1 and 57.1. Although relevant MHC gene(s) could be within a region of at least 4 Mb, most studies have favoured the area near HLA-B and -C. This region contains a large number of non-HLA genes, many of which are duplicated and polymorphic. Members of one such gene family, PERB11.1 and PERB11.2, are expressed in the skin and are encoded in the region between tumour necrosis factor and HLA-B. To investigate the relationship of PERB11.1 alleles to psoriasis, sequence based typing was performed on 97 patients classified according to age of onset and family history. The frequency of the PERB11.1*06 allele is 44% in type I psoriasis but only 7% in controls (Pc = 0.003 by Fisher's exact test, two-tailed). The major determinant of this association is a single nucleotide polymorphism (SNP) within intron 4. In normal and affected skin, expression of PERB11 is mainly in the basal layer of the epidermis including ducts and follicles. PERB11 is also present in the upper keratin layers but there is relative deficiency in the intermediate layers. These findings suggest a possible role for PERB11 and other MHC genes in the pathogenesis of psoriasis.

Fig. 1

PERB11.1 is polymorphic. The nucleotide sequence of the PERB11.1*06 allele (intron 4 and exon 5) is presented. Seven PERB11.1 alleles are compared to the PERB11.1*06 sequence. Identical residues are denoted with a ‘dot’ and deletions are indicated by dashes. Note that the frameshift in exon 5 leads to a premature termination (TAA). Two single indels (one each in intron 4 and exon 5) and various lengths of trinucleotides are present. PERB11.1*06 and *07 are identical in the transmembrane region but differ elsewhere.

Fig. 2

Type I psoriasis is associated with a specific SNP profile corresponding to PERB11.1*06 sequence. Different PERB11.1 sequences of intron 4 and exon 5 were compared. Single nucleotide polymorphisms (SNPs) were assigned (see Fig. 1). There are seven markers in total consisting of two insertions (deletions), four substitutions and one GCT expansion. A SNP profile was constructed for each individual. At each SNP position, the genotype is indicated. For example, the last five individuals in the control group are homozygous for each of the seven SNPs (insertions at positions I4.2 and E5.161, C at I4.18, G at I4.33, T at E5.206, C at E5.210 and five GCTs corresponding to the PERB11.1*01 sequence). Evidence for the co-occurence of specific SNPs is evident. Note the pattern for I4.2, I4.33, E5.206 and E5.210 whereas E5.161 is essentially independent. Nine GCTs occur with C at 206 and T at 210. The deletion at position 2 occurs with nine GCT monomers giving a specific profile (PERB11.1*06—see Fig. 1). However, not all nine GCTs include this deletion (PERB11.1*07). The distribution pattern of the PERB11.1 genotypes in controls is compared to three patient groups. The proportion of the different genotypes in the control group is similar to the pattern observed in type II psoriasis. In contrast, the distribution pattern in Type I patients differs. Specifically, the PERB11.1*06 SNP profile is increased in type I psoriasis. Seven percent of the controls carried this specific profile whereas 44% of type I psoriasis pateints carry this profile (RR = 10.6 with P_c = 0.003 by Fisher's exact test, two-tailed). In the unclassifiable patients, the distribution of the PERB11.1 profiles is intermediate.

Fig. 3

Skin (human) at × 250 magnification. Indirect immunofluorescence with serum from a rabbit immunized with PERB11–5D peptide showing bright staining specific to the cytoplasm of cells in the first two layers of the basal epidermis.