Linkage Analysis of Human Leukocyte Antigen (HLA) Markers in Familial Psoriasis: Strong Disequilibrium Effects Provide Evidence for a Major Determinant in the HLA-B/-C Region

Abstract

Although psoriasis is strongly associated with certain human leukocyte antigens (HLAs), evidence for linkage to HLA markers has been limited. The objectives of this study were (1) to provide more definitive evidence for linkage of psoriasis to HLA markers in multiplex families; (2) to compare the major HLA risk alleles in these families with those determined by previous case-control studies; and (3) to localize the gene more precisely. By applying the transmission/disequilibrium test (TDT) and parametric linkage analysis, we found evidence for linkage of psoriasis to HLA-C, -B, -DR, and -DQ, with HLA-B and -C yielding the most-significant results. Linkage was detectable by parametric methods only when marker-trait disequilibrium was considered. Case-control association tests and the TDT identified alleles belonging to the EH57.1 ancestral haplotype as the major risk alleles in our sample. Among individuals carrying recombinant ancestral haplotypes involving EH57. 1, the class I markers were retained selectively among affecteds four times more often than among unaffecteds; among the few affected individuals carrying only the class II alleles from the ancestral haplotype, all but one also carried Cw6. These data show that familial and "sporadic" psoriasis share the same risk alleles. They also illustrate that substantial parametric linkage information can be extracted by accounting for linkage disequilibrium. Finally, they strongly suggest that a major susceptibility gene resides near HLA-C.

Strong associations of psoriasis with antigen processing LMP and transport genes TAP differ by gender and phenotype

“…Consequently, presenting human leukocyte antigen (HLA) genes, notably HLA-Cw*0602, belong to the identified susceptibility genes of psoriasis. 3 Antigen presentation is essentially dependent on the proteasome, an intracellular protease complex catalyzing important steps in the breakdown of proteins to peptides to be presented as antigens. The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure.…”

Combined segregation and linkage analysis of HLA markers in familial psoriasis

“…36 This ancestral haplotype is known to be markedly increased in frequency in psoriasis (Table 2). 11,12,37 However, other alleles also contributed to the final lod scores, as shown graphically for HLA-B and HLA-C in Figure 3. Most of the B alleles identified by MBSA corresponded to HLA-B/-C haplotypes known to carry Cw6.…”

“…All of these cohorts have been described. 11 Some of their characteristics are presented in Table 1.…”

“…10 Here we outline the theoretical basis of MBSA, present a Monte Carlo method for evaluating the significance of the results, and utilize the method to analyse HLA marker data collected from multiplex families manifesting psoriasis, an inflammatory and hyperproliferative skin disease. 11,12 It has long been appreciated that psoriasis displays strong familial aggregation, with one of the highest heritabilities of any complex genetic disorder (60 ± 90%) 13 and sibling recurrence risks l s of approximately 10. 14 Genome scans have provided suggestive evidence for linkage of psoriasis to HLA as well as several non-HLA loci; 15 ± 20 the HLA-linked locus has been designated PSORS1.…”

“…15,16,20 We subsequently showed that the evidence for linkage to HLA is markedly increased when linkage disequilibrium information is taken into account. 11,12 Recently, PSORS1 has been fine-mapped to the vicinity of HLA-C by linkage disequilibrium mapping. 22,23 We have further refined this interval to an approximately 60 kb interval residing 30 to 90 kb telomeric to HLA-C (MHC).…”