Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.

By R. Nair, P. Stuart, I. Nistor, R. Hiremagalore, N. Chia, S. Jenisch, M. Weichenthal, Gonçalo R. Abecasis, H. Lim, E. Christophers and 2 more. American Journal of Human Genetics, 2006

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Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an approximately 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/1ea4dbe02ce934b978ce75b8356a7d18a04749f1

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In Immunology

1. J. Krueger
2. Frank O. Nestle
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4. Peter Parham
5. M. Lebwohl
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Citations in the corpus

• A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1 (2010, background): “Large-scale resequencing has established HLA-C as the most likely PSORS1 candidate gen”
• Pathogenesis and therapy of psoriasis (2007, background): “A consensus is now beginning to emerge that supports the location of PSORS1 as being closer to the region harbouring HLA-C/HLA-B and excluding CDSN and HCR”
• Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. (2008, background): “Detailed genetic mapping studies demonstrate that the HLA-Cw6 allele, also known as PSORS1, is the major susceptibility gene for psoriasis.(72) In addition, a number of environmental factors play an important role in the pathogenesis of psoriasis including drugs, skin trauma (Koebner’s phenomenon), ”
• Psoriasis Pathogenesis and Treatment (2019, background): “HLA-Cw6 is strongly linked to early and acute onset psoriasis [90,91].”
• Nomenclature for factors of the HLA system, 2010 (2010, background): “B*RA 29037 AJ288980 B*49:04 B*4904 — — 14319 AJ969238 (237) B*49:05 B*4905 B49(21) — 147554 AM076839 (238) B*49:06 B*4906 — — HN-02488-5 FJ346280 Histogenetics B*49:07 B*4907 B47 — CTM-8004574 GQ454860 (239) B*49:08 B*4908 — — HN-32306-0 FJ765964 Histogenetics B*49:09 B*4909 — — HN-50261-4 FJ765969 ”