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PMID: 16642438 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

American journal of human genetics ·Vol. 78 ·No. 5 ·2006-05-00 ·Pages 827-851

Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NVC, Jenisch S, Weichenthal M, Abecasis GR, Lim HW, Christophers E, Voorhees JJ, Elder JT

Abstract

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.

MeSH Terms
Adult Base Sequence Cluster Analysis Cohort Studies Gene Frequency Genetic Predisposition to Disease Glycoproteins/genetics HLA-C Antigens/genetics Haplotypes Humans Intercellular Signaling Peptides and Proteins Pedigree Polymorphism, Genetic Proteins/genetics Psoriasis/genetics RNA Splicing Risk Transcription, Genetic
Chemicals
CDSN protein, human Glycoproteins HLA-C Antigens Intercellular Signaling Peptides and Proteins PSORS1C1 protein, human Proteins
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Nair Rajan P
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Stuart Philip E
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Nistor Ioana
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Hiremagalore Ravi
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Chia Nicholas V C
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Jenisch Stefan
Department of Immunology, University of Kiel, Kiel, Germany.
Weichenthal Michael
Department of Dermatology, University of Kiel, Kiel, Germany.
Abecasis Gonçalo R
Center for Statistical Genetics, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor.
Lim Henry W
Department of Dermatology, Henry Ford Hospital, Detroit.
Christophers Enno
Department of Dermatology, University of Kiel, Kiel, Germany.
Voorhees John J
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Elder James T
Department of Dermatology, University of Michigan Medical School, Ann Arbor; Department of Radiation Oncology (Cancer Biology), University of Michigan Medical School, Ann Arbor; Department of Dermatology, Ann Arbor Veterans Affairs Hospital, Ann Arbor. Electronic address: jelder@umich.edu.
References (96)
96 references, click to expand
  1. A non-HLA gene within the MHC in psoriasis.
    Lancet. 1999 May 8;353(9164):1589-90 PMID: 10334264
  2. Natural history of psoriatic arthritis.
    Baillieres Clin Rheumatol. 1994 May;8(2):379-94 PMID: 8076393
  3. A study of PSORS1C1 gene polymorphisms in Chinese patients with psoriasis.
    Br J Dermatol. 2005 Jul;153(1):90-6 PMID: 16029332
  4. Genetic polymorphisms of the HCR gene and a genomic segment in close proximity to HLA-C are associated with patients with psoriasis in Taiwan.
    Br J Dermatol. 2004 Jun;150(6):1104-11 PMID: 15214895
  5. 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.
    Am J Hum Genet. 1998 Jul;63(1):191-9 PMID: 9634500
  6. Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C.
    Am J Hum Genet. 2000 Jun;66(6):1833-44 PMID: 10801386
  7. Immunopathogenic mechanisms in psoriasis.
    Clin Exp Immunol. 2004 Jan;135(1):1-8 PMID: 14678257
  8. An integrated haplotype map of the human major histocompatibility complex.
    Am J Hum Genet. 2003 Sep;73(3):580-90 PMID: 12920676
  9. Transgenic mouse models support HCR as an effector gene in the PSORS1 locus.
    Hum Mol Genet. 2004 Aug 1;13(15):1551-61 PMID: 15190014
  10. Psoriasis pathophysiology: current concepts of pathogenesis.
    Ann Rheum Dis. 2005 Mar;64 Suppl 2:ii30-6 PMID: 15708932
  11. Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population.
    Exp Dermatol. 2003 Aug;12(4):435-44 PMID: 12930300
  12. Unbiased application of the transmission/disequilibrium test to multilocus haplotypes.
    Am J Hum Genet. 2000 Jun;66(6):2009-12 PMID: 10775523
  13. Identification of six novel polymorphisms in the human corneodesmosin gene.
    Tissue Antigens. 2001 Jan;57(1):32-8 PMID: 11169256
  14. Association of Cw11 in Japanese patients with psoriasis vulgaris.
    Tissue Antigens. 1990 Nov;36(5):241-2 PMID: 2095005
  15. Corneodesmosin gene: no evidence for PSORS 1 gene in North-eastern Thai psoriasis patients.
    Tissue Antigens. 2003 Sep;62(3):217-24 PMID: 12956875
  16. Genetic polymorphisms of killer cell immunoglobulin-like receptors are associated with susceptibility to psoriasis vulgaris.
    J Invest Dermatol. 2004 May;122(5):1133-6 PMID: 15140215
  17. On distinguishing unique combinations in biological sequences.
    J Comput Biol. 1996 Fall;3(3):407-23 PMID: 8891958
  18. The family based association test method: strategies for studying general genotype--phenotype associations.
    Eur J Hum Genet. 2001 Apr;9(4):301-6 PMID: 11313775
  19. The inter-locus recombinant HLA-B*4601 has high selectivity in peptide binding and functions characteristic of HLA-C.
    J Exp Med. 1996 Aug 1;184(2):735-40 PMID: 8760827
  20. Corneodesmosin (MHC S) gene in guttate psoriasis.
    Lancet. 1999 Aug 14;354(9178):597 PMID: 10470726
  21. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).
    Am J Hum Genet. 1993 Mar;52(3):506-16 PMID: 8447318
  22. HCR, a candidate gene for psoriasis, is expressed differently in psoriasis and other hyperproliferative skin disorders and is downregulated by interferon-gamma in keratinocytes.
    J Invest Dermatol. 2003 Dec;121(6):1360-4 PMID: 14675183
  23. Haplotype analysis of distantly related populations implicates corneodesmosin in psoriasis susceptibility.
    J Med Genet. 2003 Jun;40(6):447-52 PMID: 12807967
  24. Activating killer cell immunoglobulin-like receptor gene KIR2DS1 is associated with psoriatic arthritis.
    Hum Immunol. 2005 Jul;66(7):836-41 PMID: 16112031
  25. Histocompatibility typing in the seronegative spondyloarthropathies: a survey.
    Semin Arthritis Rheum. 1982 Feb;11(3):375-81 PMID: 6765292
  26. A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information.
    Hum Hered. 2000 Jul-Aug;50(4):211-23 PMID: 10782012
  27. HLA antigens in psoriatic arthritis.
    J Rheumatol. 1986 Jun;13(3):586-92 PMID: 3735281
  28. A new statistical method for haplotype reconstruction from population data.
    Am J Hum Genet. 2001 Apr;68(4):978-89 PMID: 11254454
  29. Fine mapping of the psoriasis susceptibility gene PSORS1: a reassessment of risk associated with a putative risk haplotype lacking HLA-Cw6.
    J Invest Dermatol. 2005 May;124(5):921-30 PMID: 15854032
  30. HLA-Cw6 and the genetic predisposition to psoriasis: a meta-analysis of published serologic studies.
    J Invest Dermatol. 1999 Oct;113(4):693-5 PMID: 10504461
  31. Gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris.
    Hum Immunol. 2004 Jul;65(7):758-66 PMID: 15310528
  32. Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosin gene (CDSN).
    Am J Hum Genet. 2005 Jan;76(1):164-71 PMID: 15529278
  33. Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics.
    Genet Epidemiol. 2004 Jan;26(1):61-9 PMID: 14691957
  34. CD8+ T cells in psoriatic lesions preferentially use T-cell receptor V beta 3 and/or V beta 13.1 genes.
    Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9282-6 PMID: 7937756
  35. Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease.
    Immunol Rev. 1999 Feb;167:275-304 PMID: 10319268
  36. HLA-Cw*0602 associates more strongly to psoriasis in the Swedish population than variants of the novel 6p21.3 gene PSORS1C3.
    Acta Derm Venereol. 2005;85(1):2-8 PMID: 15848982
  37. Histocompatibility (HL-A) antigens associated with psoriasis.
    N Engl J Med. 1972 Oct 12;287(15):738-40 PMID: 5056734
  38. Corneodesmosin (CDSN) gene association with psoriasis vulgaris in Caucasian but not in Japanese populations.
    Clin Exp Dermatol. 2005 Jul;30(4):414-8 PMID: 15953084
  39. Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles.
    J Immunol. 2002 Sep 15;169(6):2818-22 PMID: 12218090
  40. Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.
    Hum Mol Genet. 1997 Aug;6(8):1349-56 PMID: 9259283
  41. S gene (Corneodesmosin) diversity and its relationship to psoriasis; high content of cSNP in the HLA-linked S gene.
    J Invest Dermatol. 2000 Jun;114(6):1158-63 PMID: 10844560
  42. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group.
    Hum Mutat. 1998;11(1):1-3 PMID: 9450896
  43. Correcting for a potential bias in the pedigree disequilibrium test.
    Am J Hum Genet. 2001 Apr;68(4):1065-7 PMID: 11254459
  44. Barrier repair in chronic plaque-type psoriasis.
    Skin Res Technol. 2004 Feb;10(1):10-3 PMID: 14731243
  45. STG does not associate with psoriasis in the Swedish population.
    Exp Dermatol. 2004 Jul;13(7):413-8 PMID: 15217361
  46. Serological and molecular analysis of HLA class I and II alleles in Thai patients with psoriasis vulgaris.
    Tissue Antigens. 1998 Oct;52(4):389-92 PMID: 9820604
  47. Meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage to chromosomes 6p21 and 4q28-q31 in Caucasian and Chinese Hans population.
    J Invest Dermatol. 2004 Jun;122(6):1401-5 PMID: 15175030
  48. Genetic polymorphisms in the cell growth regulated gene, SC1 telomeric of the HLA-C gene and lack of association of psoriasis vulgaris.
    Tissue Antigens. 2000 Mar;55(3):206-11 PMID: 10777095
  49. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris.
    J Am Acad Dermatol. 1985 Sep;13(3):450-6 PMID: 4056119
  50. Psoriasis.
    N Engl J Med. 2005 May 5;352(18):1899-912 PMID: 15872205
  51. Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.
    Am J Hum Genet. 2002 Sep;71(3):554-64 PMID: 12148091
  52. PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data.
    Bioinformatics. 2005 Aug 15;21(16):3445-7 PMID: 15947021
  53. HLA class I and II alleles and susceptibility to generalized pustular psoriasis: significant associations with HLA-Cw1 and HLA-DQB1*0303.
    J Dermatol. 1998 Sep;25(9):573-81 PMID: 9798343
  54. Merlin--rapid analysis of dense genetic maps using sparse gene flow trees.
    Nat Genet. 2002 Jan;30(1):97-101 PMID: 11731797
  55. Genetic polymorphisms in the keratin-like S gene within the human major histocompatibility complex and association analysis on the susceptibility to psoriasis vulgaris.
    Tissue Antigens. 1996 Sep;48(3):182-6 PMID: 8896176
  56. IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex.
    Nucleic Acids Res. 2003 Jan 1;31(1):311-4 PMID: 12520010
  57. The OTF3 gene polymorphism confers susceptibility to psoriasis independent of the association of HLA-Cw*0602.
    J Invest Dermatol. 2000 Nov;115(5):824-8 PMID: 11069619
  58. Corneodesmosin expression in psoriasis vulgaris differs from normal skin and other inflammatory skin disorders.
    Lab Invest. 2001 Jul;81(7):969-76 PMID: 11454986
  59. A study of candidate genes for psoriasis near HLA-C in Chinese patients with psoriasis.
    Br J Dermatol. 2003 Mar;148(3):418-23 PMID: 12653732
  60. Localization of PSORS1 to a haplotype block harboring HLA-C and distinct from corneodesmosin and HCR.
    Hum Genet. 2005 Dec;118(3-4):466-76 PMID: 16235096
  61. Corneodesmosin DNA polymorphisms in MHC haplotypes and Japanese patients with psoriasis.
    Tissue Antigens. 2002 Jul;60(1):77-83 PMID: 12366786
  62. Analysis of RUNX1 binding site and RAPTOR polymorphisms in psoriasis: no evidence for association despite adequate power and evidence for linkage.
    J Med Genet. 2006 Jan;43(1):12-7 PMID: 15923274
  63. Oligoclonal expansion of intraepidermal T cells in psoriasis skin lesions.
    J Invest Dermatol. 2001 Dec;117(6):1546-53 PMID: 11886521
  64. Histocompatibility alloantigens in psoriasis and psoriatic arthritis. Evidence for the influence of multiple genes in the major histocompatibility complex.
    J Clin Invest. 1980 Oct;66(4):670-5 PMID: 6932404
  65. The transmission/disequilibrium test and parental-genotype reconstruction: the reconstruction-combined transmission/ disequilibrium test.
    Am J Hum Genet. 1999 Mar;64(3):861-70 PMID: 10053021
  66. SPR1 gene near HLA-C is unlikely to be a psoriasis susceptibility gene.
    Exp Dermatol. 2003 Jun;12(3):307-14 PMID: 12823445
  67. Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.
    J Invest Dermatol. 2004 May;122(5):1235-44 PMID: 15140227
  68. The HCR gene on 6p21 is unlikely to be a psoriasis susceptibility gene.
    J Invest Dermatol. 2001 May;116(5):750-4 PMID: 11348465
  69. Comparative association analysis reveals that corneodesmosin is more closely associated with psoriasis than HLA-Cw*0602-B*5701 in German families.
    Tissue Antigens. 2001 May;57(5):440-6 PMID: 11556968
  70. Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus.
    Hum Mol Genet. 2002 Mar 1;11(5):589-97 PMID: 11875053
  71. Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers.
    Am J Hum Genet. 2005 Nov;77(5):754-67 PMID: 16252236
  72. Sequence-specific oligonucleotide probing for MICB alleles reveals associations with MICA and HLA-B.
    Immunogenetics. 2000 Jun;51(7):591-9 PMID: 10912510
  73. Implementing a unified approach to family-based tests of association.
    Genet Epidemiol. 2000;19 Suppl 1:S36-42 PMID: 11055368
  74. HLA-B39 and the axial type of psoriatic arthritis.
    Acta Derm Venereol. 1987;67(3):249-50 PMID: 2442939
  75. Gene map of the extended human MHC.
    Nat Rev Genet. 2004 Dec;5(12):889-99 PMID: 15573121
  76. Complete MHC haplotype sequencing for common disease gene mapping.
    Genome Res. 2004 Jun;14(6):1176-87 PMID: 15140828
  77. Psoriatic arthritis: a clinical, radiological and genetic study of 58 Italian patients.
    Acta Derm Venereol Suppl (Stockh). 1994;186:69-70 PMID: 8073843
  78. An update on the genetics of psoriasis.
    Dermatol Clin. 2004 Oct;22(4):339-47, vii PMID: 15450331
  79. Variations in the HCR (Pg8) gene are unlikely to be causal for familial psoriasis.
    J Invest Dermatol. 2001 May;116(5):823-4 PMID: 11348479
  80. Psoriasis is associated with a SNP haplotype of the corneodesmosin gene (CDSN).
    Tissue Antigens. 2002 Oct;60(4):292-8 PMID: 12472658
  81. Haplotype sharing analysis identifies a retroviral dUTPase as candidate susceptibility gene for psoriasis.
    J Invest Dermatol. 2005 Jan;124(1):99-102 PMID: 15654959
  82. A note on the application of the transmission disequilibrium test when a parent is missing.
    Am J Hum Genet. 1995 Mar;56(3):811-2 PMID: 7887437
  83. MHC class I molecules and KIRs in human history, health and survival.
    Nat Rev Immunol. 2005 Mar;5(3):201-14 PMID: 15719024
  84. Finishing the euchromatic sequence of the human genome.
    Nature. 2004 Oct 21;431(7011):931-45 PMID: 15496913
  85. A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele.
    Hum Mol Genet. 2000 Jun 12;9(10):1533-42 PMID: 10888604
  86. Scanning chromosome 17 for psoriasis susceptibility: lack of evidence for a distal 17q locus.
    Hum Hered. 1995 Jul-Aug;45(4):219-30 PMID: 7558055
  87. Haplotype associations of the major histocompatibility complex with psoriasis in Northeastern Thais.
    Int J Dermatol. 2002 Jun;41(6):330-4 PMID: 12100686
  88. Novel genetic association between the corneodesmosin (MHC S) gene and susceptibility to psoriasis.
    Hum Mol Genet. 1999 Jun;8(6):1135-40 PMID: 10332047
  89. TDT clarification.
    Am J Hum Genet. 1999 Feb;64(2):668 PMID: 9973308
  90. SNP profile within the human major histocompatibility complex reveals an extreme and interrupted level of nucleotide diversity.
    Genome Res. 2000 Oct;10(10):1579-86 PMID: 11042155
  91. Suicidal ideation in psoriasis.
    Int J Dermatol. 1993 Mar;32(3):188-90 PMID: 8444530
  92. Psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction.
    J Investig Dermatol Symp Proc. 2004 Mar;9(2):136-9 PMID: 15083780
  93. The genetics of psoriasis.
    Arch Dermatol. 1994 Feb;130(2):216-24 PMID: 8304761
  94. A test for linkage and association in general pedigrees: the pedigree disequilibrium test.
    Am J Hum Genet. 2000 Jul;67(1):146-54 PMID: 10825280
  95. Corneodesmosin gene polymorphism demonstrates strong linkage disequilibrium with HLA and association with psoriasis vulgaris.
    Tissue Antigens. 1999 Nov;54(5):439-49 PMID: 10599883
  96. A comparison of bayesian methods for haplotype reconstruction from population genotype data.
    Am J Hum Genet. 2003 Nov;73(5):1162-9 PMID: 14574645
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/503821
Email
jelder@umich.edu
Published
2006-05-00
Epub
2006-00-31
Pages
827-851
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1474031
Subset
IM
Grants
NCRR NIH HHS · M01 RR000042 · United States
NIAMS NIH HHS · R01 AR042742 · United States
NIAMS NIH HHS · R01 AR050511 · United States
NCRR NIH HHS · M01 RR00042 · United States
External Links
PubMed source DOI: 10.1086/503821 PMC Full Text View journal details
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