PMID- 10801386 OWN - NLM STAT- MEDLINE DCOM- 20010607 LR - 20220317 IS - 0002-9297 (Print) IS - 1537-6605 (Electronic) IS - 0002-9297 (Linking) VI - 66 IP - 6 DP - 2000 Jun TI - Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C. PG - 1833-44 AB - Recent genome scans have established the presence of a major psoriasis-susceptibility locus in the human leukocyte antigen (HLA) complex on chromosome 6p21.3. To narrow the interval for candidate gene testing, we performed a linkage-disequilibrium analysis of 339 families, with the use of 62 physically mapped microsatellite markers spanning the major histocompatibility complex (MHC). As detected by use of the transmission/disequilibrium test (TDT), individual markers yielded significant linkage disequilibrium across most of the MHC. However, the strongest evidence for marker-trait disequilibrium was found in an approximately 300-kb region extending from the MICA gene to the corneodesmosin gene. Maximum-likelihood haplotypes were constructed across the entire MHC in the original sample and across a 1.2-Mb region of the central MHC in an expanded sample containing 139 additional families. Short (two- to five-marker) haplotypes were subjected to the TDT using a "moving-window" strategy that reduced the variability of TDT P values relative to the single-locus results. Furthermore, the expanded sample yielded a sharp peak of evidence for linkage disequilibrium that spanned approximately 170 kb and that was centered 100 kb telomeric to HLA-C. The 1.2-Mb interval was further dissected by means of recombinant ancestral haplotype analysis. This analysis identified risk haplotype 1 (RH1), which is a 60-kb fragment of ancestral haplotype 57.1, on all identifiable HLA risk haplotypes. One of these haplotypes exhibits significant linkage disequilibrium with psoriasis but does not carry Cw6, which is the HLA allele most strongly associated with the disease. These results demonstrate that RH1 is highly likely to carry the disease allele at PSORS1, and they exclude HLA-C and corneodesmosin with a high degree of confidence. FAU - Nair, R P AU - Nair RP AD - Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Stuart, P AU - Stuart P FAU - Henseler, T AU - Henseler T FAU - Jenisch, S AU - Jenisch S FAU - Chia, N V AU - Chia NV FAU - Westphal, E AU - Westphal E FAU - Schork, N J AU - Schork NJ FAU - Kim, J AU - Kim J FAU - Lim, H W AU - Lim HW FAU - Christophers, E AU - Christophers E FAU - Voorhees, J J AU - Voorhees JJ FAU - Elder, J T AU - Elder JT LA - eng GR - M01EE00042/PHS HHS/United States GR - P30 HG00209-03/HG/NHGRI NIH HHS/United States GR - R01 AR4274-01/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20000505 PL - United States TA - Am J Hum Genet JT - American journal of human genetics JID - 0370475 RN - 0 (CDSN protein, human) RN - 0 (Glycoproteins) RN - 0 (HLA-C Antigens) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (MHC class I-related chain A) SB - IM EIN - Am J Hum Genet 2002 Apr;70(4):1074 MH - Alleles MH - Chromosome Mapping MH - Chromosomes, Human, Pair 6/*genetics MH - Cohort Studies MH - Female MH - Gene Order/genetics MH - Genetic Linkage/*genetics MH - Genetic Predisposition to Disease/*genetics MH - Glycoproteins/genetics MH - HLA-C Antigens/*genetics MH - Haplotypes/genetics MH - Histocompatibility Antigens Class I/genetics MH - Humans MH - Intercellular Signaling Peptides and Proteins MH - Likelihood Functions MH - Linkage Disequilibrium/genetics MH - Male MH - Microsatellite Repeats/genetics MH - Phenotype MH - Psoriasis/*genetics MH - Recombination, Genetic/genetics MH - Telomere/*genetics PMC - PMC1378062 EDAT- 2000/05/10 09:00 MHDA- 2001/06/08 10:01 PMCR- 2000/12/01 CRDT- 2000/05/10 09:00 PHST- 2000/02/23 00:00 [received] PHST- 2000/03/30 00:00 [accepted] PHST- 2000/05/10 09:00 [pubmed] PHST- 2001/06/08 10:01 [medline] PHST- 2000/05/10 09:00 [entrez] PHST- 2000/12/01 00:00 [pmc-release] AID - S0002-9297(07)63535-6 [pii] AID - 10.1086/302932 [doi] PST - ppublish SO - Am J Hum Genet. 2000 Jun;66(6):1833-44. doi: 10.1086/302932. Epub 2000 May 5.