Fine mapping of eight psoriasis susceptibility loci.

Autor: Das S; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA., Stuart PE; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA., Ding J; 1] Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA [2] Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Tejasvi T; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA., Li Y; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA., Tsoi LC; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA., Chandran V; Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON, Canada., Fischer J; Centre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, Evry, France., Helms C; National Heart and Lung Institute, Imperial College London, London, UK., Duffin KC; Department of Dermatology, University of Utah, Salt Lake City, UT, USA., Voorhees JJ; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA., Bowcock AM; National Heart and Lung Institute, Imperial College London, London, UK., Krueger GG; Department of Dermatology, University of Utah, Salt Lake City, UT, USA., Lathrop GM; Centre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, Evry, France., Nair RP; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA., Rahman P; Department of Medicine, Memorial University, St John's, NL, Canada., Abecasis GR; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA., Gladman D; 1] Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON, Canada [2] Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, Toronto, ON, Canada., Elder JT; 1] Department of Dermatology, University of Michigan, Ann Arbor, MI, USA [2] Ann-Arbor Veteran Affairs Hospital, Ann Arbor, MI, USA.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2015 Jun; Vol. 23 (6), pp. 844-53. Date of Electronic Publication: 2014 Sep 03.
DOI: 10.1038/ejhg.2014.172
Abstrakt: Previous studies have identified 41 independent genome-wide significant psoriasis susceptibility loci. After our first psoriasis genome-wide association study, we designed a custom genotyping array to fine-map eight genome-wide significant susceptibility loci known at that time (IL23R, IL13, IL12B, TNIP1, MHC, TNFAIP3, IL23A and RNF114) enabling genotyping of 2269 single-nucleotide polymorphisms (SNPs) in the eight loci for 2699 psoriasis cases and 2107 unaffected controls of European ancestry. We imputed these data using the latest 1000 Genome reference haplotypes, which included both indels and SNPs, to increase the marker density of the eight loci to 49 239 genetic variants. Using stepwise conditional association analysis, we identified nine independent signals distributed across six of the eight loci. In the major histocompatibility complex (MHC) region, we detected three independent signals at rs114255771 (P = 2.94 × 10(-74)), rs6924962 (P = 3.21 × 10(-19)) and rs892666 (P = 1.11 × 10(-10)). Near IL12B we detected two independent signals at rs62377586 (P = 7.42 × 10(-16)) and rs918518 (P = 3.22 × 10(-11)). Only one signal was observed in each of the TNIP1 (rs17728338; P = 4.15 × 10(-13)), IL13 (rs1295685; P = 1.65 × 10(-7)), IL23A (rs61937678; P = 1.82 × 10(-7)) and TNFAIP3 (rs642627; P = 5.90 × 10(-7)) regions. We also imputed variants for eight HLA genes and found that SNP rs114255771 yielded a more significant association than any HLA allele or amino-acid residue. Further analysis revealed that the HLA-C*06-B*57 haplotype tagged by this SNP had a significantly higher odds ratio than other HLA-C*06-bearing haplotypes. The results demonstrate allelic heterogeneity at IL12B and identify a high-risk MHC class I haplotype, consistent with the existence of multiple psoriasis effectors in the MHC.
Databáze: MEDLINE