Das Sayantan, Stuart Philip E, Ding Jun, Tejasvi Trilokraj, Li Yanming, Tsoi Lam C, Chandran Vinod, Fischer Judith, Helms Cynthia, Duffin Kristina Callis, Voorhees John J, Bowcock Anne M, Krueger Gerald G, Lathrop G Mark, Nair Rajan P, Rahman Proton, Abecasis Goncalo R, Gladman Dafna, Elder James T
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
Eur J Hum Genet. 2015 Jun;23(6):844-53. doi: 10.1038/ejhg.2014.172. Epub 2014 Sep 3.
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-C06-B57 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.
以往研究已确定41个全基因组显著的银屑病易感位点。在我们开展首次银屑病全基因组关联研究后，我们设计了一种定制基因分型芯片，对当时已知的8个全基因组显著易感位点（IL23R、IL13、IL12B、TNIP1、MHC、TNFAIP3、IL23A和RNF114）进行精细定位，可对2699例银屑病患者和2107名欧洲血统的未患病对照者的这8个位点中的2269个单核苷酸多态性（SNP）进行基因分型。我们使用最新的1000基因组参考单倍型（包括插入缺失和SNP）对这些数据进行填充，将这8个位点的标记密度提高到49239个遗传变异。通过逐步条件关联分析，我们在8个位点中的6个位点上确定了9个独立信号。在主要组织相容性复合体（MHC）区域，我们在rs114255771（P = 2.94×10⁻⁷⁴）、rs6924962（P = 3.21×10⁻¹⁹）和rs892666（P = 1.11×10⁻¹⁰）处检测到3个独立信号。在IL12B附近，我们在rs62377586（P = 7.42×10⁻¹⁶）和rs918518（P = 3.22×10⁻¹¹）处检测到2个独立信号。在TNIP1（rs17728338；P = 4.15×10⁻¹³）、IL13（rs1295685；P = 1.65×10⁻⁷）、IL23A（rs61937678；P = 1.82×10⁻⁷）和TNFAIP3（rs642627；P = 5.90×10⁻⁷）区域各检测到1个信号。我们还对8个HLA基因的变异进行了填充，发现SNP rs114255771产生的关联比任何HLA等位基因或氨基酸残基都更显著。进一步分析表明，该SNP标记的HLA-C06-B57单倍型的优势比显著高于其他携带HLA-C*06的单倍型。结果表明IL12B存在等位基因异质性，并确定了一种高危的MHC I类单倍型，这与MHC中存在多种银屑病效应因子一致。
