Feng Bing-Jian, Sun Liang-Dan, Soltani-Arabshahi Razieh, Bowcock Anne M, Nair Rajan P, Stuart Philip, Elder James T, Schrodi Steven J, Begovich Ann B, Abecasis Gonçalo R, Zhang Xue-Jun, Callis-Duffin Kristina P, Krueger Gerald G, Goldgar David E
Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, USA.
PLoS Genet. 2009 Aug;5(8):e1000606. doi: 10.1371/journal.pgen.1000606. Epub 2009 Aug 14.
Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw0602 in all samples with high accuracy. The association of the imputed HLA-Cw0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2 x 10(-6), OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9 x 10(-6), OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3 x 10(-47), 6 x 10(-8), and 3 x 10(-7), respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B57 was associated with an increased risk of psoriasis and HLA-B40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis.
银屑病是一种常见的炎症性皮肤病，其特征为鳞屑性红色斑块增厚。此前我们对1359例银屑病患者和1400例对照进行了全基因组关联研究（GWAS），对447249个单核苷酸多态性（SNP）进行了基因分型。最显著的发现是SNP rs12191877，它与银屑病的共同风险等位基因HLA-Cw0602处于紧密连锁不平衡状态。然而尚不清楚除HLA-C外，MHC内是否还存在其他银屑病相关基因座。在本研究中，我们通过对GWAS数据的深入分析，在人类白细胞抗原（HLA）区域寻找其他易感基因座；然后，在一个独立的1139例汉族银屑病患者和1132例对照中对我们的发现进行随访。以分型的CEPH数据集作为参考，我们在所有样本中高精度地推断出HLA-Cw0602。推断出的HLA-Cw0602剂量与疾病的关联比最显著相关的SNP rs12191877更强。校正HLA-Cw0602后，还存在两个剩余的关联信号：一个由rs2073048显示（p = 2×10⁻⁶，比值比[OR]=0.66），位于c6orf10内，c6orf10是肿瘤坏死因子-α（TNF-α）的一个潜在下游效应器；另一个由rs13437088显示（p = 9×10⁻⁶，OR = 1.3），位于HLA-B着丝粒方向30 kb处且MICA端粒方向16 kb处。当将HLA-Cw0602、rs2073048和rs13437088都纳入逻辑回归模型时，它们各自都与疾病显著相关（分别为p = 3×10⁻⁴⁷、6×10⁻⁸和3×10⁻⁷）。在控制推断出的HLA-Cw0602后，这两个假定的基因座在汉族样本中也与疾病显著相关。对两个群体中HLA-B的详细分析表明，HLA-B57与银屑病风险增加相关，而HLA-B40与风险降低相关，独立于HLA-Cw*0602和C�orf10基因座，提示HLA-B可能参与致病。这些结果表明，MHC内至少还有两个基因座会增加患银屑病的风险。
