Centre for Prognosis Studies in The Rheumatic Diseases, Toronto Western Research Institute, Toronto Western Hospital, 399 Bathurst Street, 1E-410B, Toronto, Ontario M5T 2S8, Canada.
Ann Rheum Dis. 2011 Apr;70(4):690-4. doi: 10.1136/ard.2010.133561. Epub 2011 Jan 17.
Psoriatic arthritis (PsA) has a clear familial predisposition, the major histocompatibility complex (MHC) region being the strongest genetic locus. The study primary objective was to identify single nucleotide polymorphisms (SNPs) independent of known human leucocyte antigen (HLA) alleles within the MHC region that are associated with PsA using a high-density SNP map.
In all, 914 samples were assessed, including 427 PsA cases from 2 well established PsA cohorts and 487 controls from Canada. The genotype data consisted of 2521 SNPs from 2 Illumina Goldengate MHC panels, spanning 4.9 Mb of chromosome 6 with an average spacing of 2 kb. Classical HLA alleles were genotyped in all subjects using sequence-specific oligonucleotide probes or sequence-specific primers. A conditioning approach was used to distinguish between new associations and those in linkage disequilibrium (LD) with known HLA alleles.
Unconditional association analysis revealed 43 markers with p<7.26×10(-5) (calculated experiment-wide significance threshold). In the conditional analysis, 10 SNPs showed statistically significant association at a threshold of p<7.26×10(-5). Seven SNPs were in strong LD in the study data (pairwise r(2) >0.77 in the controls) reflecting one association signal. These SNPs spanned a 1.6 Mb region. SNP rs1150735 is 1.5 kb upstream from ring finger protein 39 (RNF39). RNF39 SNPs have been associated with HIV1 disease progression and set point CD4 T cell count.
Four new loci for either psoriasis or PsA in the MHC region that are independent of known HLA alleles have been identified. The effect size of these variants is modest. Replication of these variants in multiple larger populations is necessary.
银屑病关节炎（PsA）具有明显的家族易感性，主要组织相容性复合体（MHC）区域是最强的遗传位点。本研究的主要目的是利用高密度 SNP 图谱，在 MHC 区域内鉴定与 PsA 相关的、与已知人类白细胞抗原（HLA）等位基因无关的单核苷酸多态性（SNP）。
共评估了 914 个样本，包括来自 2 个成熟的 PsA 队列的 427 个 PsA 病例和来自加拿大的 487 个对照。基因型数据包括 2521 个来自 2 个 Illumina Goldengate MHC 面板的 SNP，跨越染色体 6 的 4.9Mb，平均间距为 2kb。所有受试者均使用序列特异性寡核苷酸探针或序列特异性引物进行经典 HLA 等位基因分型。采用条件方法来区分新的关联和与已知 HLA 等位基因连锁不平衡（LD）的关联。
无条件关联分析显示，有 43 个标记物的 p 值<7.26×10(-5)（计算得出的全基因组显著性阈值）。在条件分析中，有 10 个 SNP 在 p 值<7.26×10(-5)的阈值下显示出统计学上的显著关联。在研究数据中，有 7 个 SNP 处于强 LD（对照组中两两 r(2)>0.77），反映出一个关联信号。这些 SNP 跨越了 1.6Mb 的区域。SNP rs1150735 位于环指蛋白 39（RNF39）上游 1.5kb 处。RNF39 SNP 与 HIV1 疾病进展和设定点 CD4 T 细胞计数有关。
在 MHC 区域中发现了 4 个新的与银屑病或 PsA 相关的、与已知 HLA 等位基因无关的新位点。这些变体的效应大小适中。在多个更大的人群中复制这些变体是必要的。
