A Genome-Wide Association Study of Psoriasis and Psoriatic Arthritis Identifies New Disease Loci

A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8×10−11, GWA scan; P = 1.8×10−30, replication; P = 1.8×10−39, combined; U.K. PSA: P = 6.9×10−11). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13×10−26 in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4×10−4; U.K. PSA: P = 8.0×10−4; IL12B:rs6887695, U.S. PS, P = 5×10−5 and U.K. PSA, P = 1.3×10−3) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2×10−6 for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2×10−5 for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9×10−5 for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis).

本研究开展了全基因组关联分析（genome-wide association study, GWAS），旨在鉴定与人类皮肤和关节炎症性疾病——银屑病（psoriasis, PS）及银屑病关节炎（psoriatic arthritis, PSA）易感性相关的遗传因素。研究共纳入223例银屑病患者（其中91例合并银屑病关节炎），对其进行311,398个单核苷酸多态性（single nucleotide polymorphism, SNP）的基因分型，并将分型结果与519名北欧裔健康对照进行比对。后续使用独立队列开展验证工作：包括来自美国的577例银屑病患者与737名对照，以及来自英国的576例银屑病关节炎患者与480名对照。最强的关联信号定位于主要组织相容性复合体（major histocompatibility complex, MHC）的I类区域。关联性最显著的单核苷酸多态性为rs10484554，其位于人类白细胞抗原C（human leukocyte antigen C, HLA-C）基因上游34.7 kb处（全基因组关联扫描阶段P=7.8×10⁻¹¹；验证阶段P=1.8×10⁻³⁰；合并分析阶段P=1.8×10⁻³⁹；英国银屑病关节炎亚组P=6.9×10⁻¹¹）。不过，编码I类基因HCP5内G2V多态性的rs2395029位点（美国病例组合并分析P=2.13×10⁻²⁶）在银屑病与银屑病关节炎中均展现出最高的比值比（odds ratio, OR），分别为4.1与3.2。该变异与HIV感染后较低的病毒设定点相关，且其遗传效应独立于rs10484554。本研究验证了此前已报道的白细胞介素23受体（interleukin 23 receptor, IL23R）与白细胞介素12B（interleukin 12B, IL12B）多态性在银屑病及银屑病关节炎队列中的关联：IL23R位点rs11209026，美国银屑病亚组P=1.4×10⁻⁴；英国银屑病关节炎亚组P=8.0×10⁻⁴；IL12B位点rs6887695，美国银屑病亚组P=5×10⁻⁵，英国银屑病关节炎亚组P=1.3×10⁻³。同时，本研究在IL23R区域内IL12RB2基因上游4 kb处的单核苷酸多态性中检测到了独立的关联信号（P=0.001）。在美国银屑病队列中验证得到的新关联位点包括：13q13号染色体上携带有脂肪瘤HMGIC融合伴侣（lipoma HMGIC fusion partner, LHFP）与保守寡聚高尔基复合体组分6（conserved oligomeric golgi complex component 6, COG6）基因的区域（rs7993214合并分析P=2×10⁻⁶；OR=0.71）；表皮分化复合物（PSORS4）区域内的晚期角质层包膜基因簇（late cornified envelope gene cluster, LCE）（rs6701216合并分析P=6.2×10⁻⁵；OR=1.45）；以及15q21区域的连锁不平衡（linkage disequilibrium, LD）位点（rs3803369合并分析P=2.9×10⁻⁵；OR=1.43）。该15q21区域具有研究价值，因为其携带有泛素特异性蛋白酶8基因，该基因的加工假基因定位于HLA-C基因上游。此外，15q21区域还包含信号肽肽酶样2a（signal peptide peptidase like 2a, SPPL2A）基因，其可通过切割激活肿瘤坏死因子α，进而触发人类树突状细胞中白细胞介素12的表达。本研究还在4q27号染色体上鉴定出了一个全新的银屑病关节炎（亦可能关联银屑病）易感位点。该区域携带有白细胞介素2（interleukin 2, IL2）与白细胞介素21（interleukin 21, IL21）基因，且近期已有研究表明该区域与四种自身免疫性疾病相关，分别为乳糜泻、1型糖尿病、格雷夫斯病与类风湿关节炎。