A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes
A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes
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DOI：
10.1086/511051
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发表时间：
2007-02-01
影响因子：
9.8
通讯作者：
Begovich, Ann B.
中科院分区：
文献类型：
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作者：
Cargill, Michele;Schrodi, Steven J.;Begovich, Ann B.
我们在三个独立的白色北美个体样本集（1,446例和1,432例对照）中进行了一项银屑病的多层次病例对照关联研究，其中有25,215个基因中心单核苷酸多态性（SNP），发现与IL 12 B 3 '-未标记区域SNP（rs3212227）高度显著相关，证实了一项小型日本研究的结果。该SNP在所有三个样本集中均具有显著性（比值比[OR]（共同）0.64，合并P [P-comb] = 7.85 x 10（-10））。一个Monte Carlo模拟，以解决多个测试表明，这种关联不是一个梳I型错误。对96名银屑病患者的IL 12 B编码区进行了重新测序，并对另外30个IL 12 B区域SNP进行了基因分型。单倍型进行了估计，基因型条件分析确定了第二个危险等位基因（rs6887695）位于IL 12 B编码区上游60 kb附近，经rs3212227校正后，该等位基因与银屑病相关。总之，这两个SNP标记一个共同的IL 12 B风险单倍型（OR共同1.40，P-comb = 8.11 × 10（-9））和一个不太常见的保护性单倍型（OR共同0.58，P-comb = 5.65 × 10（-12）），这在所有三个comb研究中具有统计学显著性。由于IL-12 B编码IL-12和IL-23的共同IL-12 p40亚基，我们分别对编码这些细胞因子（IL-12 A和IL-23 A）及其受体（IL-12 RB 1、IL-12 RB 2和IL-23 R）的其他链的基因中的17个SNP进行基因分型。单倍型分析确定了两个IL 23 R错义SNP，它们共同标记了所有三项研究中常见的银屑病相关单倍型（OR共同1.44，P-comb = 3.13 x 10-（6））。IL 12 B和IL 23 R梳型易感单倍型的纯合子个体具有增加的疾病风险（OR共同1.66，P-comb = 1.33 × 10（-8））。这些数据，和梳先前的观察，即对银屑病患者施用IL-12 p40亚基特异性抗体是高度有效的，表明这些基因在银屑病发病机制中起着重要作用。
We performed a multitiered, case-control association study of psoriasis in three independent sample sets of white North American individuals (1,446 cases and 1,432 controls) with 25,215 genecentric single-nucleotide polymorphisms (SNPs) and found a highly significant association with an IL12B 3'-untranslated-region SNP (rs3212227), confirming the results of a small Japanese study. This SNP was significant in all three sample sets (odds ratio [OR](common) 0.64, combined P [P-comb] = 7.85 x 10(-10)). A Monte Carlo simulation to address multiple testing suggests that this association is not a type comb I error. The coding regions of IL12B were resequenced in 96 individuals with psoriasis, and 30 additional IL12B-region SNPs were genotyped. Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele (rs6887695) located similar to 60 kb upstream of the IL12B coding region that exhibited association with psoriasis after adjustment for rs3212227. Together, these two SNPs mark a common IL12B risk haplotype (ORcommon 1.40, P-comb = 8.11 x 10(-9)) and comb a less frequent protective haplotype (ORcommon 0.58, P-comb = 5.65 x 10(-12)), which were statistically significant in all three comb studies. Since IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines (IL12A and IL23A) and their receptors (IL12RB1, IL12RB2, and IL23R). Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (ORcommon 1.44, P-comb = 3.13 x 10-(6)). Individuals homozygous for both the IL12B and the IL23R comb predisposing haplotypes have an increased risk of disease (ORcommon 1.66, P-comb = 1.33 x 10(-8)). These data, and the comb previous observation that administration of an antibody specific for the IL-12p40 subunit to patients with psoriasis is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis.