Nat Genet 2011 ;43 (12): 1247-51. [IF:36.377]
Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy.
Zhang F , Liu H , Chen S , Low H , Sun L , Cui Y , Chu T , Li Y , Fu X , Yu Y , Yu G , Shi B , Tian H , Liu D , Yu X , Li J , Lu N , Bao F , Yuan C , Liu J , Liu H , Zhang L , Sun Y , Chen M , Yang Q , Yang H , Yang R , Zhang L , Wang Q , Liu H , Zuo F , Zhang H , Khor CC , Hibberd ML , Yang S , Liu J , Zhang X .
1] Shandong Provincial Institute of Dermatology and Venereology, Provincial Academy of Medical Science, Jinan, China. [2] Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, China. [3] Shandong Provincial Key Lab for Dermatovenereology, Jinan, China. [4] Shandong Provincial Medical Center for Dermatovenereology, Jinan, China.
山东省医学科学院皮肤病性病防治研究所，山东省立医院皮肤科 ，山东大学，山东省皮肤性病学重点实验室
Abstract
We performed a genome-wide association study with 706 individuals with leprosy and 5,581 control individuals and replicated the top 24 SNPs in three independent replication samples, including a total of 3,301 individuals with leprosy and 5,299 control individuals from China. Two loci not previously associated with the disease were identified with genome-wide significance: rs2275606 (combined P = 3.94 × 10(-14), OR = 1.30) on 6q24.3 and rs3762318 (combined P = 3.27 × 10(-11), OR = 0.69) on 1p31.3. These associations implicate IL23R and RAB32 as new susceptibility genes for leprosy. Furthermore, we identified evidence of interaction between the NOD2 and RIPK2 loci, which is consistent with the biological association of the proteins encoded by these genes (NOD2-RIPK2 complex) in activating the NF-κB pathway as a part of the host defense response to infection. Our findings have expanded the biological functions of IL23R by uncovering its involvement in infectious disease susceptibility and suggest a potential involvement of autophagocytosis in leprosy pathogenesis. The IL23R association supports previous observations of the marked overlap of susceptibility genes for leprosy and Crohn's disease, implying common pathogenesis mechanisms.
摘要：
我们进行了一项与基因组相关的研究，实验对象为来自中国的706名麻风病患者以及5581名病情受控制的患者。我们复制了三个独立复制样本的前24个单核苷酸，样本包括总共3301名麻风病人以及5299病情受控的病人。我们认识到两个位点在基因组层面的意义，也就是在 6q24.3 上的rs2275606 (combined P = 3.94 × 10(-14), OR = 1.30) 和在1p31.3上的rs3762318 (combined P = 3.27 × 10(-11), OR = 0.69)，它们以前并未与麻风病联系起来。这些新的联系提示IL23R 和RAB32为麻风病新的易感基因。 此外，我们证实了NOD2 和RIPK2 位点之间的相互作用，这些作用与相关基因编码蛋白质的生物学过程也是一致的。其过程为激活NF-κB 通道作为寄主对于感染的防御反应。我们通过揭开IL23R 位点在传染性疾病感染过程中的作用，扩展了IL23R 位点的生物功能，另外还提示其可能在麻风病的发病机制中有自噬作用。IL23R联合支持了我们之前对于麻风病和克罗恩氏病易感基因重合部分的观察结果，意味着它们有共同的发病机制。
