A polymorphism in CCR1/CCR3 is associated with narcolepsy
A polymorphism in CCR1/CCR3 is associated with narcolepsy
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DOI：
10.1016/j.bbi.2015.05.003
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发表时间：
2015-10-01
影响因子：
15.1
通讯作者：
Tokunaga, Katsushi
中科院分区：
文献类型：
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作者：
Toyoda, Hiromi;Miyagawa, Taku;Tokunaga, Katsushi
发作性睡病的病因涉及多种遗传和环境因素。虽然人类白细胞抗原（HLA）-DRB 1 *15：01-DQB 1 *06：02单倍型与嗜睡症密切相关，但它不足以促进疾病的发展。为了确定其他非HLA易感基因，我们使用日本样本进行了全基因组关联研究（GWAS），初始样本集包括409例病例和1562例对照，用于GWAS的525，196个位于HLA区域外的单核苷酸多态性（SNP）。一个独立的样本集，包括240例和869名对照，然后在GWAS中确定的37个SNP的基因分型。我们发现发作性睡病与趋化因子受体1（CCR 1）启动子区的SNP相关（rs3181077，P = 1.6 x 10（-5），比值比[OR] = 1.86）。rs3181077与独立样本集的关联性重复（P = 0.032，OR = 1.36）。我们检测了38例病例和37例对照外周血中候选基因的mRNA水平。患者CCR 1和CCR 3 mRNA水平显著低于健康对照组，且CCR 1 mRNA水平与rs3181077基因型相关。还进行体外趋化性测定以测量单核细胞迁移。我们观察到rs3181077危险等位基因携带者的单核细胞与CCR 1配体的迁移指数较低。CCR 1和CCR 3是新发现的嗜睡症易感基因。这些结果突出了CCR基因在发作性睡病中的潜在作用，并支持发作性睡病患者免疫功能受损的假设。(C)2015 Elsevier Inc. All rights reserved.
Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples.An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P = 1.6 x 10(-5), odds ratio [OR] = 1.86). This rs3181077 association was replicated with the independent sample set (P = 0.032, OR = 1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand.CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function. (C) 2015 Elsevier Inc. All rights reserved.