Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome.
Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome.
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趋同基因组研究确定了 GRIK2 和 NPAS2 与慢性疲劳综合征的关联。
DOI：
10.1159/000326692
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发表时间：
2011
影响因子：
3.2
通讯作者：
Rajeevan,MangalathuS
中科院分区：
文献类型：
--
作者：
Smith,AliciaK;Fang,Hong;Whistler,Toni;Unger,ElizabethR;Rajeevan,MangalathuS
背景：目前还没有一致的证据表明，特定的基因或分子途径，有助于慢性疲劳综合征（CFS）的发病机制，治疗干预或诊断。虽然多项研究支持遗传变异在CFS中的作用，但全基因组范围内识别相关基因座的努力仍未得到探索。我们采用了一种新的融合功能基因组学方法，将单核苷酸多态性（SNP）和mRNA表达研究的结果结合起来，以确定CFS和新的候选基因之间的关联，以进行进一步的调查。方法：我们评估了40名CFS和40名非疲劳对照受试者的116，204个SNP，沿着这些受试者中一个子集的20，160个基因的mRNA表达结果：65个SNPs与CFS名义上相关CFS受试者外周血单个核细胞中有165个基因差异表达（104倍; p ≤ 0.05）。两个基因，谷氨酸受体，离子型，激酶2（GRIK 2）和神经元PAS结构域蛋白2（NPAS 2），被确定的SNP和基因表达分析。携带rs 2247215（GRIK 2）G等位基因的受试者更可能患有CFS（p = 0.0005），CFS受试者显示GRIK 2表达降低（10倍; p = 0.015）。与T等位基因的rs356653（NPAS 2）的受试者更容易有CFS（p = 0.0007），andNPAS 2表达增加（10倍; p = 0.027）在那些与CFS。结论：使用一个综合的基因组策略，这项研究表明，可能的作用，参与中枢神经传递和昼夜节律的基因在CFS和支持进一步研究的新的候选基因在独立的人群CFS科目。
Background:There is no consistent evidence of specific gene(s) or molecular pathways that contribute to the pathogenesis, therapeutic intervention or diagnosis of chronic fatigue syndrome (CFS). While multiple studies support a role for genetic variation in CFS, genome-wide efforts to identify associated loci remain unexplored. We employed a novel convergent functional genomics approach that incorporates the findings from single-nucleotide polymorphism (SNP) and mRNA expression studies to identify associations between CFS and novel candidate genes for further investigation.Methods:We evaluated 116,204 SNPs in 40 CFS and 40 nonfatigued control subjects along with mRNA expression of 20,160 genes in a subset of these subjects (35 CFS subjects and 27 controls) derived from a population-based study.Results:Sixty-five SNPs were nominally associated with CFS (p < 0.001), and 165 genes were differentially expressed (≧4-fold; p ≤ 0.05) in peripheral blood mononuclear cells of CFS subjects. Two genes, glutamate receptor, ionotropic, kinase 2(GRIK2)and neuronal PAS domain protein 2(NPAS2),were identified by both SNP and gene expression analyses. Subjects with the G allele of rs2247215(GRIK2)were more likely to have CFS (p = 0.0005), and CFS subjects showed decreasedGRIK2expression (10-fold; p = 0.015). Subjects with the T allele of rs356653(NPAS2)were more likely to have CFS (p = 0.0007), andNPAS2expression was increased (10-fold; p = 0.027) in those with CFS.Conclusion:Using an integrated genomic strategy, this study suggests a possible role for genes involved in glutamatergic neurotransmission and circadian rhythm in CFS and supports further study of novel candidate genes in independent populations of CFS subjects.