Expansion of the human mu-opioid receptor gene architecture: novel functional variants.
Expansion of the human mu-opioid receptor gene architecture: novel functional variants.
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DOI：
10.1093/hmg/ddn439
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发表时间：
2009-03-15
影响因子：
3.5
通讯作者：
Diatchenko L
中科院分区：
文献类型：
--
作者：
Shabalina SA;Zaykin DV;Gris P;Ogurtsov AY;Gauthier J;Shibata K;Tchivileva IE;Belfer I;Mishra B;Kiselycznyk C;Wallace MR;Staud R;Spiridonov NA;Max MB;Goldman D;Fillingim RB;Maixner W;Diatchenko L
μ阿片受体(OPRM1)是内源性和外源性阿片类止痛药的主要受体靶点。人类对疼痛刺激和鸦片类药物的反应有很大的个体差异，这归因于OPRM1的遗传变异。在寻找新的功能变异时，我们采用了比较基因组分析，并获得了存在扩展的人类OPRM1基因座的证据，该基因座具有新的启动子、替代外显子和调控元件。对人类OPRM1基因座内的多态进行检测，发现单核苷酸多态(SNP)rs563649与痛觉的个体差异之间存在很强的相关性。SNP rs563649位于一个新的含有OPRM1异构体(MOR-1K)的外显子13的5‘非编码区结构保守的内部核糖体进入位点(IRES)，它影响这些变异体的mRNA水平和翻译效率。此外，rs563649在整个OPRM1基因座上表现出很强的连锁不平衡，从而影响包括其他功能OPRM1 SNPs在内的相应单倍型的功能贡献。我们的结果为MOR-1K亚型在伤害性信号转导中的重要作用提供了证据，并表明替代OPRM1亚型的遗传变异可能导致阿片类药物反应的个体差异。
The μ-opioid receptor (OPRM1) is the principal receptor target for both endogenous and exogenous opioid analgesics. There are substantial individual differences in human responses to painful stimuli and to opiate drugs that are attributed to genetic variations in OPRM1. In searching for new functional variants, we employed comparative genome analysis and obtained evidence for the existence of an expanded human OPRM1 gene locus with new promoters, alternative exons and regulatory elements. Examination of polymorphisms within the human OPRM1 gene locus identified strong association between single nucleotide polymorphism (SNP) rs563649 and individual variations in pain perception. SNP rs563649 is located within a structurally conserved internal ribosome entry site (IRES) in the 5′-UTR of a novel exon 13-containing OPRM1 isoforms (MOR-1K) and affects both mRNA levels and translation efficiency of these variants. Furthermore, rs563649 exhibits very strong linkage disequilibrium throughout the entire OPRM1 gene locus and thus affects the functional contribution of the corresponding haplotype that includes other functional OPRM1 SNPs. Our results provide evidence for an essential role for MOR-1K isoforms in nociceptive signaling and suggest that genetic variations in alternative OPRM1 isoforms may contribute to individual differences in opiate responses.
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影响因子：
3.5
作者：
Diatchenko, L;Slade, GD;Maixner, W
通讯作者：
Maixner, W
影响因子：
3.5
作者：
Doyle, Glenn A.;Sheng, X. Rebecca;Berrettini, Wade H.
通讯作者：
Berrettini, Wade H.
影响因子：
4
作者：
Fillingim, RB;Ness, TJ;Staud, R
通讯作者：
Staud, R
影响因子：
4.7
作者：
Beyer, A;Koch, T;Höllt, V
通讯作者：
Höllt, V
影响因子：
8.8
作者：
Edwards, Robert R.;Haythomthwaite, Jennifer A.;Raja, Srinivasa
通讯作者：
Raja, Srinivasa