Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence in genome-wide and subsequent association studies.
Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence in genome-wide and subsequent association studies.
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DOI：
10.1186/s13041-015-0142-x
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发表时间：
2015-08-20
期刊：
影响因子：
3.6
通讯作者：
Ikeda K
中科院分区：
文献类型：
--
作者：
Nishizawa D;Kasai S;Hasegawa J;Sato N;Yamada H;Tanioka F;Nagashima M;Katoh R;Satoh Y;Tagami M;Ujike H;Ozaki N;Inada T;Iwata N;Sora I;Iyo M;Yamada M;Kondo N;Won MJ;Naruse N;Uehara-Aoyama K;Itokawa M;Ohi K;Hashimoto R;Tanisawa K;Arai T;Mori S;Sawabe M;Naka-Mieno M;Yamada Y;Yamada M;Sato N;Muramatsu M;Tanaka M;Irukayama-Tomobe Y;Saito YC;Sakurai T;Hayashida M;Sugimura H;Ikeda K
尼古丁依赖的病因涉及多种遗传和环境因素。尽管候选基因研究或全基因组关联研究(GWAS)报告了几个候选基因变异与吸烟行为和尼古丁依赖的易感性有关，但此类研究大多是对具有欧洲血统的受试者进行的。然而，作为GWASs的日本人群的遗传因素很少被研究。为了阐明与日本人尼古丁依赖有关的遗传因素，本研究利用日本受试者20多万个标记的全基因组基因分型阵列，全面探索了尼古丁依赖的遗传因素。GWAS和复制研究的对象分别为148名和374名患者。使用尼古丁依赖的Fagerström测试(FTND)、烟草依赖筛查(TDS)和每天吸烟的数量(CPD)作为尼古丁依赖的指标，进行了两阶段的GWAS。为了进行额外的关联分析，招募了腹部大手术的患者、甲基苯丙胺依赖/精神病患者和具有分裂型人格特征数据的健康受试者。对各种疾病的尸检标本也进行了评估。在研究了20多万个标记单核苷酸多态(SNPs)与FTND、TDS和CPD的关系后，非同义的rs2653349SNP(位于食欲素受体2的编码基因上)被选为与FTND相关的最显著的SNP，在两个阶段的GWAs中p值为0.0005921。对于剩余的374个样本，重复了这种可能的关联。这种SNP还与术后疼痛、开始使用甲基苯丙胺、分裂型人格特征以及对甲状腺肿的易感性有关。尽管在我们的两个阶段的GWA中，p值没有达到传统的全基因组水平，但我们在随后的分析中获得了显著的结果，表明rs2653349 SNP(Val308Ile)可能是一个遗传因素，与日本人群中的尼古丁依赖和可能的疼痛、分裂型人格特征和甲状腺肿有关。本文的在线版本(doi：10.1186/s13041-0150142-x)包含补充材料，授权用户可以使用。
Many genetic and environmental factors are involved in the etiology of nicotine dependence. Although several candidate gene variations have been reported by candidate gene studies or genome-wide association studies (GWASs) to be associated with smoking behavior and the vulnerability to nicotine dependence, such studies have been mostly conducted with subjects with European ancestry. However, genetic factors have rarely been investigated for the Japanese population as GWASs. To elucidate genetic factors involved in nicotine dependence in Japanese, the present study comprehensively explored genetic contributors to nicotine dependence by using whole-genome genotyping arrays with more than 200,000 markers in Japanese subjects. The subjects for the GWAS and replication study were 148 and 374 patients, respectively. A two-stage GWAS was conducted using the Fagerström Test for Nicotine Dependence (FTND), Tobacco Dependence Screener (TDS), and number of cigarettes smoked per day (CPD) as indices of nicotine dependence. For the additional association analyses, patients who underwent major abdominal surgery, patients with methamphetamine dependence/psychosis, and healthy subjects with schizotypal personality trait data were recruited. Autopsy specimens with various diseases were also evaluated. After the study of associations between more than 200,000 marker single-nucleotide polymorphisms (SNPs) and the FTND, TDS, and CPD, the nonsynonymous rs2653349 SNP (located on the gene that encodes orexin [hypocretin] receptor 2) was selected as the most notable SNP associated with FTND, with a p value of 0.0005921 in the two-stage GWAS. This possible association was replicated for the remaining 374 samples. This SNP was also associated with postoperative pain, the initiation of methamphetamine use, schizotypal personality traits, and susceptibility to goiter. Although the p value did not reach a conventional genome-wide level of significance in our two-stage GWAS, we obtained significant results in the subsequent analyses that suggest that the rs2653349 SNP (Val308Ile) could be a genetic factor that is related to nicotine dependence and possibly pain, schizotypal personality traits, and goiter in the Japanese population. The online version of this article (doi:10.1186/s13041-015-0142-x) contains supplementary material, which is available to authorized users.