张亚平院士研究组解析激素通路遗传多态性

　　

生物通报道，昆明动物所的张亚平院士研究小组近期继在慢性阻塞性肺病遗传机理研究取得进展后又发表新文章，对褪黑激素通路基因多态性与日照时长的相关性进行了系统分析，相关成果文章Association of disease-predisposition polymorphisms of the melatonin receptors and sunshine duration in the global human populations公布在Journal of Pineal Research上。

 

褪黑激素通路是生物节律信号转导的主要途径之一，受环境日/夜周期影响。世界范围内不同的日照时长及相应的昼夜节律的自然选择作用很可能对褪黑激素通路的遗传多态起着重要的作用。

 

在张亚平院士带领及香港中文大学邓亮生教授的共同指导下，博士生季林丹等对世界人群（CEPH-HGDP）褪黑激素通路基因多态性与日照时长的相关性进行了系统分析。

 

研究提示在全世界范围内人群中褪黑激素受体MT2（MTNR1B）基因的多态性与日照密切相关，该结果同时在中国群体中得到验证。因此，褪黑激素通路，尤其MT2受体的遗传多态性很可能经历了日照的自然选择。

 

此外，该遗传多态性在前期与香港中文大学的合作研究中发现与青少年特发性脊柱侧凸（Adolescent Idiopathic scoliosis, AIS）发病相关；近期报道的全基因组研究（GWAs）也提示其为二型糖尿病(Type 2 Diabetes Mellitus, T2D)的易感位点。

 

综合研究结果提示，日照时长的自然选择作用可能促使形成了MTNR1B基因遗传位点的多态；但随着自然环境及生活方式的改变，该多态性反而可能成为疾病易感因素。该研究是阐释复杂疾病易感位点经历环境自然选择假说的一次成功示例，更重要是也可为二型糖尿病及青少年特发性脊柱侧凸等疾病临床诊治等提供新的信息。

 

慢性阻塞性肺病遗传机理研究

昆明动物研究所张亚平院士研究组近期又出新成果，他们在慢性阻塞性肺病遗传机理研究取得进展，相关成果文章公布在The American Journal of Respiratory and Critical Care Medicine上。

 

慢性阻塞性肺病(Chronic Obstructive Pulmonary Disease, COPD)是一种以气流不可逆受限为特征的呼吸道疾病，多发于老年人中，目前排全世界死亡原因的第四位，对人类健康造成了极大危害。谷胱甘肽S转移酶P1(Glutathione S-transferase P1, GSTP1)为可溶性同功酶超基因家族成员之一，是代谢多种内源性或外源性化学物质，尤其毒性物质的重要解毒酶。GSTP1基因第5外显子内的基因多态rs1659，可导致所编码的异亮氨酸(Ile)替换为缬氨酸(Val)，并改变酶分子的空间构象，进而影响到酶与亲电子底物结合的特异性、稳定性及催化活性。由此导致氧化-抗氧化失衡，是COPD的潜在病理之一。然而目前有关GSTP1基因105位点与COPD的关系仍有争议。

 

 为进一步探讨这一问题，在张亚平院士指导下，云南大学博士研究生钟丽及昆明医学院第一附属医院呼吸内科的傅炜萍等人，收集了来自中国西南地区的汉族样本(327个病例和349个对照)，并对其I105V位点进行了扫描。

 

结果表明，在东亚群体中，I105V位点与COPD并无显著相关。这一结论也与此前大多数研究相符，而与近期Smolonska等人发表的一篇荟萃分析(meta analysis)的结果相反。进一步数据核查发现，该文错误地颠倒了两篇文献(Vibhuti et al.2007和Chan-Yeung et al.2007)中疾病组和对照组的数据。当这一错误得以修正后，得出了与张亚平院士研究组相同的结论。此外，此前所有的分析，都假设GSTP1基因是以显性模式发挥作用的，然而这一点实际并不明确。对已发表的15篇文献数据的重新分析表明，这一基因更有可能遵循隐形遗传模式。在隐性模式下，此位点在欧洲群体中与COPD显著相关，而在亚洲人群中未观察到任何显著相关性。该研究为解析COPD的遗传机理研究提供了新的视角。

（生物通 小茜）

Roche免费派送实时定量PCR技术指导手册 赶快点击索取

生物通推荐原文检索

Association of disease-predisposition polymorphisms of the melatonin receptors and sunshine duration in the global human populations

Lin-dan Ji 1,2,3*, Jin Xu 4*, Dong-dong Wu 2,5 , Si-da Xie 3,6 , Nelson L. S. Tang 3,6,7 and Ya-ping Zhang 2,3,8

  1 Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou, China ;   2 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China ;   3 KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, China ;   4 Institute of Public Health, School of Medicine, Ningbo University, Ningbo, China ;   5 Graduate School of the Chinese Academy of Sciences, Beijing, China ;   6 Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China ;   7 Laboratory for Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China ;   8 Laboratory for Conservation and Utilization of Bio-resource, Yunnan University, Kunming, China

Correspondence to Address reprint request to Ya-Ping Zhang, State Key Laboratory of Genetic resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, 32 East Jiao-Chang Road, Kunming 650223, Yunnan, China; Nelson L.S. Tang, Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.

E-mail: [e-mail]; [e-mail]

  *These authors contributed equally to this work.

 

Copyright Journal compilation © 2010 John Wiley & Sons A/S

KEYWORDS

association study • melatonin pathway • melatonin receptor 1B • natural selection • sunshine duration

ABSTRACT

Abstract: Melatonin is predominantly involved in signaling circadian and seasonal rhythms, and its synthesis is regulated by the environmental light/dark cycle. The selection pressure by geographically different environmental light/dark cycles, which is predominantly determined by sunshine duration, on the global distribution of genetic polymorphisms in the melatonin pathway is not well understood. Recent genetic association studies identified various disease-predisposition polymorphisms in this pathway. We investigated the correlations between the prevalence of these clinically important single nucleotide polymorphisms (SNPs) and sunshine duration among worldwide human populations from twelve regions in the CEPH-HGDP database rs4753426, a recently reported predisposition SNP for type 2 diabetes in the promoter of the MT2 melatonin receptor gene (MTNR1B), which was not included in the CEPH-HGDP genotyping array, was additionally genotyped. This SNP showed a marginally significant correlation in 760 CEPH-HGDP DNA samples (r = −0.5346, P = 0.0733), and it showed the most prominent association among the candidate melatonin pathway SNPs examined. To control for population structure, which may lead to a false positive correlation, we genotyped this SNP in a replication set of 1792 subjects from China. The correlation was confirmed among Chinese populations (r = −0.8694, P = 0.0002), and was also statistically significant after correction of other climatic and geographical covariants in multiple regression analysis (β = −0.907, P = 1.94 × 10−5). Taken together, it suggests that the human melatonin signaling pathway, particularly MT2 melatonin receptor may have undergone a selective pressure in response to global variation in sunshine duration.