PLoS等两篇文章解析疾病基因易感性

　　

生物通报道：麻风病是麻风分枝杆菌引起的慢性传染病，是世界上三大慢性传染病（结核、麻风和梅毒）之一。这种疾病在古代几乎令人闻风丧胆，不少名著中都有提及这种疾病。近期来自中科院昆明动物研究所的研究人员与其他研究结构合作，接连发表了两篇文章，获得了麻风遗传易感性基因研究新成果。

在第一篇“Mitochondrial DNA Copy Number, but Not Haplogroup, Confers a Genetic Susceptibility to Leprosy in Han Chinese from Southwest China”文章中，昆明动物研究所的姚永刚课题组与昆明医学院第一附属医院皮肤科李玉叶副主任医师及玉溪市疾病预防控制中心李孝安医师合作，针对麻风分枝杆菌丢失大量能量代谢相关基因和对宿主严重的生存依赖性，推测认为宿主细胞“能量工厂”线粒体的差异可能影响麻风分枝杆菌的感染。

因此研究人员对玉溪地区麻风患者和正常对照个体线粒体DNA（mtDNA）遗传背景进行了分析，发现mtDNA遗传背景不影响麻风发病，但瘤型麻风患者中具有更高的mtDNA拷贝数，提示线粒体在麻风发病过程中具有一定的作用。

之前这一研究团队曾针对云南玉溪地区麻风流行和遗传易感性开展研究工作，为更好地认识麻风遗传易感性和积极防治提供了相关理论依据。前期，他们总结了玉溪地区57年（1952-2008）来麻风流行情况，并对近年来麻风流行趋势新动向进行了归纳（Leprosy Review，2011, 82: 6-16）。

在第二篇文章（Genetic variants of the MRC1 gene and the IFNG gene are associated with leprosy in Han Chinese from Southwest China ）中，研究人员对近期文献报道的与麻风相关的MRC1和IFNG基因进行了基因分型，在所研究的来自玉溪地区的527例麻风病人和583例对照人群中，没有验证到前人报道的MRC1基因（rs1926736，p.G396S)和IFNG基因（rs2430561，+874 T>A)的易感位点，但他们在这两个基因上发现其他的易感位点。

分析结果显示，MRC1基因的rs692527和rs34856358位点变异与少菌型麻风显著相关，IFNG基因rs3138557位点变异与多菌型麻风显著相关。该结果支持MRC1和IFNG基因是麻风的易感基因，但提示不同人群的易感遗传变异存在差异。这一研究结果发表在国际期刊Human Genetics上。

这两项研究结果对人们进一步了解麻风的遗传易感性提供了新证据，也为其它传染性疾病的研究提供了一定的参考。

（生物通：万纹）

原文摘要：

Mitochondrial DNA Copy Number, but Not Haplogroup, Confers a Genetic Susceptibility to Leprosy in Han Chinese from Southwest China

Background
Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an unculturable pathogen with an exceptionally eroded genome. The high level of inactivation of gene function in M. leprae, including many genes in its metabolic pathways, has led to a dependence on host energy production and nutritional products. We hypothesized that host cellular powerhouse - the mitochondria - may affect host susceptibility to M. leprae and the onset of clinical leprosy, and this may be reflected by mitochondrial DNA (mtDNA) background and mtDNA copy number.

Methods
We analyzed the mtDNA sequence variation of 534 leprosy patients and 850 matched controls from Yunnan Province and classified each subject by haplogroup. mtDNA copy number, taken to be proportional to mtDNA content, was measured in a subset of these subjects (296 patients and 231 controls) and 12 leprosy patients upon diagnosis.

Results
Comparison of matrilineal components of the case and control populations revealed no significant difference. However, measurement of mtDNA copy number showed that lepromatous leprosy patients had a significantly higher mtDNA content than controls (P = 0.008). Past medical treatments had no effect on the alteration of mtDNA copy number.

Conclusions
Our results suggested that mtDNA content, but not haplogroup, affects leprosy and this influence is limited to the clinical subtype of lepromatous leprosy.

Genetic variants of the MRC1 gene and the IFNG gene are associated with leprosy in Han Chinese from Southwest China

Leprosy is an ancient infectious disease, with over 200,000 affected people (mainly in Asia and Africa) being registered annually. Genetic factors may confer susceptibility to this disease. In the present study, we genotyped 12 genetic variants of the MRC1 gene and the IFNG gene in 527 Han Chinese with leprosy and 583 healthy individuals from Yunnan, China, to discern potential association of these two genes with leprosy. In particular, we aimed to validate the recently reported association of MRC1 variant rs1926736 (p.G396S) and IFNG variant rs2430561 (+874 T>A) with leprosy, which were initially observed in Vietnamese and Brazilian populations, respectively. Our results failed to confirm the reported association between variants rs1926736 and rs2430561 and leprosy in Han Chinese. However, we found that variants rs692527 (P = 0.022) and rs34856358 (P = 0.022) of the MRC1 gene were associated with paucibacillary leprosy, and rs3138557 of the IFNG gene was significantly associated with multibacillary leprosy. The exact role of the MRC1 gene and the IFNG gene in leprosy awaits future study.