Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
J Dermatol Sci. 2017 Dec;88(3):349-356. doi: 10.1016/j.jdermsci.2017.09.001. Epub 2017 Sep 14.
The pathogen Mycobacterium leprae of leprosy is heavily dependent on the host energy metabolites and nutritional products for survival. Previously we and others have identified associations of several mitochondrion-related genes and mitochondrial DNA (mtDNA) copy number alterations with leprosy and/or its subtype. We hypothesized that genetic variants of mtDNA replication-related genes would affect leprosy.
We aimed to identify genetic associations between the mtDNA replication-related genes TFAM, POLG and leprosy.
Genetic association study was performed in 2898 individuals from two independent sample sets in Yunnan Province, China. We first screened 7 tag SNPs of TFAM and POLG in 527 leprosy cases and 583 controls (Sample I). Expression quantitative trait loci (eQTL) analysis and differential mRNA expression were analyzed to discern potential effect of risk variants. The entire exon region of TFAM and POLG were further analyzed in 798 leprosy cases and 990 controls (Sample II; 4327 East Asians from the ExAC dataset was included as a reference control) by using targeted gene sequencing for fine mapping potentially causal variants.
Two tag SNPs of TFAM (rs1049432, P=0.007) and POLG (rs3176238, P=0.006) were associated with multibacillary leprosy (MB) in Sample I and the significance survived correction for multiple comparisons. SNPs rs1937 of TFAM (which was linked with rs1049432) and rs61756401 of POLG were associated with leprosy, whereas no potentially causative coding variants were identified in Sample II. The eQTL analysis showed that rs1049432 was a significant cis eQTL for TFAM in nerve tissue (P=1.20×10), and rs3176238 was a significant cis eQTL for POLG in nerve (P=3.90×10) and skin tissues (P=2.50×10). Consistently, mRNA level of POLG was differentially expressed in leprotic skin lesions.
Genetic variants of TFAM and POLG were associated with leprosy in Han Chinese, presumably by affecting gene expression.
麻风分枝杆菌是麻风病的病原体，它严重依赖于宿主的能量代谢物和营养产物来生存。此前，我们和其他人已经发现了几个与麻风病及其亚型相关的线粒体相关基因和线粒体 DNA（mtDNA）拷贝数改变的关联。我们假设 mtDNA 复制相关基因的遗传变异会影响麻风病。
我们旨在确定 mtDNA 复制相关基因 TFAM、POLG 与麻风病之间的遗传关联。
在中国云南省的两个独立样本集中，对 2898 个人进行了遗传关联研究。我们首先在 527 例麻风病例和 583 例对照（样本 I）中筛选了 TFAM 和 POLG 的 7 个标签 SNP。通过表达数量性状基因座（eQTL）分析和差异 mRNA 表达分析，来辨别风险变异的潜在影响。我们进一步通过靶向基因测序对 TFAM 和 POLG 的整个外显子区域进行了分析，以在 798 例麻风病例和 990 例对照（样本 II；纳入了来自 ExAC 数据集的 4327 名东亚人作为参考对照）中进行精细定位潜在的因果变异。
TFAM 的两个标签 SNP（rs1049432，P=0.007）和 POLG 的 rs3176238（P=0.006）与样本 I 中的多菌型麻风（MB）相关，且在多重比较校正后仍具有统计学意义。TFAM 的 rs1937 与 rs1049432 相关，POLG 的 rs61756401 与麻风病相关，而在样本 II 中未发现潜在的致病变异。eQTL 分析表明，rs1049432 是神经组织中 TFAM 的显著顺式 eQTL（P=1.20×10），rs3176238 是神经组织（P=3.90×10）和皮肤组织（P=2.50×10）中 POLG 的显著顺式 eQTL。同样，POLG 的 mRNA 水平在麻风病变皮肤中存在差异表达。
TFAM 和 POLG 的遗传变异与汉族人群的麻风病相关，可能是通过影响基因表达。
