The mtDNA replication-related genes TFAM and POLG are associated with leprosy in Han Chinese from Southwest China

Autor: Guo-Dong Li, Heng Long, Yong-Gang Yao, Yu-Ye Li, Yu Fan, Xiu-Feng Yu, Deng-Feng Zhang, Dong Wang, Rui Bi
Rok vydání: 2017
Předmět:
Adult
DNA Replication
Male
0301 basic medicine
China
Mitochondrial DNA
Adolescent
DNA Copy Number Variations
Quantitative Trait Loci
Single-nucleotide polymorphism
Dermatology
Biology
DNA
Mitochondrial
Polymorphism
Single Nucleotide
Biochemistry
Mitochondrial Proteins
Young Adult
03 medical and health sciences
Exon
Asian People
Humans
Genetic Predisposition to Disease
RNA
Messenger
Child
Molecular Biology
Gene
Mycobacterium leprae
Genetic Association Studies
Aged
Skin
Genetic association
Aged
80 and over
Genetics
High-Throughput Nucleotide Sequencing
Exons
Sequence Analysis
DNA
Middle Aged
TFAM
biology.organism_classification
DNA Polymerase gamma
DNA-Binding Proteins
030104 developmental biology
Case-Control Studies
Leprosy
Multibacillary
Expression quantitative trait loci
Female
Leprosy
Paucibacillary
Transcription Factors
Zdroj: Journal of Dermatological Science. 88:349-356
ISSN: 0923-1811
DOI: 10.1016/j.jdermsci.2017.09.001
Popis: Background 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. Objective We aimed to identify genetic associations between the mtDNA replication-related genes TFAM, POLG and leprosy. Methods 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. Results 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 × 10−12), and rs3176238 was a significant cis eQTL for POLG in nerve (P = 3.90 × 10−13) and skin tissues (P = 2.50 × 10−11). Consistently, mRNA level of POLG was differentially expressed in leprotic skin lesions. Conclusions Genetic variants of TFAM and POLG were associated with leprosy in Han Chinese, presumably by affecting gene expression.
Databáze: OpenAIRE
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