Next-generation sequencing profiling of mitochondrial genomes in gout View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-07-06

AUTHORS

Chia-Chun Tseng, Chung-Jen Chen, Jeng-Hsien Yen, Hsi-Yuan Huang, Jan-Gowth Chang, Shun-Jen Chang, Wei-Ting Liao

ABSTRACT

BackgroundAccumulating evidence implicates mitochondrial DNA (mtDNA) alleles, which are independent of the nuclear genome, in disease, especially in human metabolic diseases. However, this area of investigation has lagged behind in researching the nuclear alleles in complex traits, for example, in gout.MethodsNext-generation sequencing was utilized to investigate the relationship between mtDNA alleles and phenotypic variations in 52 male patients with gout and 104 age-matched male non-gout controls from the Taiwan Biobank whole-genome sequencing samples. Differences from a reference sequence (GRCh38) were identified. The sequence kernel association test (SKAT) was applied to identify gout-associated alleles in mitochondrial genes. The tools Polymorphism Phenotyping, Sorting Intolerant From Tolerant (SIFT), Predict the pathology of Mutations (PMUT), Human Mitochondrial Genome Database (mtDB), Multiple Alignment using Fast Fourier Transform (MAFFT), and Mammalian Mitochondrial tRNA Genes (Mamit-tRNA) were used to evaluate pathogenicity of alleles. Validation of selected alleles by quantitative polymerase chain reaction of single nucleotide polymorphisms (qPCR SNPs) was also performed.ResultsWe identified 456 alleles in patients with gout and 640 alleles in non-gout controls with 274 alleles shared by both. Mitochondrial genes were associated with gout, with MT-CO3, MT-TA, MT-TC, and MT-TT containing potentially pathogenic gout-associated alleles and displaying evidence of gene-gene interactions. All heteroplasmy levels of potentially pathogenic alleles exceeded metabolic thresholds for pathogenicity. Validation assays confirmed the next-generation sequencing results of selected alleles. Among them, potentially pathogenic MT-CO3 alleles correlated with high-density lipoprotein (HDL) levels (P = 0.034).ConclusionThis study provided two scientific insights. First, this was the most extensive mitochondrial genomic profiling associated with gout. Second, our results supported the roles of mitochondria in gout and HDL, and this comprehensive analysis framework can be applied to other diseases in which mitochondrial dysfunction has been implicated. More... »

PAGES

137

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s13075-018-1637-5

DOI

http://dx.doi.org/10.1186/s13075-018-1637-5

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https://app.dimensions.ai/details/publication/pub.1105317910

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29976239


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42 DNA alleles
43 Fourier transform
44 HDL
45 MT-CO3
46 MethodsNext-generation sequencing
47 Polymorphism Phenotyping
48 ResultsWe
49 alignment
50 alleles
51 analysis framework
52 area
53 area of investigation
54 assays
55 chain reaction
56 complex traits
57 comprehensive analysis framework
58 containing
59 control
60 database
61 differences
62 disease
63 dysfunction
64 evidence
65 example
66 fast Fourier transform
67 framework
68 gene-gene interactions
69 genes
70 genome
71 genome database
72 genomic profiling
73 gout
74 heteroplasmy levels
75 high-density lipoprotein levels
76 human metabolic diseases
77 human mitochondrial genome database
78 insights
79 interaction
80 intolerant
81 investigation
82 kernel association test
83 levels
84 lipoprotein levels
85 male patients
86 metabolic diseases
87 metabolic threshold
88 mitochondria
89 mitochondrial DNA (mtDNA) alleles
90 mitochondrial dysfunction
91 mitochondrial genes
92 mitochondrial genome
93 mitochondrial genome database
94 mitochondrial tRNA genes
95 mtDNA alleles
96 multiple alignment
97 mutations
98 next-generation sequencing profiling
99 next-generation sequencing results
100 non-gout controls
101 nuclear alleles
102 nuclear genome
103 nucleotide polymorphisms
104 pathogenic alleles
105 pathogenicity
106 pathology
107 patients
108 phenotypic variation
109 phenotyping
110 polymerase chain reaction
111 polymorphism
112 profiling
113 quantitative polymerase chain reaction
114 reaction
115 reference sequence
116 relationship
117 results
118 role
119 role of mitochondria
120 samples
121 scientific insights
122 sequence
123 sequence kernel association test
124 sequencing
125 sequencing profiling
126 sequencing results
127 sequencing samples
128 single nucleotide polymorphisms
129 study
130 tRNA genes
131 test
132 threshold
133 tolerant
134 traits
135 transform
136 validation
137 validation assays
138 variation
139 whole-genome sequencing samples
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