Next-generation sequencing profiling of mitochondrial genomes in gout
Abstract Background Accumulating 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 exa...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-07-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13075-018-1637-5 |
| _version_ | 1818026515832504320 |
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| author | Chia-Chun Tseng Chung-Jen Chen Jeng-Hsien Yen Hsi-Yuan Huang Jan-Gowth Chang Shun-Jen Chang Wei-Ting Liao |
| author_facet | Chia-Chun Tseng Chung-Jen Chen Jeng-Hsien Yen Hsi-Yuan Huang Jan-Gowth Chang Shun-Jen Chang Wei-Ting Liao |
| author_sort | Chia-Chun Tseng |
| collection | DOAJ |
| description | Abstract Background Accumulating 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. Methods Next-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. Results We 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). Conclusion This 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. |
| first_indexed | 2024-12-10T04:33:14Z |
| format | Article |
| id | doaj.art-a6c474c52a54431abcdfab66acd9914c |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-10T04:33:14Z |
| publishDate | 2018-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-a6c474c52a54431abcdfab66acd9914c2022-12-22T02:02:05ZengBMCArthritis Research & Therapy1478-63622018-07-0120111310.1186/s13075-018-1637-5Next-generation sequencing profiling of mitochondrial genomes in goutChia-Chun Tseng0Chung-Jen Chen1Jeng-Hsien Yen2Hsi-Yuan Huang3Jan-Gowth Chang4Shun-Jen Chang5Wei-Ting Liao6Department of Internal Medicine, Kaohsiung Municipal Ta-Tung HospitalDepartment of Internal Medicine, Kaohsiung Medical University HospitalDivision of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University HospitalDepartment of Laboratory Medicine and Epigenome Research Center, China Medical University Hospital, China Medical UniversityDepartment of Laboratory Medicine and Epigenome Research Center, China Medical University Hospital, China Medical UniversityDepartment of Kinesiology, Health and Leisure Studies, National University of KaohsiungDepartment of Biotechnology, College of Life Science, Kaohsiung Medical UniversityAbstract Background Accumulating 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. Methods Next-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. Results We 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). Conclusion This 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.http://link.springer.com/article/10.1186/s13075-018-1637-5MitochondriaGoutNext-generation sequencing |
| spellingShingle | Chia-Chun Tseng Chung-Jen Chen Jeng-Hsien Yen Hsi-Yuan Huang Jan-Gowth Chang Shun-Jen Chang Wei-Ting Liao Next-generation sequencing profiling of mitochondrial genomes in gout Arthritis Research & Therapy Mitochondria Gout Next-generation sequencing |
| title | Next-generation sequencing profiling of mitochondrial genomes in gout |
| title_full | Next-generation sequencing profiling of mitochondrial genomes in gout |
| title_fullStr | Next-generation sequencing profiling of mitochondrial genomes in gout |
| title_full_unstemmed | Next-generation sequencing profiling of mitochondrial genomes in gout |
| title_short | Next-generation sequencing profiling of mitochondrial genomes in gout |
| title_sort | next generation sequencing profiling of mitochondrial genomes in gout |
| topic | Mitochondria Gout Next-generation sequencing |
| url | http://link.springer.com/article/10.1186/s13075-018-1637-5 |
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