{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T11:17:14Z","timestamp":1779275834265,"version":"3.51.4"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T00:00:00Z","timestamp":1694995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Mitochondrial DNA (mtDNA) variants have been implicated in keratoconus (KC). The present study aimed to characterize the mtDNA heteroplasmy profile in KC and explore the association of mitochondrial heteroplasmic levels with KC.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Mitochondrial sequencing of peripheral blood samples and corneal tomography were conducted in 300 KC cases and 300 matched controls. The number of heteroplasmic and homoplasmic variants was calculated across the mitochondrial genome. Spearman\u2019s correlation was used to analyze the correlation between the number of heteroplasmic variants and age. The association of mtDNA heteroplasmic level with KC was analyzed by logistic regression analysis. Moreover, the relationship between mitochondrial heteroplasmic levels and clinical parameters was determined by linear regression analysis.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The distribution of mtDNA heteroplasmic variants showed the highest number of heteroplasmic variants in the non-coding region, while the <jats:italic>COX3<\/jats:italic> gene exhibited the highest number in protein-coding genes. Comparisons of the number of heteroplasmic and homoplasmic non-synonymous variants in protein-coding genes revealed no significant differences between KC cases and controls (all <jats:italic>p<\/jats:italic> &amp;gt; 0.05). In addition, the number of heteroplasmic variants was positively associated with age in all subjects (<jats:italic>r<\/jats:italic> = 0.085, <jats:italic>p<\/jats:italic> = 0.037). The logistic regression analyses indicated that the heteroplasmic levels of m.16180_16181delAA was associated with KC (<jats:italic>p<\/jats:italic> &amp;lt; 0.005). Linear regression analyses demonstrated that the heteroplasmic levels of m.16180_16181delAA and m.302A&amp;gt;C were not correlated with thinnest corneal thickness (TCT), steep keratometry (Ks), and flat keratometry (Kf) (all <jats:italic>p<\/jats:italic> &amp;gt; 0.05) in KC cases and controls separately.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The current study characterized the mtDNA heteroplasmy profile in KC, and revealed that the heteroplasmic levels of m.16180_16181delAA were associated with KC.<\/jats:p>","DOI":"10.3389\/fgene.2023.1251951","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T06:52:46Z","timestamp":1695106366000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Mitochondrial DNA heteroplasmy analysis in keratoconus patients from China"],"prefix":"10.3389","volume":"14","author":[{"given":"Liyan","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaili","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuwei","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengwei","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"641708","DOI":"10.1155\/2014\/641708","article-title":"Genetics of keratoconus: where do we stand?","volume":"2014","author":"Abu-Amero","year":"","journal-title":"J. Ophthalmol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.1167\/iovs.14-13938","article-title":"Mitochondrial sequence changes in keratoconus patients","volume":"55","author":"Abu-Amero","year":"","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1167\/iovs.04-1395","article-title":"Accumulation of mitochondrial DNA damage in keratoconus corneas","volume":"46","author":"Atilano","year":"2005","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e0246114","DOI":"10.1371\/journal.pone.0246114","article-title":"Low frequency mitochondrial DNA heteroplasmy SNPs in blood, retina, and [RPE+choroid] of age-related macular degeneration subjects","volume":"16","author":"Atilano","year":"2021","journal-title":"PloS one"},{"key":"B5","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1021\/acs.est.2c02556","article-title":"In utero exposure to air pollutants and mitochondrial heteroplasmy in neonates","volume":"57","author":"Cosemans","year":"2023","journal-title":"Environ. Sci. Technol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.mito.2020.12.006","article-title":"Polymorphisms and haplotype of mitochondrial DNA D-loop region are associated with polycystic ovary syndrome in a Chinese population","volume":"57","author":"Deng","year":"2021","journal-title":"Mitochondrion"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.3390\/cancers12071933","article-title":"Profiling of mitochondrial DNA heteroplasmy in a prospective oral squamous cell carcinoma study","volume":"12","author":"Fendt","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.jtos.2020.03.006","article-title":"The keratoconus enigma: A review with emphasis on pathogenesis","volume":"18","author":"Ferrari","year":"2020","journal-title":"Ocul. Surf."},{"key":"B9","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1111\/dme.13874","article-title":"Mitochondrial DNA mutation m.3243A>G is associated with altered mitochondrial function in peripheral blood mononuclear cells, with heteroplasmy levels and with clinical phenotypes","volume":"36","author":"Geng","year":"2019","journal-title":"Diabet. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"392","DOI":"10.3390\/antiox8090392","article-title":"Mitochondrial genome (mtDNA) mutations that generate reactive oxygen species","volume":"8","author":"Hahn","year":"2019","journal-title":"Antioxidants (Basel)"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1167\/iovs.63.13.1","article-title":"Insufficient dose of ERCC8 protein caused by a frameshift mutation is associated with keratoconus with congenital cataracts","volume":"63","author":"Hao","year":"2022","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"415","DOI":"10.3390\/antiox10030415","article-title":"Generation of reactive oxygen species by mitochondria","volume":"10","author":"Hernansanz-Agustin","year":"2021","journal-title":"Antioxidants (Basel)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1146\/annurev-vision-121219-081723","article-title":"Genetic and environmental risk factors for keratoconus","volume":"6","author":"Lucas","year":"2020","journal-title":"Annu. Rev. Vis. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.survophthal.2017.06.009","article-title":"A review of keratoconus: diagnosis, pathophysiology, and genetics","volume":"62","author":"Mas Tur","year":"2017","journal-title":"Surv. Ophthalmol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The genome analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"109062","DOI":"10.1016\/j.exer.2022.109062","article-title":"Pathogenesis of keratoconus: NRF2-antioxidant, extracellular matrix and cellular dysfunctions","volume":"219","author":"Monteiro de Barros","year":"2022","journal-title":"Exp. Eye Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"eabe7520","DOI":"10.1126\/sciadv.abe7520","article-title":"Nuclear genome-wide associations with mitochondrial heteroplasmy","volume":"7","author":"Nandakumar","year":"2021","journal-title":"Sci. Adv."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e777","DOI":"10.1111\/aos.14714","article-title":"Oxidative and antioxidative stress markers in keratoconus: a systematic review and meta-analysis","volume":"99","author":"Navel","year":"2021","journal-title":"Acta Ophthalmol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"633","DOI":"10.3390\/life11070633","article-title":"mtDNA heteroplasmy: origin, detection, significance, and evolutionary consequences","volume":"11","author":"Parakatselaki","year":"2021","journal-title":"Life (Basel)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1514","DOI":"10.1016\/j.fsigss.2011.09.012","article-title":"Mitochondrial complex 1 gene analysis in keratoconus","volume":"17","author":"Pathak","year":"2011","journal-title":"Mol. Vis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/s0039-6257(97)00119-7","article-title":"Keratoconus","volume":"42","author":"Rabinowitz","year":"1998","journal-title":"Surv. Ophthalmol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/j.drudis.2018.10.017","article-title":"Interplay between hereditary and environmental factors to establish an in vitro disease model of keratoconus","volume":"24","author":"Roy","year":"2019","journal-title":"Drug Discov. Today"},{"key":"B24","doi-asserted-by":"publisher","first-page":"101559","DOI":"10.1016\/j.clae.2021.101559","article-title":"Keratoconus: an updated review","volume":"45","author":"Santodomingo-Rubido","year":"2022","journal-title":"Cont. Lens Anterior Eye"},{"key":"B25","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1097\/ICO.0000000000001083","article-title":"Trends in corneal transplantation in keratoconus","volume":"36","author":"Sarezky","year":"2017","journal-title":"Cornea"},{"key":"B26","doi-asserted-by":"publisher","first-page":"852","DOI":"10.3390\/antiox9090852","article-title":"Oxidative stress: concept and some practical aspects","volume":"9","author":"Sies","year":"2020","journal-title":"Antioxidants (Basel)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1007\/978-3-319-55330-6_30","article-title":"Mitochondrial heteroplasmy","volume":"982","author":"Stefano","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/s41576-020-00284-x","article-title":"Extreme heterogeneity of human mitochondrial DNA from organelles to populations","volume":"22","author":"Stewart","year":"2021","journal-title":"Nat. Rev. Genet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.mito.2017.05.009","article-title":"Mitochondrial dysfunction and oxidative stress in corneal disease","volume":"36","author":"Vallabh","year":"2017","journal-title":"Mitochondrion"},{"key":"B30","doi-asserted-by":"publisher","first-page":"a021220","DOI":"10.1101\/cshperspect.a021220","article-title":"Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease","volume":"5","author":"Wallace","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.nbd.2018.02.015","article-title":"Mitochondrial DNA variants modulate genetic susceptibility to Parkinson's disease in Han Chinese","volume":"114","author":"Wu","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"B32","first-page":"270","article-title":"Whole mitochondrial genome analysis in Chinese patients with keratoconus","volume":"27","author":"Xu","year":"2021","journal-title":"Mol. Vis."},{"key":"B33","doi-asserted-by":"publisher","first-page":"7559","DOI":"10.1038\/s41598-021-87291-y","article-title":"A hospital-based study on clinical data, demographic data and visual function of keratoconus patients in Central China","volume":"11","author":"Yang","year":"2021","journal-title":"Sci. Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"10654","DOI":"10.1073\/pnas.1403521111","article-title":"Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals","volume":"111","author":"Ye","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1251951\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T06:52:48Z","timestamp":1695106368000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1251951\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,18]]},"references-count":34,"alternative-id":["10.3389\/fgene.2023.1251951"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2023.1251951","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,18]]},"article-number":"1251951"}}