Leukocyte mitochondrial DNA copy number is a potential non-invasive biomarker for psoriasis

Materah Salem Alwehaidah 1, Suad AlFadhli 1, Ghada Al-Kafaji 2

Affiliations

29 June 2022

-

doi: 10.1371/journal.pone.0270714

Abstract

Abnormalities in the mitochondria have been linked to psoriasis, a chronic immune-mediated inflammatory skin disease. The mitochondrial DNA (mtDNA) is present in thousands of copies per cell and altered mtDNA copy number (mtDNA-CN), a common indicator of mitochondrial function, has been proposed as a biomarker for several diseases including autoimmune diseases. In this case-control study, we investigated whether the mtDNA-CN is related to psoriasis, correlates with the disease duration and severity, and can serve as a disease biomarker. Relative mtDNA-CN as compared with nuclear DNA was measured by a quantitative real-time polymerase chain reaction in peripheral blood buffy coat samples from 56 patients with psoriasis and 44 healthy controls. The receiver operating characteristic (ROC) curve analysis was performed to evaluate the value of mtDNA-CN as a biomarker. We found that the mtDNA-CN was significantly decreased in patients with psoriasis compared to healthy controls (93.6±5.3 vs. 205±71; P = 0.04). Sub-group analyses with stratification of patients based on disease duration under or over 10 years and disease severity indicated that the mtDNA-CN was significantly lower in patients with longer disease duration (74±4.3 in disease duration >10 years vs. 79±8.3 in disease duration <10 years, P = 0.009), and higher disease severity (72±4.3 in moderate-to-severe index vs. 88.3 ± 6 in mild index, P = 0.017). Moreover, the mtDNA-CN was negatively correlated with the disease duration and disease severity (r = -0.36, P = 0.006; r = -0.41, P = 0.003 respectively). The ROC analysis of mtDNA-CN showed an area under the curve (AUC) of 0.84 (95% confidence interval: 0.69-0.98; P = 0.002) for differentiating patients from healthy controls. Our study suggests that low mtDNA-CN may be an early abnormality in psoriasis and associates with the disease progression. Our study also suggests that mtDNA-CN may be a novel blood-based biomarker for the early detection of psoriasis.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. mtDNA-CN in psoriasis patients and healthy controls. The mtDNA-CN was quantified by real-time qPCR in peripheral blood buffy coat samples from patients with psoriasis (n = 56) and healthy controls (n = 44). A: Bar graph of data expressed as the mean ± standard deviation (SD). B: Dot plot of data.

Fig 1. mtDNA-CN in psoriasis patients and healthy controls. The mtDNA-CN was quantified by real-time qPCR in peripheral blood buffy coat samples from patients with psoriasis (n = 56) and healthy controls (n = 44). A: Bar graph of data expressed as the mean ± standard deviation (SD). B: Dot plot of data.

Fig 2. Relationship of mtDNA-CN with disease duration. The patients were sub-divided into two groups based on disease duration as <10 years (n = 23) and >10 years (n = 33). A: Bar graph of data expressed as the mean ± standard deviation (SD). B: Dot plot of data.

Fig 2. Relationship of mtDNA-CN with disease duration. The patients were sub-divided into two groups based on disease duration as <10 years (n = 23) and >10 years (n = 33). A: Bar graph of data expressed as the mean ± standard deviation (SD). B: Dot plot of data.

Fig 3. Relationship of mtDNA-CN with the disease severity. The patients were sub-divided based on PASI scores into two groups as mild (n = 23) and moderate-to-severe (n = 33). A: Bar graph of data expressed as the mean ± standard deviation (SD). B: Dot plot of data.

Fig 3. Relationship of mtDNA-CN with the disease severity. The patients were sub-divided based on PASI scores into two groups as mild (n = 23) and moderate-to-severe (n = 33). A: Bar graph of data expressed as the mean ± standard deviation (SD). B: Dot plot of data.

Fig 4. ROC analysis of mtDNA-CN. ROC curve was generated to evaluate the diagnostic value of mtDNA-CN as a biomarker for psoriasis. The AUC for discriminating psoriasis patients from healthy controls was 0.84 (95% CI: 0.694–0.977, P = 0.002).

Fig 4. ROC analysis of mtDNA-CN. ROC curve was generated to evaluate the diagnostic value of mtDNA-CN as a biomarker for psoriasis. The AUC for discriminating psoriasis patients from healthy controls was 0.84 (95% CI: 0.694–0.977, P = 0.002).

Similar articles

GWAS and ExWAS of blood mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia.

Chong M, Mohammadi-Shemirani P, Perrot N, Nelson W, Morton R, Narula S, Lali R, Khan I, Khan M, Judge C, Machipisa T, Cawte N, O'Donnell M, Pigeyre M, Akhabir L, Paré G.Elife. 2022 Jan 13;11:e70382. doi: 10.7554/eLife.70382.PMID: 35023831 Free PMC article.

Peripheral blood mitochondrial DNA copy number as a novel potential biomarker for diabetic nephropathy in type 2 diabetes patients.

Al-Kafaji G, Aljadaan A, Kamal A, Bakhiet M.Exp Ther Med. 2018 Aug;16(2):1483-1492. doi: 10.3892/etm.2018.6319. Epub 2018 Jun 15.PMID: 30116398 Free PMC article.

Mitochondrial DNA Copy Number in Peripheral Blood as a Potential Non-invasive Biomarker for Multiple Sclerosis.

Al-Kafaji G, Bakheit HF, Alharbi MA, Farahat AA, Jailani M, Ebrahin BH, Bakhiet M.Neuromolecular Med. 2020 Jun;22(2):304-313. doi: 10.1007/s12017-019-08588-w. Epub 2020 Jan 4.PMID: 31902116

Thinking outside the nucleus: Mitochondrial DNA copy number in health and disease.

Castellani CA, Longchamps RJ, Sun J, Guallar E, Arking DE.Mitochondrion. 2020 Jul;53:214-223. doi: 10.1016/j.mito.2020.06.004. Epub 2020 Jun 13.PMID: 32544465 Free PMC article. Review.

Mitochondrial DNA Copy Number Variations in Gastrointestinal Tract Cancers: Potential Players.

Alikhani M, Touati E, Karimipoor M, Vosough M, Mohammadi M.J Gastrointest Cancer. 2022 Sep;53(3):770-781. doi: 10.1007/s12029-021-00707-w. Epub 2021 Sep 6.PMID: 34486088 Review.

KMEL References

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

References

  1.  
    1. Raychaudhuri SP, Farber EM. The prevalence of psoriasis in the world. J Eur Acad Dermatol Venereol 2001;15:16–17. doi: 10.1046/j.1468-3083.2001.00192.x - DOI - PubMed
  2.  
    1. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis 2005;64 Suppl 2:ii18–23 - PMC - PubMed
  3.  
    1. Mallbris L, Ritchlin CT, Stahle M. Metabolic disorders in patients with psoriasis and psoriatic arthritis. Curr Rheumatol Rep 2006;8:355–363. doi: 10.1007/s11926-006-0065-8 - DOI - PubMed
  4.  
    1. Boehncke WH, Schon MP. Psoriasis. Lancet 2015;386:983–994. doi: 10.1016/S0140-6736(14)61909-7 - DOI - PubMed
  5.  
    1. Onumah N, Kircik LH. Psoriasis and its comorbidities. J Drugs Dermatol 2012;11:s5–10. - PubMed
  6.  
    1. Kim WB, Jerome D, Yeung J. Diagnosis and management of psoriasis. Can Fam Physician 2017;63:278–285. - PMC - PubMed
  7.  
    1. Yang H, Zheng J. Influence of stress on the development of psoriasis. Clin Exp Dermatol 2019;45:284–288. doi: 10.1111/ced.14105 - DOI - PubMed
  8.  
    1. Snekvik I, Nilsen TIL, Romundstad PR, Saunes M. Metabolic syndrome and risk of incident psoriasis: prospective data from the HUNT Study, Norway Br J Dermatol 2019;180:94–99. doi: 10.1111/bjd.16885 - DOI - PubMed
  9.  
    1. Alshobaili HA, Shahzad M, Al-Marshood A, Khalil A, Settin A, Barrimah I. Genetic background of psoriasis. Int J Health Sci (Qassim) 2010;4:23–29. - PMC - PubMed
  10.  
    1. Hamanaka RB, Chandel NS. Mitochondrial metabolism as a regulator of keratinocyte differentiation. Cell Logist 2013;3:e25456. doi: 10.4161/cl.25456 - DOI - PMC - PubMed
  11.  
    1. Arul S, Dayalan H, Jegadeesan M, Damodharan P. Induction of differentiation in psoriatic keratinocytes by propylthiouracil and fructose. BBA Clin 2016;6:82–86. doi: 10.1016/j.bbacli.2016.06.002 - DOI - PMC - PubMed
  12.  
    1. Osellame LD, Blacker TS, Duchen MR. Cellular and molecular mechanisms of mitochondrial function. Best Pract Res Clin Endocrinol Metab 2012;26:711–723. doi: 10.1016/j.beem.2012.05.003 - DOI - PMC - PubMed
  13.  
    1. Garcia I, Jones E, Ramos M, Innis-Whitehouse W, Gilkerson R. The little big genome: the organization of mitochondrial DNA. Front Biosci (Landmark Ed) 2017;22:710–721. doi: 10.2741/4511 - DOI - PMC - PubMed
  14.  
    1. Clay Montier LL, Deng JJ, Bai Y. Number matters: control of mammalian mitochondrial DNA copy number. J Genet Genomics 2009;36:125–131. doi: 10.1016/S1673-8527(08)60099-5 - DOI - PMC - PubMed
  15.  
    1. Bohr VA, Stevnsner T, de Souza-Pinto NC. Mitochondrial DNA repair of oxidative damage in mammalian cells. Gene 2002;286:127–134. doi: 10.1016/s0378-1119(01)00813-7 - DOI - PubMed
  16.  
    1. Santos JH, Hunakova L, Chen Y, Bortner C, Van Houten B. Cell sorting experiments link persistent mitochondrial DNA damage with loss of mitochondrial membrane potential and apoptotic cell death. J Biol Chem 2003;278:1728–1734. doi: 10.1074/jbc.M208752200 - DOI - PubMed
  17.  
    1. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell 2005;120:483–495. doi: 10.1016/j.cell.2005.02.001 - DOI - PubMed
  18.  
    1. Al-Kafaji G, Sabry MA, Bakhiet M. Increased expression of mitochondrial DNA-encoded genes in human renal mesangial cells in response to high glucose-induced reactive oxygen species. Mol Med Rep 2016;13:1774–1780. doi: 10.3892/mmr.2015.4732 - DOI - PubMed
  19.  
    1. Al-Kafaji G, Sabry MA, Skrypnyk C. Time-course effect of high-glucose-induced reactive oxygen species on mitochondrial biogenesis and function in human renal mesangial cells. Cell Biol Int 2016;40:36–48. doi: 10.1002/cbin.10520 - DOI - PubMed
  20.  
    1. Lee HC, Wei YH. Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol 2005;37:822–834. doi: 10.1016/j.biocel.2004.09.010 - DOI - PubMed
  21.  
    1. Pagano G, Talamanca AA, Castello G, Cordero MD, d’Ischia M, Gadaleta MN, et al.. Oxidative stress and mitochondrial dysfunction across broad-ranging pathologies: toward mitochondria-targeted clinical strategies. Oxid Med Cell Longev 2014;2014:541230. doi: 10.1155/2014/541230 - DOI - PMC - PubMed
  22.  
    1. Mizuguchi S, Gotoh K, Nakashima Y, Setoyama D, Takata Y, Ohga S, et al.. Mitochondrial reactive oxygen species are essential for the development of psoriaticinflammation. Front Immunol 2021;12:714897. doi: 10.3389/fimmu.2021.714897 - DOI - PMC - PubMed
  23.  
    1. Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 2011;11:738–749. doi: 10.1038/nri3071 - DOI - PMC - PubMed
  24.  
    1. Feichtinger RG, Sperl W, Bauer JW, Kofler B. Mitochondrial dysfunction: a neglected component of skin diseases. Exp Dermatol 2014;23:607–614. doi: 10.1111/exd.12484 - DOI - PubMed
  25.  
    1. Raby BA, Klanderman B, Murphy A, Mazza S, Camargo CA Jr, Silverman EK, et al.. A common mitochondrial haplogroup is associated with elevated total serum IgE levels. J Allergy Clin Immunol 2007;120:351–358. doi: 10.1016/j.jaci.2007.05.029 - DOI - PubMed
  26.  
    1. Alwehaidah MS, Bakhiet M, AlFadhli S. Mitochondrial haplogroup reveals the genetic basis of diabetes mellitus type 2 comorbidity in psoriasis. Med Princ Pract 2021;30:62–68. doi: 10.1159/000509937 - DOI - PMC - PubMed
  27.  
    1. Alwehaidah MS, Al-Kafaji G, Bakhiet M, Alfadhli S. Next-generation sequencing of the whole mitochondrial genome identifies novel and common variants in patients with psoriasis, type 2 diabetes mellitus and psoriasis with comorbid type 2 diabetes mellitus. Biomed Rep 2021;14:41. doi: 10.3892/br.2021.1417 - DOI - PMC - PubMed
  28.  
    1. Therianou A, Vasiadi M, Delivanis DA, Petrakopoulou T, Katsarou-Katsari A, Antoniou C, et al.. Mitochondrial dysfunction in affected skin and increased mitochondrial DNA in serum from patients with psoriasis. Exp Dermatol 2019;28:72–75. doi: 10.1111/exd.13831 - DOI - PubMed
  29.  
    1. Svendsen AJ, Tan Q, Jakobsen MA, Thyagarajan B, Nygaard M, Christiansen L, et al.. White blood cell mitochondrial DNA copy number is decreased in rheumatoid arthritis and linked with risk factors. A twin study. J Autoimmun 2019;96:142–146. doi: 10.1016/j.jaut.2018.09.008 - DOI - PubMed
  30.  
    1. Al-Kafaji G, Bakheit HF, Alharbi MA, Farahat AA, Jailani M, Ebrahin BH, et al.. Mitochondrial DNA copy number in peripheral blood as a potential non-invasive biomarker for multiple sclerosis. Neuromolecular Med 2020;22:304–313. doi: 10.1007/s12017-019-08588-w - DOI - PubMed
  31.  
    1. Xu E, Sun W, Gu J, Chow WH, Ajani JA, Wu X. Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma. Carcinogenesis 2013;34:2521–2524. doi: 10.1093/carcin/bgt230 - DOI - PMC - PubMed
  32.  
    1. Al-Kafaji G, Aljadaan A, Kamal A, Bakhiet M. Peripheral blood mitochondrial DNA copy number as a novel potential biomarker for diabetic nephropathy in type 2 diabetes patients. Exp Ther Med 2018;16:1483–1492. doi: 10.3892/etm.2018.6319 - DOI - PMC - PubMed
  33.  
    1. Kim JH, Im JA, Lee DC. The relationship between leukocyte mitochondrial DNA contents and metabolic syndrome in postmenopausal women. Menopause 2012;19:582–587. doi: 10.1097/gme.0b013e31823a3e46 - DOI - PubMed
  34.  
    1. Chong MR, Narula S, Morton R, Judge C, Akhabir L, Cawte N, et al.. Mitochondrial DNA copy number as a marker and mediator of stroke prognosis: Observational and mendelian randomization analyses. Neurology 2022;98:e470–e482. doi: 10.1212/WNL.0000000000013165 - DOI - PMC - PubMed
  35.  
    1. Liu LP, Cheng K, Ning MA, Li HH, Wang HC, Li F, et al.. Association between peripheral blood cells mitochondrial DNA content and severity of coronary heart disease. Atherosclerosis 2017;261:105–110. doi: 10.1016/j.atherosclerosis.2017.02.013 - DOI - PubMed
  36.  
    1. Gottlieb AB, Chaudhari U, Baker DG, Perate M, Dooley LT. The National Psoriasis Foundation Psoriasis Score (NPF-PS) system versus the Psoriasis Area Severity Index (PASI) and Physician’s Global Assessment (PGA): a comparison. J Drugs Dermatol 2003;2:260–266. - PubMed
  37.  
    1. Zhan D, Tanavalee A, Tantavisut S, Ngarmukos S, Edwards SW, Honsawek S. Relationships between blood leukocyte mitochondrial DNA copy number and inflammatory cytokines in knee osteoarthritis J Zhejiang Univ Sci B 2020;21:42–52. doi: 10.1631/jzus.B1900352 - DOI - PMC - PubMed
  38.  
    1. Kumagai S, Jikimoto T, Saegusa J. Pathological roles of oxidative stress in autoimmune diseases. Rinsho Byori 2003;51:126–132. - PubMed
  39.  
    1. Kadam DP, Suryakar AN, Ankush RD, Kadam CY, Deshpande KH. Role of oxidative stress in various stages of psoriasis. Indian J Clin Biochem 2010;25:388–392. doi: 10.1007/s12291-010-0043-9 - DOI - PMC - PubMed
  40.  
    1. Liu CS, Tsai CS, Kuo CL, Chen HW, Lii CK, Ma YS, et al.. Oxidative stress-related alteration of the copy number of mitochondrial DNA in human leukocytes. Free Radic Res 2003;37:1307–1317. doi: 10.1080/10715760310001621342 - DOI - PubMed
  41.  
    1. Knez J, Winckelmans E, Plusquin M, Thijs L, Cauwenberghs N, Gu Y, et al.. Correlates of peripheral blood mitochondrial DNA content in a general population. Am J Epidemiol 2016;183:138–146. doi: 10.1093/aje/kwv175 - DOI - PMC - PubMed
  42.  
    1. Hurtado-Roca Y, Ledesma M, Gonzalez-Lazaro M, Moreno-Loshuertos R, Fernandez-Silva P, Enriquez JA, et al.. Adjusting MtDNA quantification in whole blood for peripheral bood platelet and leukocyte counts. PLoS One 2016;11:e0163770. doi: 10.1371/journal.pone.0163770 - DOI - PMC - PubMed
  43.  
    1. Yoon CY, Park JT, Kee YK, Han SG, Han IM, Kwon YE, et al.. Low Mitochondrial DNA copy number is associated with adverse clinical outcomes in peritoneal dialysispatients. Medicine (Baltimore) 2016;95:e2717. - PMC - PubMed
  44.  
    1. Angrand L, Boukouaci W, Lajnef M, Richard JR, Andreazza A, Wu CL, et al.. Low peripheral mitochondrial DNA copy number during manic episodes of bipolar disorders is associated with disease severity and inflammation. Brain Behav Immun 2021;98:349–356. doi: 10.1016/j.bbi.2021.09.003 - DOI - PubMed
  45.  
    1. Lee HK, Song JH, Shin CS, Park DJ, Park KS, Lee KU, et al.. Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 1998;42:161–167. doi: 10.1016/s0168-8227(98)00110-7 - DOI - PubMed
  46.  
    1. Pyle A, Brennan R, Kurzawa-Akanbi M, Yarnall A, Thouin A, Mollenhauer B, et al.. Reduced cerebrospinal fluid mitochondrial DNA is a biomarker for early-stage Parkinson’s disease. Ann Neurol 2015;78:1000–1004. doi: 10.1002/ana.24515 - DOI - PMC - PubMed
  47.  
    1. Podlesniy P, Figueiro-Silva J, Llado A, Antonell A, Sanchez-Valle R, Alcolea D, et al.. Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. Ann Neurol 2013;74:655–68. doi: 10.1002/ana.23955 - DOI - PubMed
  48.  
    1. Rao M, Li L, Demello C, Guo D, Jaber BL, Pereira BJ, et al.. Mitochondrial DNA injury and mortality in hemodialysis patients. J Am Soc Nephrol 2009;20:189–196. doi: 10.1681/ASN.2007091031 - DOI - PMC - PubMed
  49.  
    1. Jiang S, Hinchliffe TE, Wu T. Biomarkers of an autoimmune skin disease-psoriasis. Genomics Proteomics Bioinformatics 2015;13:224–233. doi: 10.1016/j.gpb.2015.04.002 - DOI - PMC - PubMed
  50.  
    1. Pyle A, Anugrha H, Kurzawa-Akanbi M, Yarnall A, Burn D, Hudson G. Reduced mitochondrial DNA copy number is a biomarker of Parkinson’s disease. Neurobiol Aging 2016;38:216 e217–216 e210. doi: 10.1016/j.neurobiolaging.2015.10.033 - DOI - PMC - PubMed
  51.  
    1. Filograna R, Mennuni M, Alsina D, Larsson NG. Mitochondrial DNA copy number in human disease: the more the better? FEBS Lett 2021;595:976–1002. doi: 10.1002/1873-3468.14021 - DOI - PMC - PubMed

Page Navigation