Identification of Immune Infiltration and Iron Metabolism-Related Subgroups in Autism Spectrum Disorder.
Autism spectrum disorder
Immune infiltration
Iron metabolism
Machine learning
Molecular clusters
Journal
Journal of molecular neuroscience : MN
ISSN: 1559-1166
Titre abrégé: J Mol Neurosci
Pays: United States
ID NLM: 9002991
Informations de publication
Date de publication:
18 Jan 2024
18 Jan 2024
Historique:
received:
08
07
2023
accepted:
01
11
2023
medline:
18
1
2024
pubmed:
18
1
2024
entrez:
18
1
2024
Statut:
epublish
Résumé
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with a broad spectrum of symptoms and prognoses. Effective therapy requires understanding this variability. ASD children's cognitive and immunological development may depend on iron homoeostasis. This study employs a machine learning model that focuses on iron metabolism hub genes to identify ASD subgroups and describe immune infiltration patterns. A total of 97 control and 148 ASD samples were obtained from the GEO database. Differentially expressed genes (DEGs) and an iron metabolism gene collection achieved the intersection of 25 genes. Unsupervised cluster analysis determined molecular subgroups in individuals with ASD based on 25 genes related to iron metabolism. We assessed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, gene set variation analysis (GSVA), and immune infiltration analysis to compare iron metabolism subtype effects. We employed machine learning to identify subtype-predicting hub genes and utilized both training and validation sets to assess gene subtype prediction accuracy. ASD can be classified into two iron-metabolizing molecular clusters. Metabolic enrichment pathways differed between clusters. Immune infiltration showed that clusters differed immunologically. Cluster 2 had better immunological scores and more immune cells, indicating a stronger immune response. Machine learning screening identified SELENBP1 and CAND1 as important genes in ASD's iron metabolism signaling pathway. These genes express in the brain and have AUC values over 0.8, implying significant predictive power. The present study introduces iron metabolism signaling pathway indicators to predict ASD subtypes. ASD is linked to immune cell infiltration and iron metabolism disorders.
Identifiants
pubmed: 38236354
doi: 10.1007/s12031-023-02179-y
pii: 10.1007/s12031-023-02179-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
12Subventions
Organisme : the General Guidelines of Guangzhou Health Science and Technology Project
ID : 20231A011105
Organisme : Guangzhou Liwan District Livelihood science and Technology plan Project
ID : 20220043
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Arteaga-Henríquez G, Lugo-Marín J, Gisbert L et al (2022) Activation of the monocyte/macrophage system and abnormal blood levels of lymphocyte subpopulations in individuals with autism spectrum disorder: a systematic review and meta-analysis. Int J Mol Sci 23:14329. https://doi.org/10.3390/ijms232214329
doi: 10.3390/ijms232214329
pubmed: 36430805
pmcid: 9699353
Baker JF, Ghio AJ (2009) Iron homoeostasis in rheumatic disease. Rheumatology (Oxford) 48:1339–1344. https://doi.org/10.1093/rheumatology/kep221
Bener A, Khattab AO, Bhugra D, Hoffmann GF (2017) Iron and vitamin D levels among autism spectrum disorders children. Ann Afr Med 16:186–191. https://doi.org/10.4103/aam.aam_17_17
doi: 10.4103/aam.aam_17_17
pubmed: 29063903
pmcid: 5676409
Bjørklund G, Meguid NA, El-Bana MA et al (2020) Oxidative stress in autism spectrum disorder. Mol Neurobiol 57:2314–2332. https://doi.org/10.1007/s12035-019-01742-2
doi: 10.1007/s12035-019-01742-2
pubmed: 32026227
Campbell RK, Buhimschi CS, Zhao G et al (2022) Prevalence of and risk factors for iron deficiency in twin and singleton newborns. Nutrients 14:3854. https://doi.org/10.3390/nu14183854
doi: 10.3390/nu14183854
pubmed: 36145230
pmcid: 9500937
Cheli VT, Correale J, Paez PM, Pasquini JM (2020) Iron metabolism in oligodendrocytes and astrocytes, implications for myelination and remyelination. ASN Neuro 12:1759091420962681. https://doi.org/10.1177/1759091420962681
doi: 10.1177/1759091420962681
pubmed: 32993319
pmcid: 7545512
Chen L, Fu Q, Du Y et al (2023) Transcriptome analysis and epigenetics regulation in the hippocampus and the prefrontal cortex of VPA-induced rat model. Mol Neurobiol. https://doi.org/10.1007/s12035-023-03560-z
doi: 10.1007/s12035-023-03560-z
pubmed: 38159197
pmcid: 10415527
Cuomo BM, Vaz S, Lee EAL et al (2017) Effectiveness of sleep-based interventions for children with autism spectrum disorder: a meta-synthesis. Pharmacotherapy 37:555–578. https://doi.org/10.1002/phar.1920
doi: 10.1002/phar.1920
pubmed: 28258648
David S, Jhelum P, Ryan F et al (2022) Dysregulation of iron homeostasis in the central nervous system and the role of ferroptosis in neurodegenerative disorders. Antioxid Redox Signal 37:150–170. https://doi.org/10.1089/ars.2021.0218
doi: 10.1089/ars.2021.0218
pubmed: 34569265
De Giacomo A, Medicamento S, Pedaci C et al (2022) Peripheral iron levels in autism spectrum disorders vs. other neurodevelopmental disorders: preliminary data. Int J Environ Res Public Health 19:4006. https://doi.org/10.3390/ijerph19074006
Du Y, Chen L, Yan M-C et al (2023) Neurometabolite levels in the brains of patients with autism spectrum disorders: a meta-analysis of proton magnetic resonance spectroscopy studies (N = 1501). Mol Psychiatry. https://doi.org/10.1038/s41380-023-02079-y
doi: 10.1038/s41380-023-02079-y
pubmed: 37402852
pmcid: 10615752
Dusek P, Hofer T, Alexander J et al (2022) Cerebral iron deposition in neurodegeneration. Biomolecules 12:714. https://doi.org/10.3390/biom12050714
East P, Doom JR, Blanco E et al (2021) Iron deficiency in infancy and neurocognitive and educational outcomes in young adulthood. Dev Psychol 57:962–975. https://doi.org/10.1037/dev0001030
doi: 10.1037/dev0001030
pubmed: 34424013
pmcid: 8386013
Elhodaky M, Diamond AM (2018) Selenium-binding protein 1 in human health and disease. Int J Mol Sci 19:3437. https://doi.org/10.3390/ijms19113437
doi: 10.3390/ijms19113437
pubmed: 30400135
pmcid: 6274749
Gesundheit B, Rosenzweig JP, Naor D et al (2013) Immunological and autoimmune considerations of autism spectrum disorders. J Autoimmun 44:1–7. https://doi.org/10.1016/j.jaut.2013.05.005
doi: 10.1016/j.jaut.2013.05.005
pubmed: 23867105
Ghosh MC, Zhang D-L, Rouault TA (2015) Iron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins. Neurobiol Dis 81:66–75. https://doi.org/10.1016/j.nbd.2015.02.026
doi: 10.1016/j.nbd.2015.02.026
pubmed: 25771171
pmcid: 4567523
Gillberg C, Fernell E, Kočovská E et al (2017) The role of cholesterol metabolism and various steroid abnormalities in autism spectrum disorders: a hypothesis paper. Autism Res 10:1022–1044. https://doi.org/10.1002/aur.1777
doi: 10.1002/aur.1777
pubmed: 28401679
pmcid: 5485071
Gu X, Lai D, Liu S et al (2022) Hub genes, diagnostic model, and predicted drugs related to iron metabolism in Alzheimer’s disease. Front Aging Neurosci 14:949083. https://doi.org/10.3389/fnagi.2022.949083
doi: 10.3389/fnagi.2022.949083
pubmed: 35875800
pmcid: 9300955
Gunes S, Ekinci O, Celik T (2017) Iron deficiency parameters in autism spectrum disorder: clinical correlates and associated factors. Ital J Pediatr 43:86. https://doi.org/10.1186/s13052-017-0407-3
doi: 10.1186/s13052-017-0407-3
pubmed: 28934988
pmcid: 5609017
Gyawali S, Patra BN (2019) Autism spectrum disorder: trends in research exploring etiopathogenesis. Psychiatry Clin Neurosci 73:466–475. https://doi.org/10.1111/pcn.12860
doi: 10.1111/pcn.12860
pubmed: 31077508
Hare D, Ayton S, Bush A, Lei P (2013) A delicate balance: iron metabolism and diseases of the brain. Front Aging Neurosci 5:34. https://doi.org/10.3389/fnagi.2013.00034
doi: 10.3389/fnagi.2013.00034
pubmed: 23874300
pmcid: 3715022
Haschka D, Hoffmann A, Weiss G (2021) Iron in immune cell function and host defense. Semin Cell Dev Biol 115:27–36. https://doi.org/10.1016/j.semcdb.2020.12.005
doi: 10.1016/j.semcdb.2020.12.005
pubmed: 33386235
Hergüner S, Keleşoğlu FM, Tanıdır C, Cöpür M (2012) Ferritin and iron levels in children with autistic disorder. Eur J Pediatr 171:143–146. https://doi.org/10.1007/s00431-011-1506-6
doi: 10.1007/s00431-011-1506-6
pubmed: 21643649
Heyer NJ, Echeverria D, Woods JS (2012) Disordered porphyrin metabolism: a potential biological marker for autism risk assessment. Autism Res 5:84–92. https://doi.org/10.1002/aur.236
doi: 10.1002/aur.236
pubmed: 22298513
pmcid: 3329579
Hoffbrand AV (2009) Recent advances in the understanding of iron metabolism and iron-related diseases. Acta Haematol 122:75–77. https://doi.org/10.1159/000243790
doi: 10.1159/000243790
pubmed: 19907143
Huang L, Bian M, Zhang J, Jiang L (2022) Iron metabolism and ferroptosis in peripheral nerve injury. Oxid Med Cell Longev 2022:5918218. https://doi.org/10.1155/2022/5918218
doi: 10.1155/2022/5918218
pubmed: 36506935
pmcid: 9733998
Hughes HK, Mills Ko E, Rose D, Ashwood P (2018) Immune dysfunction and autoimmunity as pathological mechanisms in autism spectrum disorders. Front Cell Neurosci 12:405. https://doi.org/10.3389/fncel.2018.00405
doi: 10.3389/fncel.2018.00405
pubmed: 30483058
pmcid: 6242891
Hyman SL, Levy SE, Myers SM (2020) Identification, evaluation, and management of children with autism spectrum disorder. Pediatrics 145:e20193447. https://doi.org/10.1542/peds.2019-3447
doi: 10.1542/peds.2019-3447
pubmed: 31843864
Katz J, Reichenberg A, Kolevzon A (2021) Prenatal and perinatal metabolic risk factors for autism: a review and integration of findings from population-based studies. Curr Opin Psychiatry 34:94–104. https://doi.org/10.1097/YCO.0000000000000673
doi: 10.1097/YCO.0000000000000673
pubmed: 33278157
pmcid: 9341035
Kumar S, Reynolds K, Ji Y et al (2019) Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk. J Neurodev Disord 11:10. https://doi.org/10.1186/s11689-019-9268-y
doi: 10.1186/s11689-019-9268-y
pubmed: 31202261
pmcid: 6571119
Lai X, Wu X, Hou N et al (2018) Vitamin A deficiency induces autistic-like behaviors in rats by regulating the RARβ-CD38-oxytocin axis in the hypothalamus. Mol Nutr Food Res 62. https://doi.org/10.1002/mnfr.201700754
Li H, Xu Y, Li W et al (2022) Novel insights into the immune cell landscape and gene signatures in autism spectrum disorder by bioinformatics and clinical analysis. Front Immunol 13:1082950. https://doi.org/10.3389/fimmu.2022.1082950
doi: 10.3389/fimmu.2022.1082950
pubmed: 36761165
Li X, Chauhan A, Sheikh AM et al (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207:111–116. https://doi.org/10.1016/j.jneuroim.2008.12.002
doi: 10.1016/j.jneuroim.2008.12.002
pubmed: 19157572
pmcid: 2770268
Liu Y, Yang Z, Du Y et al (2022) Antioxidant interventions in autism spectrum disorders: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 113:110476. https://doi.org/10.1016/j.pnpbp.2021.110476
doi: 10.1016/j.pnpbp.2021.110476
pubmed: 34793863
Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J (2018) Autism spectrum disorder. Lancet 392:508–520. https://doi.org/10.1016/S0140-6736(18)31129-2
Maenner MJ, Shaw KA, Bakian AV et al (2021) Prevalence and characteristics of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2018. MMWR Surveill Summ 70:1–16. https://doi.org/10.15585/mmwr.ss7011a1
Maenner MJ, Warren Z, Williams AR et al (2023) Prevalence and characteristics of autism spectrum disorder among children aged 8 years - autism and developmental disabilities monitoring network, 11 sites, United States, 2020. MMWR Surveill Summ 72:1–14. https://doi.org/10.15585/mmwr.ss7202a1
Mead J, Ashwood P (2015) Evidence supporting an altered immune response in ASD. Immunol Lett 163:49–55. https://doi.org/10.1016/j.imlet.2014.11.006
doi: 10.1016/j.imlet.2014.11.006
pubmed: 25448709
Meltzer A, Van de Water J (2017) The role of the immune system in autism spectrum disorder. Neuropsychopharmacology 42:284–298. https://doi.org/10.1038/npp.2016.158
doi: 10.1038/npp.2016.158
pubmed: 27534269
Mencarelli C, Martinez-Martinez P (2013) Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci 70:181–203. https://doi.org/10.1007/s00018-012-1038-x
doi: 10.1007/s00018-012-1038-x
pubmed: 22729185
Mohammadi A, Rashidi E, Amooeian VG (2018) Brain, blood, cerebrospinal fluid, and serum biomarkers in schizophrenia. Psychiatry Res 265:25–38. https://doi.org/10.1016/j.psychres.2018.04.036
doi: 10.1016/j.psychres.2018.04.036
pubmed: 29680514
Nadeem MS, Al-Abbasi FA, Kazmi I et al (2020) Multiple risk factors: a challenge in the management of autism. Curr Pharm Des 26:743–754. https://doi.org/10.2174/1381612826666200226101218
doi: 10.2174/1381612826666200226101218
pubmed: 32101114
Nadeem MS, Hosawi S, Alshehri S et al (2021) Symptomatic, genetic, and mechanistic overlaps between autism and Alzheimer’s disease. Biomolecules 11:1635. https://doi.org/10.3390/biom11111635
doi: 10.3390/biom11111635
pubmed: 34827633
pmcid: 8615882
Nour-Eldine W, Ltaief SM, Abdul Manaph NP, Al-Shammari AR (2022) In search of immune cellular sources of abnormal cytokines in the blood in autism spectrum disorder: a systematic review of case-control studies. Front Immunol 13:950275. https://doi.org/10.3389/fimmu.2022.950275
doi: 10.3389/fimmu.2022.950275
pubmed: 36268027
pmcid: 9578337
Qian T-M, Zhao L-L, Wang J et al (2016) miR-148b-3p promotes migration of Schwann cells by targeting cullin-associated and neddylation-dissociated 1. Neural Regen Res 11:1001–1005. https://doi.org/10.4103/1673-5374.184504
doi: 10.4103/1673-5374.184504
pubmed: 27482232
pmcid: 4962562
Reynolds A, Krebs NF, Stewart PA et al (2012) Iron status in children with autism spectrum disorder. Pediatrics 130(Suppl 2):S154–S159. https://doi.org/10.1542/peds.2012-0900M
Robinson-Agramonte MDLA, Noris García E, Fraga Guerra J et al (2022) Immune dysregulation in autism spectrum disorder: what do we know about it? Int J Mol Sci 23:3033. https://doi.org/10.3390/ijms23063033
Ruhrberg C, Bautch VL (2013) Neurovascular development and links to disease. Cell Mol Life Sci 70:1675–1684. https://doi.org/10.1007/s00018-013-1277-5
doi: 10.1007/s00018-013-1277-5
pubmed: 23475065
pmcid: 3632722
Sanchack KE, Thomas CA (2016) Autism spectrum disorder: primary care principles. Am Fam Physician 94:972–979. PMID: 28075089
Schmidt RJ, Tancredi DJ, Krakowiak P et al (2014) Maternal intake of supplemental iron and risk of autism spectrum disorder. Am J Epidemiol 180:890–900. https://doi.org/10.1093/aje/kwu208
doi: 10.1093/aje/kwu208
pubmed: 25249546
pmcid: 4207718
Sidrak S, Yoong T, Woolfenden S (2014) Iron deficiency in children with global developmental delay and autism spectrum disorder. J Paediatr Child Health 50:356–361. https://doi.org/10.1111/jpc.12483
doi: 10.1111/jpc.12483
pubmed: 24372984
Stankiewicz JM, Neema M, Ceccarelli A (2014) Iron and multiple sclerosis. Neurobiol Aging 35(Suppl 2):S51–S58. https://doi.org/10.1016/j.neurobiolaging.2014.03.039
Talvio K, Kanninen KM, White AR et al (2021) Increased iron content in the heart of the Fmr1 knockout mouse. Biometals 34:947–954. https://doi.org/10.1007/s10534-021-00320-1
doi: 10.1007/s10534-021-00320-1
pubmed: 34089433
pmcid: 8313461
Tang S, Xu Y, Liu X et al (2021) Quantitative susceptibility mapping shows lower brain iron content in children with autism. Eur Radiol 31:2073–2083. https://doi.org/10.1007/s00330-020-07267-w
doi: 10.1007/s00330-020-07267-w
pubmed: 32945969
Taylor JL, Corbett BA (2014) A review of rhythm and responsiveness of cortisol in individuals with autism spectrum disorders. Psychoneuroendocrinology 49:207–228. https://doi.org/10.1016/j.psyneuen.2014.07.015
doi: 10.1016/j.psyneuen.2014.07.015
pubmed: 25108163
pmcid: 4165710
Thirupathi A, Chang Y-Z (2019) Brain iron metabolism and CNS diseases. Adv Exp Med Biol 1173:1–19. https://doi.org/10.1007/978-981-13-9589-5_1
doi: 10.1007/978-981-13-9589-5_1
pubmed: 31456202
Thul PJ, Åkesson L, Wiking M et al (2017) A subcellular map of the human proteome. Science 356:eaal3321. https://doi.org/10.1126/science.aal3321
Uhlén M, Fagerberg L, Hallström BM et al (2015) Proteomics. Tissue-based map of the human proteome. Science 347:1260419. https://doi.org/10.1126/science.1260419
Uhlen M, Zhang C, Lee S et al (2017) A pathology atlas of the human cancer transcriptome. Science 357:eaan2507. https://doi.org/10.1126/science.aan2507
Varghese M, Keshav N, Jacot-Descombes S et al (2017) Autism spectrum disorder: neuropathology and animal models. Acta Neuropathol 134:537–566. https://doi.org/10.1007/s00401-017-1736-4
doi: 10.1007/s00401-017-1736-4
pubmed: 28584888
pmcid: 5693718
Ward RJ, Zucca FA, Duyn JH et al (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 13:1045–1060. https://doi.org/10.1016/S1474-4422(14)70117-6
doi: 10.1016/S1474-4422(14)70117-6
pubmed: 25231526
pmcid: 5672917
Xu X, Li C, Gao X et al (2018) Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders. Cell Res 28:48–68. https://doi.org/10.1038/cr.2017.132
doi: 10.1038/cr.2017.132
pubmed: 29076503
Zhou Y, Gao J (2022) Why not try to predict autism spectrum disorder with crucial biomarkers in cuproptosis signaling pathway? Front Psychiatry 13:1037503. https://doi.org/10.3389/fpsyt.2022.1037503
doi: 10.3389/fpsyt.2022.1037503
pubmed: 36405901
pmcid: 9667021