Abstract
Background
Α number of genetic variants have been associated with amyotrophic lateral sclerosis (ALS). A recent study supports that rs591486 across the ERCC6L2 gene and exposure to pesticides seem to have a joint effect on the development of Parkinson’s disease, a disease which shares a few common characteristics with ALS.
Objective
To detect a possible contribution of rs591486 ERCC6L2 to ALS.
Methods
A total of 155 patients with ALS and 155 healthy controls were included in the study and genotyped for rs591486. Using logistic regression analyses (crude and adjusted for age and sex), rs591486 was tested for association with ALS risk. Subgroup analysis based on ALS site of onset was also performed. Cox regression analysis was applied in order for the effect of ERCC6L2 rs591486 on ALS age of onset to be tested.
Results
Adjusted analysis showed that ERCC6L2 rs591486 was associated with an increased risk of ALS development, in dominant [odds ratio, OR (95% confidence interval, CI) 2.15 (1.04–4.46), p = 0.037] and over-dominant [OR (95%CI) = 1.91 (1.01–3.60), p = 0.043], modes. Subgroup analysis based on ALS site of onset revealed an association between ERCC6L2 rs591486 and ALS with limb onset. Results for Cox regression analysis indicated that G/A carriers had a lower age of ALS limb onset when compared to G/G carriers.
Conclusions
The current study provides preliminary indication for an implication of ERCC6L2 rs591486 in ALS development, as a possible genetic risk factor. These results possibly suggest that oxidative stress may be the main contributor in the pathophysiology of ALS.
Similar content being viewed by others
References
Al-Chalabi A, Hardiman O, Kiernan MC, Chio A, Rix-Brooks B, van den Berg LH (2016) Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol 15(11):1182–1194. https://doi.org/10.1016/s1474-4422(16)30199-5
Liu J, Zhang X, Ding X, Song M, Sui K (2019) Analysis of clinical and electrophysiological characteristics of 150 patients with amyotrophic lateral sclerosis in China. Neurol Sci 40(2):363–369. https://doi.org/10.1007/s10072-018-3633-6
Tortarolo M, Lo Coco D, Veglianese P, Vallarola A, Giordana MT, Marcon G, Beghi E, Poloni M, Strong MJ, Iyer AM, Aronica E, Bendotti C (2017) Amyotrophic lateral sclerosis, a multisystem pathology: insights into the role of TNFalpha. Mediat Inflamm 2017:2985051. https://doi.org/10.1155/2017/2985051
Dardiotis E, Siokas V, Sokratous M, Tsouris Z, Aloizou AM, Florou D, Dastamani M, Mentis AA, Brotis AG (2018) Body mass index and survival from amyotrophic lateral sclerosis: a meta-analysis. Neurol Clin Pract 8(5):437–444. https://doi.org/10.1212/cpj.0000000000000521
Dardiotis E, Siokas V, Sokratous M, Tsouris Z, Michalopoulou A, Andravizou A, Dastamani M, Ralli S, Vinceti M, Tsatsakis A, Hadjigeorgiou GM (2018) Genetic polymorphisms in amyotrophic lateral sclerosis: evidence for implication in detoxification pathways of environmental toxicants. Environ Int 116:122–135. https://doi.org/10.1016/j.envint.2018.04.008
Chen Y, Zhou Q, Gu X, Wei Q, Cao B, Liu H, Hou Y, Shang H (2018) An association study between SCFD1 rs10139154 variant and amyotrophic lateral sclerosis in a Chinese cohort. Amyotroph Lateral Scler Frontotemporal Degener 19(5–6):413–418. https://doi.org/10.1080/21678421.2017.1418006
Dardiotis E, Aloizou AM, Siokas V, Patrinos GP, Deretzi G, Mitsias P, Aschner M, Tsatsakis A (2018) The role of microRNAs in patients with amyotrophic lateral sclerosis. J Mol Neurosci 66(4):617–628. https://doi.org/10.1007/s12031-018-1204-1
Cui R, Tuo M, Li P, Zhou C (2018) Association between TBK1 mutations and risk of amyotrophic lateral sclerosis/frontotemporal dementia spectrum: a meta-analysis. Neurol Sci 39(5):811–820. https://doi.org/10.1007/s10072-018-3246-0
Ning P, Yang X, Yang B, Zhao Q, Huang H, An R, Chen Y, Hu F, Xu Z, Xu Y (2018) Meta-analysis of the association between ZNF512B polymorphism rs2275294 and risk of amyotrophic lateral sclerosis. Neurol Sci 39(7):1261–1266. https://doi.org/10.1007/s10072-018-3411-5
Da Cruz S, Bui A, Saberi S, Lee SK, Stauffer J, McAlonis-Downes M, Schulte D, Pizzo DP, Parone PA, Cleveland DW, Ravits J (2017) Misfolded SOD1 is not a primary component of sporadic ALS. Acta Neuropathol 134(1):97–111. https://doi.org/10.1007/s00401-017-1688-8
Turner MR, Bowser R, Bruijn L, Dupuis L, Ludolph A, McGrath M, Manfredi G, Maragakis N, Miller RG, Pullman SL, Rutkove SB, Shaw PJ, Shefner J, Fischbeck KH (2013) Mechanisms, models and biomarkers in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 14(Suppl 1):19–32. https://doi.org/10.3109/21678421.2013.778554
Salim S (2017) Oxidative stress and the central nervous system. J Pharmacol Exp Ther 360(1):201–205. https://doi.org/10.1124/jpet.116.237503
Contestabile A (2001) Oxidative stress in neurodegeneration: mechanisms and therapeutic perspectives. Curr Top Med Chem 1(6):553–568
Bond L, Bernhardt K, Madria P, Sorrentino K, Scelsi H, Mitchell CS (2018) A metadata analysis of oxidative stress etiology in preclinical amyotrophic lateral sclerosis: benefits of antioxidant therapy. Front Neurosci 12:10. https://doi.org/10.3389/fnins.2018.00010
Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, Dominov JA, Kenna BJ, Nalls MA, Keagle P, Rivera AM, van Rheenen W, Murphy NA, van Vugt J, Geiger JT, Van der Spek RA, Pliner HA, Shankaracharya, Smith BN, Marangi G, Topp SD, Abramzon Y, Gkazi AS, Eicher JD, Kenna A, Mora G, Calvo A, Mazzini L, Riva N, Mandrioli J, Caponnetto C, Battistini S, Volanti P, La Bella V, Conforti FL, Borghero G, Messina S, Simone IL, Trojsi F, Salvi F, Logullo FO, D'Alfonso S, Corrado L, Capasso M, Ferrucci L, Moreno CAM, Kamalakaran S, Goldstein DB, Gitler AD, Harris T, Myers RM, Phatnani H, Musunuri RL, Evani US, Abhyankar A, Zody MC, Kaye J, Finkbeiner S, Wyman SK, LeNail A, Lima L, Fraenkel E, Svendsen CN, Thompson LM, Van Eyk JE, Berry JD, Miller TM, Kolb SJ, Cudkowicz M, Baxi E, Benatar M, Taylor JP, Rampersaud E, Wu G, Wuu J, Lauria G, Verde F, Fogh I, Tiloca C, Comi GP, Soraru G, Cereda C, Corcia P, Laaksovirta H, Myllykangas L, Jansson L, Valori M, Ealing J, Hamdalla H, Rollinson S, Pickering-Brown S, Orrell RW, Sidle KC, Malaspina A, Hardy J, Singleton AB, Johnson JO, Arepalli S, Sapp PC, McKenna-Yasek D, Polak M, Asress S, Al-Sarraj S, King A, Troakes C, Vance C, de Belleroche J, Baas F, Ten Asbroek A, Munoz-Blanco JL, Hernandez DG, Ding J, Gibbs JR, Scholz SW, Floeter MK, Campbell RH, Landi F, Bowser R, Pulst SM, Ravits JM, MacGowan DJL, Kirby J, Pioro EP, Pamphlett R, Broach J, Gerhard G, Dunckley TL, Brady CB, Kowall NW, Troncoso JC, Le Ber I, Mouzat K, Lumbroso S, Heiman-Patterson TD, Kamel F, Van Den Bosch L, Baloh RH, Strom TM, Meitinger T, Shatunov A, Van Eijk KR, de Carvalho M, Kooyman M, Middelkoop B, Moisse M, McLaughlin RL, Van Es MA, Weber M, Boylan KB, Van Blitterswijk M, Rademakers R, Morrison KE, Basak AN, Mora JS, Drory VE, Shaw PJ, Turner MR, Talbot K, Hardiman O, Williams KL, Fifita JA, Nicholson GA, Blair IP, Rouleau GA, Esteban-Perez J, Garcia-Redondo A, Al-Chalabi A, Rogaeva E, Zinman L, Ostrow LW, Maragakis NJ, Rothstein JD, Simmons Z, Cooper-Knock J, Brice A, Goutman SA, Feldman EL, Gibson SB, Taroni F, Ratti A, Gellera C, Van Damme P, Robberecht W, Fratta P, Sabatelli M, Lunetta C, Ludolph AC, Andersen PM, Weishaupt JH, Camu W, Trojanowski JQ, Van Deerlin VM, Brown RH Jr, van den Berg LH, Veldink JH, Harms MB, Glass JD, Stone DJ, Tienari P, Silani V, Chio A, Shaw CE, Traynor BJ, Landers JE (2018) Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron 97(6):1268–1283.e1266. https://doi.org/10.1016/j.neuron.2018.02.027
Taylor JP, Brown RH Jr, Cleveland DW (2016) Decoding ALS: from genes to mechanism. Nature 539(7628):197–206. https://doi.org/10.1038/nature20413
Vinceti M, Filippini T, Violi F, Rothman KJ, Costanzini S, Malagoli C, Wise LA, Odone A, Signorelli C, Iacuzio L, Arcolin E, Mandrioli J, Fini N, Patti F, Lo Fermo S, Pietrini V, Teggi S, Ghermandi G, Scillieri R, Ledda C, Mauceri C, Sciacca S, Fiore M, Ferrante M (2017) Pesticide exposure assessed through agricultural crop proximity and risk of amyotrophic lateral sclerosis. Environ Health 16(1):91. https://doi.org/10.1186/s12940-017-0297-2
De Marchi F, Corrado L, Bersano E, Sarnelli MF, Solara V, D'Alfonso S, Cantello R, Mazzini L (2018) Ptosis and bulbar onset: an unusual phenotype of familial ALS? Neurol Sci 39(2):377–378. https://doi.org/10.1007/s10072-017-3186-0
Tummala H, Kirwan M, Walne AJ, Hossain U, Jackson N, Pondarre C, Plagnol V, Vulliamy T, Dokal I (2014) ERCC6L2 mutations link a distinct bone-marrow-failure syndrome to DNA repair and mitochondrial function. Am J Hum Genet 94(2):246–256. https://doi.org/10.1016/j.ajhg.2014.01.007
Dutta A, Sardiu M, Gogol M, Gilmore J, Zhang D, Florens L, Abmayr SM, Washburn MP, Workman JL (2017) Composition and function of mutant Swi/Snf complexes. Cell Rep 18(9):2124–2134. https://doi.org/10.1016/j.celrep.2017.01.058
Flaus A, Martin DM, Barton GJ, Owen-Hughes T (2006) Identification of multiple distinct Snf2 subfamilies with conserved structural motifs. Nucleic Acids Res 34(10):2887–2905. https://doi.org/10.1093/nar/gkl295
Biernacka JM, Chung SJ, Armasu SM, Anderson KS, Lill CM, Bertram L, Ahlskog JE, Brighina L, Frigerio R, Maraganore DM (2016) Genome-wide gene-environment interaction analysis of pesticide exposure and risk of Parkinson’s disease. Parkinsonism Relat Disord 32:25–30. https://doi.org/10.1016/j.parkreldis.2016.08.002
Theuns J, Verstraeten A, Sleegers K, Wauters E, Gijselinck I, Smolders S, Crosiers D, Corsmit E, Elinck E, Sharma M, Kruger R, Lesage S, Brice A, Chung SJ, Kim MJ, Kim YJ, Ross OA, Wszolek ZK, Rogaeva E, Xi Z, Lang AE, Klein C, Weissbach A, Mellick GD, Silburn PA, Hadjigeorgiou GM, Dardiotis E, Hattori N, Ogaki K, Tan EK, Zhao Y, Aasly J, Valente EM, Petrucci S, Annesi G, Quattrone A, Ferrarese C, Brighina L, Deutschlander A, Puschmann A, Nilsson C, Garraux G, LeDoux MS, Pfeiffer RF, Boczarska-Jedynak M, Opala G, Maraganore DM, Engelborghs S, De Deyn PP, Cras P, Cruts M, Van Broeckhoven C (2014) Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology 83(21):1906–1913. https://doi.org/10.1212/wnl.0000000000001012
Ludolph A, Drory V, Hardiman O, Nakano I, Ravits J, Robberecht W, Shefner J (2015) A revision of the El Escorial criteria - 2015. Amyotroph Lateral Scler Frontotemporal Degener 16(5–6):291–292. https://doi.org/10.3109/21678421.2015.1049183
Dardiotis E, Paterakis K, Siokas V, Tsivgoulis G, Dardioti M, Grigoriadis S, Simeonidou C, Komnos A, Kapsalaki E, Fountas K, Hadjigeorgiou GM (2015) Effect of angiotensin-converting enzyme tag single nucleotide polymorphisms on the outcome of patients with traumatic brain injury. Pharmacogenet Genomics 25(10):485–490. https://doi.org/10.1097/fpc.0000000000000161
Siokas V, Kardaras D, Aloizou AM, Asproudis I, Boboridis KG, Papageorgiou E, Hadjigeorgiou GM, Tsironi EE, Dardiotis E (2018) BDNF rs6265 (Val66Met) polymorphism as a risk factor for blepharospasm. NeuroMolecular Med 21:68–74. https://doi.org/10.1007/s12017-018-8519-5
Siokas V, Kardaras D, Aloizou AM, Asproudis I, Boboridis KG, Papageorgiou E, Spandidos DA, Tsatsakis A, Tsironi EE, Dardiotis E (2019) Lack of association of the rs11655081 ARSG gene with blepharospasm. J Mol Neurosci. https://doi.org/10.1007/s12031-018-1255-3
Dardiotis E, Paterakis K, Tsivgoulis G, Tsintou M, Hadjigeorgiou GF, Dardioti M, Grigoriadis S, Simeonidou C, Komnos A, Kapsalaki E, Fountas K, Hadjigeorgiou GM (2014) AQP4 tag single nucleotide polymorphisms in patients with traumatic brain injury. J Neurotrauma 31(23):1920–1926. https://doi.org/10.1089/neu.2014.3347
Skol AD, Scott LJ, Abecasis GR, Boehnke M (2006) Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet 38(2):209–213. https://doi.org/10.1038/ng1706
Sole X, Guino E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22(15):1928–1929. https://doi.org/10.1093/bioinformatics/btl268
Dardiotis E, Siokas V, Marogianni C, Aloizou AM, Sokratous M, Paterakis K, Dardioti M, Grigoriadis S, Brotis A, Kapsalaki E, Fountas K, Jagiella J, Hadjigeorgiou GM (2018) AQP4 tag SNPs in patients with intracerebral hemorrhage in Greek and Polish population. Neurosci Lett 696:156–161. https://doi.org/10.1016/j.neulet.2018.12.025
Di Meo S, Reed TT, Venditti P, Victor VM (2016) Role of ROS and RNS sources in physiological and pathological conditions. Oxidative Med Cell Longev 2016:1245049–1245044. https://doi.org/10.1155/2016/1245049
Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34(4):521–533
Giasson BI, Ischiropoulos H, Lee VM, Trojanowski JQ (2002) The relationship between oxidative/nitrative stress and pathological inclusions in Alzheimer’s and Parkinson’s diseases. Free Radic Biol Med 32(12):1264–1275
Zintzaras E (2010) Impact of Hardy-Weinberg equilibrium deviation on allele-based risk effect of genetic association studies and meta-analysis. Eur J Epidemiol 25(8):553–560. https://doi.org/10.1007/s10654-010-9467-z
Rasmussen L, Delabio R, Horiguchi L, Mizumoto I, Terazaki CR, Mazzotti D, Bertolucci PH, Pinhel MA, Souza D, Krieger H, Kawamata C, Minett T, Smith MC, Payao SL (2013) Association between interleukin 6 gene haplotype and Alzheimer’s disease: a Brazilian case-control study. J Alzheimers Dis 36(4):733–738. https://doi.org/10.3233/jad-122407
Mitropoulos K, Merkouri Papadima E, Xiromerisiou G, Balasopoulou A, Charalampidou K, Galani V, Zafeiri KV, Dardiotis E, Ralli S, Deretzi G, John A, Kydonopoulou K, Papadopoulou E, di Pardo A, Akcimen F, Loizedda A, Dobricic V, Novakovic I, Kostic VS, Mizzi C, Peters BA, Basak N, Orru S, Kiskinis E, Cooper DN, Gerou S, Drmanac R, Bartsakoulia M, Tsermpini EE, Hadjigeorgiou GM, Ali BR, Katsila T, Patrinos GP (2017) Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients. Hum Genomics 11(1):30. https://doi.org/10.1186/s40246-017-0126-2
Pan LS, Deng XB, Wang Z, Leng HL, Zhu XP, Ding D (2016) Lack of association between the Angiogenin (ANG) rs11701 polymorphism and amyotrophic lateral sclerosis risk: a meta-analysis. Neurol Sci 37(5):655–662. https://doi.org/10.1007/s10072-015-2473-x
Pehar M, Beeson G, Beeson CC, Johnson JA, Vargas MR (2014) Mitochondria-targeted catalase reverts the neurotoxicity of hSOD1G(9)(3)A astrocytes without extending the survival of ALS-linked mutant hSOD1 mice. PLoS One 9(7):e103438. https://doi.org/10.1371/journal.pone.0103438
Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX, Rahmani Z, Krizus A, McKenna-Yasek D, Cayabyab A, Gaston SM, Berger R, Tanzi RE, Halperin JJ, Herzfeldt B, van den Bergh R, Hung WY, Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Pericak–Vance MA, Haines J, Rouleau GA, Gusella JS, Horvitz HR, Brown RH (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415):59–62. https://doi.org/10.1038/362059a0
Carri MT, Valle C, Bozzo F, Cozzolino M (2015) Oxidative stress and mitochondrial damage: importance in non-SOD1 ALS. Front Cell Neurosci 9:41. https://doi.org/10.3389/fncel.2015.00041
Rabdano SO, Izmailov SA, Luzik DA, Groves A, Podkorytov IS, Skrynnikov NR (2017) Onset of disorder and protein aggregation due to oxidation-induced intermolecular disulfide bonds: case study of RRM2 domain from TDP-43. Sci Rep 7(1):11161. https://doi.org/10.1038/s41598-017-10574-w
Stefanidis I, Vainas A, Dardiotis E, Giannaki CD, Gourli P, Papadopoulou D, Vakianis P, Patsidis E, Eleftheriadis T, Liakopoulos V, Pournaras S, Sakkas GK, Zintzaras E, Hadjigeorgiou GM (2013) Restless legs syndrome in hemodialysis patients: an epidemiologic survey in Greece. Sleep Med 14(12):1381–1386. https://doi.org/10.1016/j.sleep.2013.05.022
Paganoni S, Cudkowicz M, Berry JD (2014) Outcome measures in amyotrophic lateral sclerosis clinical trials. Clin Investig 4(7):605–618
Siokas V, Aloizou AM, Tsouris Z, Michalopoulou A, Mentis AA, Dardiotis E (2018) Risk factor genes in patients with dystonia: a comprehensive review. Tremor Other Hyperkinet Mov (N Y) 8:559. https://doi.org/10.7916/d8h438gs
Dardiotis E, Koutsou P, Zamba-Papanicolaou E, Vonta I, Hadjivassiliou M, Hadjigeorgiou G, Cariolou M, Christodoulou K, Kyriakides T (2009) Complement C1Q polymorphisms modulate onset in familial amyloidotic polyneuropathy TTR Val30Met. J Neurol Sci 284(1–2):158–162. https://doi.org/10.1016/j.jns.2009.05.018
Anastasiou CA, Yannakoulia M, Kosmidis MH, Dardiotis E, Hadjigeorgiou GM, Sakka P, Arampatzi X, Bougea A, Labropoulos I, Scarmeas N (2017) Mediterranean diet and cognitive health: initial results from the Hellenic longitudinal investigation of ageing and diet. PLoS One 12(8):e0182048. https://doi.org/10.1371/journal.pone.0182048
Dardiotis E, Aloizou AM, Siokas V, Tsouris Z, Rikos D, Marogianni C, Aschner M, Kovatsi L, Bogdanos DP, Tsatsakis A (2019) Paraoxonase-1 genetic polymorphisms in organophosphate metabolism. Toxicology 411:24–31. https://doi.org/10.1016/j.tox.2018.10.012
Hadjigeorgiou GM, Malizos K, Dardiotis E, Aggelakis K, Dardioti M, Zibis A, Dimitroulias A, Scarmeas N, Tsezou A, Karantanas A (2007) Paraoxonase 1 gene polymorphisms in patients with osteonecrosis of the femoral head with and without cerebral white matter lesions. J Orthop Res 25(8):1087–1093. https://doi.org/10.1002/jor.20393
Castelnovo V, Caminiti SP, Riva N, Magnani G, Silani V, Perani D (2018) Heterogeneous brain FDG-PET metabolic patterns in patients with C9orf72 mutation. Neurol Sci. https://doi.org/10.1007/s10072-018-3685-7
Funding
The study was supported in part by a research grant of the Research Committee of the University of Thessaly, Greece (Code: 5287).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 15 kb)
Rights and permissions
About this article
Cite this article
Dardiotis, E., Karampinis, E., Siokas, V. et al. ERCC6L2 rs591486 polymorphism and risk for amyotrophic lateral sclerosis in Greek population. Neurol Sci 40, 1237–1244 (2019). https://doi.org/10.1007/s10072-019-03825-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10072-019-03825-3