UNC13A confers risk for sporadic ALS and influences survival in a Spanish cohort

详细信息    查看全文

• 作者：Jose Manuel Vidal-Taboada ; Alan Lopez-Lopez ; Maria Salvado&#8230
• 关键词：Amyotrophic lateral sclerosis ; ALS ; UNC13A ; rs12608932 ; Susceptibility ; Modifying gene
• 刊名：Journal of Neurology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：262
• 期：10
• 页码：2285-2292
• 全文大小：540 KB
• 参考文献：1.Chi貌 A, Calvo A, Moglia C et al (2011) Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry 82:740鈥?46. doi:10.鈥?136/鈥媕nnp.鈥?010.鈥?35952 CrossRef PubMed
  2.Van den Berg LH (2011) ALS: disease or syndrome? J Neurol Neurosurg Psychiatry 82:711. doi:10.鈥?136/鈥媕nnp.鈥?011.鈥?41513 CrossRef PubMed
  3.Andersen PM, Al-Chalabi A (2011) Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 7:603鈥?15. doi:10.鈥?038/鈥媙rneurol.鈥?011.鈥?50 CrossRef PubMed
  4.Ince PG, Highley JR, Kirby J et al (2011) Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. Acta Neuropathol 122:657鈥?71. doi:10.鈥?007/鈥媠00401-011-0913-0 CrossRef PubMed
  5.Al-Chalabi A, Hardiman O (2013) The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol 9:617鈥?28. doi:10.鈥?038/鈥媙rneurol.鈥?013.鈥?03 CrossRef PubMed
  6.Renton AE, Chi貌 A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17:17鈥?3. doi:10.鈥?038/鈥媙n.鈥?584 PubMed Central CrossRef PubMed
  7.Van Es MA, Veldink JH, Saris CGJ et al (2009) Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet 41:1083鈥?087. doi:10.鈥?038/鈥媙g.鈥?42 CrossRef PubMed
  8.Shatunov A, Mok K, Newhouse S et al (2010) Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol 9:986鈥?94. doi:10.鈥?016/鈥婼1474-4422(10)70197-6 PubMed Central CrossRef PubMed
  9.Daoud H, Belzil V, Desjarlais A et al (2010) Analysis of the UNC13A gene as a risk factor for sporadic amyotrophic lateral sclerosis. Arch Neurol 67:516鈥?17. doi:10.鈥?001/鈥媋rchneurol.鈥?010.鈥?6 CrossRef PubMed
  10.Laaksovirta H, Peuralinna T, Schymick JC et al (2010) Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol 9:978鈥?85. doi:10.鈥?016/鈥婼1474-4422(10)70184-8 PubMed Central CrossRef PubMed
  11.Iida A, Takahashi A, Deng M et al (2011) Replication analysis of SNPs on 9p21.2 and 19p13.3 with amyotrophic lateral sclerosis in East Asians. Neurobiol Aging 32(757):e13鈥揺14. doi:10.鈥?016/鈥媕.鈥媙eurobiolaging.鈥?010.鈥?2.鈥?11 PubMed
  12.Diekstra FP, van Vught PWJ, van Rheenen W et al (2012) UNC13A is a modifier of survival in amyotrophic lateral sclerosis. Neurobiol Aging 33(630):e3鈥揺8. doi:10.鈥?016/鈥媕.鈥媙eurobiolaging.鈥?011.鈥?0.鈥?29 PubMed
  13.Kwee LC, Liu Y, Haynes C et al (2012) A high-density genome-wide association screen of sporadic ALS in US veterans. PLoS One 7:e32768. doi:10.鈥?371/鈥媕ournal.鈥媝one.鈥?032768 PubMed Central CrossRef PubMed
  14.Chi貌 A, Mora G, Restagno G et al (2013) UNC13A influences survival in Italian amyotrophic lateral sclerosis patients: a population-based study. Neurobiol Aging 34(357):e1鈥揺5. doi:10.鈥?016/鈥媕.鈥媙eurobiolaging.鈥?012.鈥?7.鈥?16 PubMed
  15.Fogh I, Ratti A, Gellera C et al (2014) A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Hum Mol Genet 23:2220鈥?231. doi:10.鈥?093/鈥媓mg/鈥媎dt587 PubMed Central CrossRef PubMed
  16.Chen X, Huang R, Chen Y et al (2014) Association analysis of four candidate genetic variants with sporadic amyotrophic lateral sclerosis in a Chinese population. Neurol Sci 35:1089鈥?095. doi:10.鈥?007/鈥媠10072-014-1656-1 CrossRef PubMed
  17.Forbes RB, Colville S, Swingler RJ (2001) Are the El Escorial and Revised El Escorial criteria for ALS reproducible? A study of inter-observer agreement. Amyotroph Lateral Scler Other Motor Neuron Disord 2:135鈥?38CrossRef PubMed
  18.Gamez J, Corbera-Bellalta M, Nogales G et al (2006) Mutational analysis of the Cu/Zn superoxide dismutase gene in a Catalan ALS population: should all sporadic ALS cases also be screened for SOD1? J Neurol Sci 247:21鈥?8CrossRef PubMed
  19.Syriani E, Salvans C, Salvad贸 M, Morales M, Lorenzo L, Cazorla S, Gamez J (2014) PFN1 mutations are also rare in the Catalan population with amyotrophic lateral sclerosis. J Neurol 261:2387鈥?392. doi:10.鈥?007/鈥媠00415-014-7501-x CrossRef PubMed
  20.Gordon PH, Moore DH, Miller RG et al (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6:1045鈥?053. doi:10.鈥?016/鈥婼1474-4422(07)70270-3 CrossRef PubMed
  21.Miller RG, Moore DH, Forshew DA et al (2011) Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. Neurology 77:973鈥?79. doi:10.鈥?212/鈥媁NL.鈥?b013e31822dc7a5鈥?/span> PubMed Central CrossRef PubMed
  22.Simon NG, Turner MR, Vucic S, Al-Chalabi A, Shefner J, Lomen-Hoerth C, Kiernan MC (2014) Quantifying disease progression in amyotrophic lateral sclerosis. Ann Neurol. 76:643鈥?57. doi:10.鈥?002/鈥媋na.鈥?4273 PubMed Central CrossRef PubMed
  23.Creemers H, Grupstra H, Nollet F, van den Berg LH, Beelen A (2015) Prognostic factors for the course of functional status of patients with ALS: a systematic review. J Neurol 262:1407鈥?423. doi:10.鈥?007/鈥媠00415-014-7564-8 CrossRef PubMed
  24.Elamin M, Bede P, Montuschi A, Pender N, Chio A, Hardiman O (2015) Predicting prognosis in amyotrophic lateral sclerosis: a simple algorithm. J Neurol 262:1447鈥?454. doi:10.鈥?007/鈥媠00415-015-7731-6 PubMed Central CrossRef PubMed
  25.Gonzalez JR, Armengol L, Sole X et al (2007) SNPassoc: an R package to perform whole genome association studies. Bioinformatics 23:654鈥?55. doi:10.鈥?093/鈥媌ioinformatics/鈥媌tm025 CrossRef
  26.Ballana E, Senserrich J, Pauls E et al (2010) ZNRD1 (zinc ribbon domain-containing 1) is a host cellular factor that influences HIV-1 replication and disease progression. Clin Infect Dis 50:1022鈥?032. doi:10.鈥?086/鈥?51114 CrossRef PubMed
  27.Lopez-Lopez A, Gamez J, Syriani E et al (2014) CX3CR1 is a modifying gene of survival and progression in amyotrophic lateral sclerosis. PLoS One 9:e96528. doi:10.鈥?371/鈥媕ournal.鈥媝one.鈥?096528 PubMed Central CrossRef PubMed
  28.Gauderman WJ MJ (2006) QUANTO 1.1: a computer program for power and sample size calculations for genetic-epidemiology studies. http://鈥媓ydra.鈥媢sc.鈥媏du/鈥媑xe . Accessed 20 May 2015
  29.Ahmeti KB, Ajroud-Driss S, Al-Chalabi A et al (2013) Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1. Neurobiol Aging 34(357):e7鈥揺19. doi:10.鈥?016/鈥媕.鈥媙eurobiolaging.鈥?012.鈥?7.鈥?17 PubMed
  30.Varoqueaux F, Sons MS, Plomp JJ, Brose N (2005) Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse. Mol Cell Biol 25:5973鈥?984. doi:10.鈥?128/鈥婱CB.鈥?5.鈥?4.鈥?973-5984.鈥?005 PubMed Central CrossRef PubMed
  31.Augustin I, Rosenmund C, S眉dhof TC, Brose N (1999) Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 400:457鈥?61. doi:10.鈥?038/鈥?2768 CrossRef PubMed
  32.Olmos G, Llad贸 J (2014) Tumor necrosis factor : a link between neuroinflammation and excitotoxicity. Mediators Inflamm 2014:861231. doi:10.鈥?155/鈥?014/鈥?61231 PubMed Central CrossRef PubMed
  33.Batlle M, Ferri L, Andrade C et al (2015) Astroglia-microglia cross talk during neurodegeneration in the rat hippocampus. Biomed Res Int 2015:102419. doi:10.鈥?155/鈥?015/鈥?02419 PubMed Central CrossRef PubMed
  34.Espinosa-Parrilla JF, Mart铆nez-Moreno M, Gasull X et al (2015) The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity. Mol Cell Neurosci 64:104鈥?15. doi:10.鈥?016/鈥媕.鈥媘cn.鈥?014.鈥?2.鈥?04 CrossRef PubMed
  35.Appel SH, Zhao W, Beers DR, Henkel JS (2011) The microglial-motoneuron dialogue in ALS. Acta Myol 30:4鈥?PubMed Central PubMed
  36.Beers DR, Henkel JS, Zhao W et al (2011) Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 134:1293鈥?314. doi:10.鈥?093/鈥媌rain/鈥媋wr074 PubMed Central CrossRef PubMed
  37.McCombe PA, Henderson RD (2011) The role of immune and inflammatory mechanisms in ALS. Curr Mol Med 11:246鈥?54PubMed Central CrossRef PubMed
  38.Boill茅e S, Yamanaka K, Lobsiger CS et al (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 80(312):1389鈥?392. doi:10.鈥?126/鈥媠cience.鈥?123511 CrossRef
  39.Henkel JS, Beers DR, Zhao W, Appel SH (2009) Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol 4:389鈥?98. doi:10.鈥?007/鈥媠11481-009-9171-5 CrossRef PubMed
  40.Brettschneider J, Toledo JB, Van Deerlin VM et al (2012) Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS One 7:e39216. doi:10.鈥?371/鈥媕ournal.鈥媝one.鈥?039216 PubMed Central CrossRef PubMed
  41.Corcia P, Tauber C, Vercoullie J et al (2012) Molecular imaging of microglial activation in amyotrophic lateral sclerosis. PLoS One 7:e52941. doi:10.鈥?371/鈥媕ournal.鈥媝one.鈥?052941 PubMed Central CrossRef PubMed
  42.Rock RB, Hu S, Deshpande A et al (2005) Transcriptional response of human microglial cells to interferon-gamma. Genes Immun 6:712鈥?19. doi:10.鈥?038/鈥媠j.鈥媑ene.鈥?364246 PubMed
  43.Yoshino T, Tabunoki H, Sugiyama S et al (2011) Non-phosphorylated FTY720 induces apoptosis of human microglia by activating SREBP2. Cell Mol Neurobiol 31:1009鈥?020. doi:10.鈥?007/鈥媠10571-011-9698-x CrossRef PubMed
  44.Mori R, Ikematsu K, Kitaguchi T et al (2011) Release of TNF-伪 from macrophages is mediated by small GTPase Rab37. Eur J Immunol 41:3230鈥?239. doi:10.鈥?002/鈥媏ji.鈥?01141640 CrossRef PubMed
  45.Pradas J, Puig T, Rojas-Garc铆a R, Viguera ML, Gich I, Logroscino G (2013) Amyotrophic lateral sclerosis in Catalonia: a population based study. Amyotroph Lateral Scler Frontotemporal Degener 14(4):278鈥?83. doi:10.鈥?109/鈥?1678421.鈥?012.鈥?49915 CrossRef PubMed
  46.Ingre C, Roos PM, Piehl F et al (2015) Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol 7:181鈥?93. doi:10.鈥?147/鈥婥LEP.鈥婼37505 PubMed Central PubMed
  
• 作者单位：Jose Manuel Vidal-Taboada (1) (2)
  Alan Lopez-Lopez (1) (2)
  Maria Salvado (3)
  Laura Lorenzo (3)
  Cecilia Garcia (3)
  Nicole Mahy (1) (2)
  Manuel J. Rodr铆guez (1) (2)
  Josep Gamez (3)
  
  1. Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine, IDIBAPS, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Spain
  2. Centro de Investigaci贸n Biom茅dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain
  3. ALS Unit, Neurology Department, Hospital Universitari Vall d鈥橦ebron, VHIR, Medicine Department, Autonomous University of Barcelona, FEDER, Passeig Vall d鈥橦ebron 119, 08035, Barcelona, Spain
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Neurology
  Neurosciences
  Neuroradiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1459

文摘

To investigate the association of functional variants of the human UNC13A gene with the risk of ALS, survival and the disease progression rate in a Spanish ALS cohort. 136 sporadic ALS (sALS) patients and 487 healthy controls were genotyped for the UNC13A rs12608932 variant. Clinical characterization of ALS patients included gender, age at first symptom, initial topography, disease progression rate, and survival. Genetic association was analyzed under five inheritance models. The sALS patients with the rs12608932CC genotype had an increased risk of ALS under a recessive genetic model [OR 2.16; 95 % CI (1.23, 3.8), p = 0.009; corrected p = 0.028]. Genotypes with a C allele are also associated with increased risk [OR 1.47; 95 % CI (1.11, 1.95); p = 0.008; corrected p = 0.023] under an additive model. sALS patients with a C/C genotype had a shorter survival than patients with A/A and A/C genotypes [HR 1.44; 95 % CI (1.11, 1.873); p = 0.007] under a recessive model. In an overdominant model, heterozygous patients had a longer survival than homozygous patients [HR 0.36; 95 % CI (0.22, 0.59); p = 0.001]. The rs12608932 genotypes modify the progression of symptoms measured using the ALSFRS-R. No association with age of onset, initial topography or rate of decline in FVC was found. Our results show that rs12608932 is a risk factor for ALS in the Spanish population and replicate the findings described in other populations. The rs12608932 is a modifying factor for survival and disease progression rate in our series. Our results also corroborated that it did not influence the age of onset. Keywords Amyotrophic lateral sclerosis ALS UNC13A rs12608932 Susceptibility Modifying gene