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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2018

Open Access 01-12-2018 | Research article

S100B polymorphisms are associated with age of onset of Parkinson’s disease

Authors: Camilla Fardell, Anna Zettergren, Caroline Ran, Andrea Carmine Belin, Agneta Ekman, Olof Sydow, Lars Bäckman, Björn Holmberg, Nil Dizdar, Peter Söderkvist, Hans Nissbrandt

Published in: BMC Medical Genetics | Issue 1/2018

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Abstract

Background

In this study we investigated the association between SNPs in the S100B gene and Parkinson’s disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD.

Methods

The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar® PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset.

Results

The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population.

Conclusions

rs9722, a functional SNP in the 3’-UTR of the S100B gene, was strongly associated with age of onset of PD.
Literature
1.
2.
Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev. 2011;91:1161–218.CrossRefPubMed
3.
Schapira AH. Mitochondrial pathology in Parkinson’s disease. Mount Sinai J Med. 2011;78:872–81.CrossRef
4.
Barnum CJ, Tansey MG. Modeling neuroinflammatory pathogenesis of Parkinson's disease. Prog Brain Res. 2010;184:113–32.CrossRefPubMed
5.
Håkansson A, Westberg L, Nilsson S, Buervenich S, Carmine A, Holmberg B, et al. Investigation of genes coding for inflammatory components in Parkinson's disease. Mov Disord. 2005;20:569–73.CrossRefPubMed
6.
Håkansson A, Westberg L, Nilsson S, Buervenich S, Carmine A, Holmberg B, et al. Interaction of polymorphisms in the genes encoding interleukin-6 and estrogen receptor beta on the susceptibility to Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet. 2005;133B:88–92.CrossRefPubMed
7.
Lerner A, Bagic A. Olfactory pathogenesis of idiopathic Parkinson disease revisited. Mov Disord. 2008;23:1076–84.CrossRefPubMed
8.
Dunning CJ, Reyes JF, Steiner JA, Brundin P. Can Parkinson’s disease pathology be propagated from one neuron to another? Prog Neurobiol. 2012;97:205–19.CrossRefPubMed
9.
10.
11.
Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014;46:989–93.CrossRefPubMedPubMedCentral
12.
Keller MF, Saad M, Bras J, Bettella F, Nicolaou N, Simón-Sánchez J, et al. Using genome-wide complex trait analysis to quantify ‘missing heritability’ in Parkinson's disease. Hum Mol Genet. 2012;21:4996–5009.CrossRefPubMedPubMedCentral
13.
Rickmann M, Wolff JR. S100 protein expression in subpopulations of neurons of rat brain. Neurosci. 1995;67:977–91.CrossRef
14.
Vives V, Alonso G, Solal AC, Joubert D, Legraverend C. Visualization of S100B-positive neurons and glia in the central nervous system of EGFP transgenic mice. J Comp Neurol. 2003;457:404–19.CrossRefPubMed
15.
Cirillo C, Sarnelli G, Esposito G, Turco F, Steardo L, Cuomo R. S100B protein in the gut: the evidence for enteroglial-sustained intestinal inflammation. World J Gastroenterol. 2011;17:1261–6.CrossRefPubMedPubMedCentral
16.
Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, et al. S100B’s double life: intracellular regulator and extracellular signal. Biochim Biophys Acta. 2009;1793:1008–22.CrossRefPubMed
17.
Rothoerl RD, Woertgen C, Holzschuh M, Metz C, Brawanski A. S-100 serum levels after minor and major head injury. J Trauma. 1998;45:765–7.CrossRefPubMed
18.
Rothermundt M, Ponath G, Glaser T, Hetzel G, Arolt V. S100B serum levels and long-term improvement of negative symptoms in patients with schizophrenia. Neuropsychopharmacology. 2004;29:1004–11.CrossRefPubMed
19.
Schmitt A, Bertsch T, Henning U, Tost H, Klimke A, Henn FA, et al. Increased serum S100B in elderly, chronic schizophrenic patients: negative correlation with deficit symptoms. Schizophr Res. 2005;80:305–13.CrossRefPubMed
20.
Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989;86:7611–5.CrossRefPubMedPubMedCentral
21.
Schaf DV, Tort AB, Fricke D, Schestatsky P, Portela LV, Souza DO, et al. S100B and NSE serum levels in patients with Parkinson’s disease. Parkinsonism Relat Disord. 2005;11:39–43.CrossRefPubMed
22.
Wilhelm KR, Yanamandra K, Gruden MA, Zamotin V, Malisauskas M, Casaite V, et al. Immune reactivity towards insulin, its amyloid and protein S100B in blood sera of Parkinson's disease patients. Eur J Neurol. 2007;14:327–34.PubMed
23.
Sathe K, Maetzler W, Lang JD, Mounsey RB, Fleckenstein C, Martin HL, et al. S100B is increased in Parkinson's disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain. 2012;135:3336–47.CrossRefPubMedPubMedCentral
24.
Liu J, Wang H, Zhang L, Xu Y, Deng W, Zhu H, et al. S100B transgenic mice develop features of Parkinson's disease. Arch Med Res. 2011;42:1–7.CrossRefPubMed
25.
Nishiyama H, Knopfel T, Endo S, Itohara S. Glial protein S100B modulates long-term neuronal synaptic plasticity. Proc Natl Acad Sci U S A. 2002;99:4037–42.CrossRefPubMedPubMedCentral
26.
Li Y-J, Scott WK, Hedges DJ, Zhang F, Gaskell PC, Nance MA, et al. Age at onset in two common neurodegenerative diseases is genetically controlled. Am J Hum Gen. 2002;70:985–93.CrossRef
27.
Searles Nielsen S, Bammler TK, Gallagher LG, Farin FM, Longstreth W Jr, Franklin GM, et al. Genotype and age at Parkinson disease diagnosis. Int J Mol Epidemiol Genet. 2013;4:61–9.PubMedPubMedCentral
28.
Fratiglioni L, Viitanen M, Backman L, Sandman PO, Winblad B. Occurrence of dementia in advanced age: the study design of the Kungsholmen project. Neuroepidemiology. 1992;11(Suppl 1):29–36.CrossRefPubMed
29.
Daniel SE, Lees AJ. Parkinson's disease society brain Bank, London: overview and research. J Neural Transm Suppl. 1993;39:165–72.PubMed
30.
Mizuta I, Nishimura M, Mizuta E, Yamasaki S, Ohta M, Kuno S, et al. Relation between the high production related allele of the interferon-gamma (IFN-gamma) gene and age at onset of idiopathic Parkinson's disease in Japan. J Neurol Neurosurg Psychiatry. 2001;71:818–9.CrossRefPubMedPubMedCentral
31.
Wang J, Zhao CY, Si YM, Liu ZL, Chen B, Yu L. ACT and UCH-L1 polymorphisms in Parkinson's disease and age of onset. Mov Disord. 2002;17:767–71.CrossRefPubMed
32.
Håkansson A, Belin AC, Stiller C, Sydow O, Johnels B, Olson L, et al. Investigation of genes related to familial forms of Parkinson’s disease – with focus on the Parkin gene. Parkinsonism Relat Disord. 2008;14:520–2.CrossRefPubMed
33.
Anvret A, Blackinton JG, Westerlund M, Ran C, Sydow O, Willows T, et al. DJ-1 mutations are rare in a Swedish Parkinson cohort. Open Neurol J. 2011;5:8–11.CrossRefPubMedPubMedCentral
34.
Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet. 2010;42:781–5.CrossRefPubMedPubMedCentral
35.
36.
Consortium, U. K. P. S. D., Wellcome Trust Case Control, C, Spencer CC, Plagnol V, Strange A, Gardner M, Paisan-Ruiz C, Band G, et al. Dissection of the genetics of Parkinson's disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21. Hum Mol Genet. 2011;20:345–53.CrossRef
37.
Guo Y, Yang H, Deng X, Song Z, Yang Z, Xiong W, et al. Genetic analysis of the S100B gene in Chinese patients with Parkinson disease. Neurosci Lett. 2013;555:134–6.CrossRefPubMed
38.
Winningham-Major F, Staecker JL, Barger SW, Coats S, Van Eldik LJ. Neurite extension and neuronal survival activities of recombinant S100 beta proteins that differ in the content and position of cysteine residues. J Cell Biol. 1989;109:3063–71.CrossRefPubMed
39.
Haglid KG, Yang Q, Hamberger A, Bergman S, Widerberg A, Danielsen N. S-100beta stimulates neurite outgrowth in the rat sciatic nerve grafted with acellular muscle transplants. Brain Res. 1997;753:196–201.CrossRefPubMed
40.
Li Y, Barger SW, Liu L, Mrak RE, Griffin WS. S100beta induction of the proinflammatory cytokine interleukin-6 in neurons. J Neurochem. 2000;74:143–50.PubMedPubMedCentral
41.
Adami C, Sorci G, Blasi E, Agneletti AL, Bistoni F, Donato R. S100B expression in and effects on microglia. Glia. 2001;33:131–42.CrossRefPubMed
42.
Bianchi R, Kastrisianaki E, Giambanco I, Donato R. S100B protein stimulates migration via RAGE-dependent up-regulation of chemokine expression and release. J Biol Chem. 2011;286:7214–26.CrossRefPubMedPubMedCentral
43.
Lam V, Albrecht MA, Takechi R, Giles C, James AP, Foster JK, et al. The serum concentration of the calcium binding protein S100B is positively associated with cognitive performance in older adults. Front Aging Neurosci. 2013;5:61.CrossRefPubMedPubMedCentral
44.
Huttunen HJ, Kuja-Panula J, Sorci G, Agneletti AL, Donato R, Rauvala H. Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem. 2000;275:40096–105.CrossRefPubMed
45.
Villarreal A, Aviles Reyes RX, Angelo MF, Reines AG, Ramos AJ. S100B alters neuronal survival and dendrite extension via RAGE-mediated NF-kappaB signaling. J Neurochem. 2011;117:321–32.CrossRefPubMed
46.
Ahlemeyer B, Beier H, Semkova I, Schaper C, Krieglstein J. S-100beta protects cultured neurons against glutamate- and staurosporininduced damage and is involved in the anti-apoptotic action of the 5 HT(1A)-receptor agonist, bay x 3702. Brain Res. 2000;858:121–8.CrossRefPubMed
47.
Businaro R, Leone S, Fabrizi C, Sorci G, Donato R, Lauro GM, et al. S100B protects LAN-5 neuroblastoma cells against Abeta amyloid-induced nheurotoxicity via RAGE engagement at low doses but increases Abeta amyloid neurotoxicity at high doses. J Neurosci Res. 2006;83:897–906.CrossRefPubMed
48.
Hohoff C, Ponath G, Freitag CM, Kästner F, Krakowitzky P, Domschke K, et al. Risk variants in the S100B gene predict elevated S100B serum concentrations in healthy individuals. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:291–7.PubMed
49.
Cunha C, Giovannini G, Pierini A, Bell AS, Sorci G, Riuzzi F, et al. Genetically-determined hyperfunction of the S100B/RAGE axis is a risk factor for aspergillosis in stem cell transplant recipients. PLoS One. 2011;6:e27962.CrossRefPubMedPubMedCentral
50.
Escott-Price V, Nalls MA, Morris HR, Lubbe S, Brice A, Gasser T, et al. Polygenic risk of Parkinson disease is correlated with disease age at onset. Ann Neurol. 2015;77:582–91.CrossRefPubMedPubMedCentral
51.
52.
Wirdefeldt K, Gatz M, Schalling M, Pedersen NL. No evidence for heritability of Parkinson disease in Swedish twins. Neurol. 2004;6:305–11.CrossRef
53.
Wirdefeldt K, Gatz M, Reynolds CA, Prescott CA, Pedersen NL. Heritability of Parkinson disease in Swedish twins: a longitudinal study. Neurobiol Aging. 2011;32:1923e1–8.CrossRef
54.
Payami H, Kay DM, Zabetian CP, Schellenberg GD, Factor SA, McCulloch CC. Visualizing disease associations: graphic analysis of frequency distributions as a function of age using moving average plots (MAP) with application to Alzheimer's and Parkinson's disease. Genet Epidemiol. 2010;34:92–9.PubMedPubMedCentral
55.
Zareparsi S, Taylor TD, Harris EL, Payami H. Segregation analysis of Parkinson disease. Am J Med Genet. 1998;80:410–7.CrossRefPubMed
56.
Maher NE, Currie LJ, Lazzarini AM, Wilk JB, Taylor CA, Saint-Hilaire MH, et al. Segregation analysis of Parkinson disease revealing evidence for a major causative gene. Am J Med Genet. 2002;109:191–7.CrossRefPubMed
Metadata
Title
S100B polymorphisms are associated with age of onset of Parkinson’s disease
Authors
Camilla Fardell
Anna Zettergren
Caroline Ran
Andrea Carmine Belin
Agneta Ekman
Olof Sydow
Lars Bäckman
Björn Holmberg
Nil Dizdar
Peter Söderkvist
Hans Nissbrandt
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2018
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-018-0547-3

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