Association between synapsin III gene promoter SNPs and multiple sclerosis in Basque patients

Abstract

Background

Synapsins are a family of neuron-specific phosphoproteins, one of whose subunits is encoded by the SYN3 gene. This gene is located close to one of the multiple sclerosis susceptibility regions (in 22q13.1). Two single-nucleotide polymorphisms (SNPs) (rs133945 and rs133946) in the promoter region of this gene have been proposed as factors protecting against MS. This relationship is not clear because another report failed to found such association.

Objectives

In an attempt to clarify this association, the frequency of these SNPs was analyzed in a population of 221 Spanish MS patients with a cluster of 72 Basque patients and in 373 controls with a cluster of 138 controls of a Basque origin.

Methods

The SNis analysis was performed by 9 PCR.

Results

According to our findings, these SNPs are differently distributed in the two populations. This significant bias should therefore be taken into account in association studies. Our data suggest that the C/C genotype in rs133946 and the G/G genotype in rs133945 could be protecting factors against MS in the Basque population.

Keywords

Basque multiple sclerosis rs133945 rs133946 syn III

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References

1 Oksenberg JR Barcellos LF . Multiple sclerosis genetics: leaving no stone unturned. Genes Immun 2005; 6: 375–387.

2 De Santis ML Roth GA Cumar FA . Cellular immune crossreactivity between myelin basic protein and synapsin in rats with experimental allergic encephalomyelitis. J Neurosci Res 1992; 31: 46–51.

3 Pedraza LT Roth GA Cumar FA . Identification as synapsin of a synaptosomal protein immunoreacting with anti-myelin basic protein antiserum. J Neurochem 1988; 51: 413–420.

4 Polak T Schlaf G Scholl U . Characterization of the human T cell response against the neuronal protein synapsin in patients with multiple sclerosis. J Neuroimmunol 2001; 115: 176–181.

5 Ryan TA Li L Chin LS Greengard P Smith SJ . Synaptic vesicle recycling in synapsin I knock-out mice. J Cell Biol 1996; 134: 1219–1227.

6 Zurmohle U Herms J Schlingensiepen R Brysch W Schlingensiepen KH . Changes in the expression of synapsin I and II messenger RNA during postnatal rat brain development. Exp Brain Res 1996; 108: 441–449.

7 Hilfiker S Pieribone VA Czernik AJ Kao HT Augustine GJ Greengard P . Synapsins as regulators of neurotransmitter release. Philos Trans R Soc Lond B Biol Sci 1999; 354: 269–279.

8 Jovanovic JN Benfenati F Siow YL . Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions. Proc Natl Acad Sci U S A 1996; 93: 3679–3683.

9 D’Alfonso S Nistico L Zavattari P . Linkage analysis of multiple sclerosis with candidate region markers in Sardinian and Continental Italian families. Eur J Hum Genet 1999; 7: 377–385.

10.

10 Goertsches R Villoslada P Comabella M . A genomic screen of Spanish multiple sclerosis patients reveals multiple loci associated with the disease. J Neuroimmunol 2003; 143: 124–128.

11.

11 Haskin Fernald G; Ru-Fang Y; Hauser SL; Oksenberg J; Baranzini SE; . Mapping gene activity in complex disorders: integration of expression and genomic scans for multiple sclerosis. Journal of Immunology 2005; 167: 157–159 [Generic].

12.

12 Liguori M Cittadella R Manna I . Association between Synapsin III gene promoter polymorphisms and multiple sclerosis. J Neurol 2004; 251: 165–170.

13.

13 Akkad D Godde R Epplen JT . No association between synapsin III gene promoter polymorphisms and multiple sclerosis in German patients. J Neurol 2006; 253: 1365–1366.

14.

14 McDonald WI Compston A Edan G . Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.

15.

15 Kurtzke JF . Rating neurologic impairment in multiple sclerosis. An expanded disability status scale (EDSS). Neurology 1983; 33: 144–152.

16.

16 Roxburgh RH Seaman SR Masterman T . Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology 2005; 64: 1144–1151.

17.

17 Otaegui D Sáenz A Martínez-Zabaleta M . Mitochondrial haplogroups in Basque multiple sclerosis patients. Mult Scler 2004; 10: 532–535.

18.

18 Bland JM Altman DG . Multiple significance tests: the Bonferroni method. BMJ 1995; 310: 170.

19.

19 Bonferroni CE; . Teoria statistica delle classi e calcolo delle probabilita. Pubblizaziononi del R istituto Superiore di Scienze Economiche e Commerciali di Firenze 1936; pp. 15–46.

20.

20 Holm S . A simple sequentially rejective multiple test procedure. Scand J Stat 1979; 6: 65–70.

21.

21 Otaegui D Ruiz-Martinez J Olaskoaga J Emparanza JI López de Munain A . Influence of CCR5-delta32 genotype in Spanish population with multiple sclerosis. Neurogenetics 2007; 21(3): 201–205.

22.

22 Lin P Vance JM Pericak-Vance M Martin ER . No gene is an island: the flip-flop phenomenon. Am J Hum Genet 2007; 80: 531–538.

23.

23 Otaegui D Sáenz A Martínez-Zabaleta M . Mitochondrial haplogroups in Basque multiple sclerosis patients. Mult Scler 2004; 10: 532–535.

24.

24 Otaegui D Sáenz A Ruiz-Martínez J Olaskoaga J López de Munain A . UCP2 and mitochondrial haplogroups as an MS risk-factor. Mult Scler 2006; 13(4): 454–458.