Determining the Effect of the HNMT, STK39, and NMD3 Polymorphisms on the Incidence of Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Multiple System Atrophy in Chinese Populations
Large-scale meta-analyses of genome-wide association studies have identified several loci linked to sporadic Parkinson’s disease (PD). However, the roles of some important loci, such as HNMT Thr105Ile, STK39 rs2390669, and NMD3 rs34016896, have not been clarified in Chinese populations. Accumulating evidence indicates that some common clinicopathological characteristics are shared by different neurodegenerative diseases. Consequently, we conducted a large sample study to investigate associations between these variants and PD, multiple system atrophy (MSA), and amyotrophic lateral sclerosis (ALS) in Chinese populations. A total of 2417 patients, including 1237 PD, 850 SALS, and 330 MSA patients, along with 836 healthy controls (HCs) were examined in this study. All patients were genotyped for SNPs using the Sequenom iPLEX assay. No significant differences were found in the genotype and allele frequency distributions between the three neurodegenerative diseases and three candidate variants investigated. In subgroup analysis, compared with PD patients with initial symptom of tremor and HCs, the minor allele frequency of NMD3 rs34016896 in PD patients with initial symptoms of rigidity/bradykinesia was significantly lower. In addition, female patients carrying the rs34016896 minor allele had an increased risk of developing MSA (OR 1.25, 95% CI [1.09–1.43]), and ALS patients carrying the Ile105 polymorphism on the Thr105Ile allele in the HNMT gene exhibited a trend toward a delay in symptom onset of 3.010 ± 1.629 years. Our results indicate that the presence of the rs34016896 allele in the NMD3 gene may contribute to the development of synucleinopathies and that the Thr105Ile allele in the HNMT gene could potentially be an important therapeutic target for the treatment of ALS.
KeywordsParkinson’s disease Amyotrophic lateral sclerosis Multiple system atrophy Variants Association analysis
The authors thank all subjects for their participation in the study.
The present study was supported by funding from the National Science Fund of China (Grant Nos. 81571247 and 81701249) and the National Key Research and Development Program of China (Grant No. 2017YFC0909101).
Compliance with Ethical Standards
Signed informed consent forms were obtained from all subjects, and the study was approved by the Ethics Committee of Sichuan University (approval no.2015-236).
The authors declare that they have no conflicts of interest.
- Agundez JA, Luengo A, Herraez O, Martinez C, Alonso-Navarro H, Jimenez-Jimenez FJ, Garcia-Martin E (2008) Nonsynonymous polymorphisms of histamine-metabolising enzymes in patients with Parkinson's disease. NeuroMolecular Med 10:10–16. https://doi.org/10.1007/s12017-007-8017-7 CrossRefPubMedGoogle Scholar
- Davis AA, Andruska KM, Benitez BA, Racette BA, Perlmutter JS, Cruchaga C (2016) Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression. Neurobiol Aging 37:209 e201–209 e207. https://doi.org/10.1016/j.neurobiolaging.2015.09.014 CrossRefGoogle Scholar
- Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676. https://doi.org/10.1212/01.wnl.0000324625.00404.15 CrossRefPubMedPubMedCentralGoogle Scholar
- Jansen IE et al (2017) Establishing the role of rare coding variants in known Parkinson’s disease risk loci. Neurobiol Aging 59:220 e211–220 e218. https://doi.org/10.1016/j.neurobiolaging.2017.07.009 CrossRefGoogle Scholar
- Keeling BH, Vilariño-Güell C, Soto-Ortolaza AI, Ross OA, Uitti RJ, Rajput A, Wszolek ZK, Farrer MJ (2010) Histamine N-methyltransferase Thr105Ile is not associated with Parkinson’s disease or essential tremor. Parkinsonism Relat Disord 16:112–114. https://doi.org/10.1016/j.parkreldis.2009.08.011 CrossRefPubMedGoogle Scholar
- Kovacs GG (2016) Molecular pathological classification of neurodegenerative diseases: turning towards precision medicine Int J Mol Sci 17(2). pii: E189. https://doi.org/10.3390/ijms17020189
- Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide BMM, Schjeide LM, Meissner E, Zauft U, Allen NC, Liu T, Schilling M, Anderson KJ, Beecham G, Berg D, Biernacka JM, Brice A, DeStefano AL, Do CB, Eriksson N, Factor SA, Farrer MJ, Foroud T, Gasser T, Hamza T, Hardy JA, Heutink P, Hill-Burns EM, Klein C, Latourelle JC, Maraganore DM, Martin ER, Martinez M, Myers RH, Nalls MA, Pankratz N, Payami H, Satake W, Scott WK, Sharma M, Singleton AB, Stefansson K, Toda T, Tung JY, Vance J, Wood NW, Zabetian CP, 23andMe, The Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium, The International Parkinson's Disease Genomics Consortium (IPDGC), The Parkinson's Disease GWAS Consortium, The Wellcome Trust Case Control Consortium 2 (WTCCC2), Young P, Tanzi RE, Khoury MJ, Zipp F, Lehrach H, Ioannidis JPA, Bertram L (2012) Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: the PDGene database. PLoS Genet 8:e1002548. https://doi.org/10.1371/journal.pgen.1002548 CrossRefPubMedPubMedCentralGoogle Scholar
- Liu ZH, Guo JF, Li K, Wang YQ, Kang JF, Wei Y, Sun QY, Xu Q, Wang DL, Xia K, Yan XX, Xu CS, Tang BS (2015) Analysis of several loci from genome-wide association studies in Parkinson’s disease in mainland China. Neurosci Lett 587:68–71. https://doi.org/10.1016/j.neulet.2014.12.027 CrossRefPubMedGoogle Scholar
- Palada V, Terzić J, Mazzulli J, Bwala G, Hagenah J, Peterlin B, Hung AY, Klein C, Krainc D (2012) Histamine N-methyltransferase Thr105Ile polymorphism is associated with Parkinson’s disease. Neurobiol Aging 33(836):e831–e833. https://doi.org/10.1016/j.neurobiolaging.2011.06.015 Google Scholar
- Yang X, Liu C, Zhang J, Han H, Wang X, Liu Z, Xu Y (2015) Association of histamine N-methyltransferase Thr105Ile polymorphism with Parkinson’s disease and schizophrenia in Han Chinese: a case-control study. PLoS One 10:e0119692. https://doi.org/10.1371/journal.pone.0119692 CrossRefPubMedPubMedCentralGoogle Scholar