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| ORIGINAL ARTICLE |
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| Year : 2013 | Volume
: 61
| Issue : 4 | Page : 360-364 |
Association of polymorphism in rs2736990 of the α-synuclein gene with Parkinson's disease in a Chinese population
Fenghua Pan1, Haixia Ding2, Hairong Dong3, Min Ye4, Weiguo Liu5, Guiyun Cui6, Jiechun Chen7, Yanfeng Wu8, Hui Wang8, Xingzhen Dai8, Haicun Shi9, Xinsheng Ding3
1 Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Jiangjiayuan, Nanjing, Jiangsu Province 210011, People's Republic of China
2 Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, People's Republic of China
3 Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, People's Republic of China
4 The BenQ Neurological Institute, Nanjing Medical University, Nanjing, Jiangsu Province 210029, People's Republic of China
5 Department of Neurology, The Nanjing Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, People's Republic of China
6 The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province 221002, People's Republic of China
7 The Second People's Hospital of Lianyungang, Haizhou, Jiangsu Province 222023, People's Republic of China
8 The Second Affiliated Hospital of Nanjing Medical University, Jiangjiayuan, Nanjing, Jiangsu Province 210011, People's Republic of China
9 The Third People's Hospital of Yancheng, Jiangsu Province 224001, People's Republic of China
| Date of Submission | 24-Feb-2013 |
| Date of Decision | 29-Mar-2013 |
| Date of Acceptance | 21-Jul-2013 |
| Date of Web Publication | 4-Sep-2013 |
Correspondence Address:
Xinsheng Ding
Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029
People's Republic of China
 Source of Support: Nanjing Medical University Technology
Development Foundation (2010NJMUZ57, Fenghua Pan)., Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.117595
Background and Objective: Previous genetic studies in Parkinson's disease (PD) have provided conclusive evidence for association of genes with strong biological rationale for PD. Recently several studies in different populations have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs2736990, located within an intron of the α-synuclein (SNCA) gene. In this study, we aimed to verify these findings and to explore the characteristic of the association in a subset of Chinese Han PD patients. Materials and Methods: A total of 515 unrelated patients with sporadic PD and 450 healthy ethnically matched control subjects were recruited consecutively for the study. Patients and healthy controls were genotyped for SNCA rs2736990 variant by polymerase chain reaction - ligase detection reaction. Results: Our data showed a significant association between the rs2736990 polymorphism and PD, the frequency of the allele C in PD patients was significantly higher than that in controls (P = 0.017, OR = 1.26, 95% confident intervals (CI) =1.04-1.51). The distribution of C > T genotypes was different between patients and controls (P = 0.027). Furthermore, allele C of SNP rs2736990 in early-onset PD was significantly more frequent than that in healthy controls (P = 0.007, odds ratio = 1.60, 95% CI = 1.13-2.26). Conclusions: Our study demonstrated that SNCA rs2736990 C > T polymorphism was associated with susceptibility to PD in Chinese Han population. Further studies are needed to replicate the association we found.
Keywords: Parkinson′s disease, rs2736990, single-nucleotide polymorphism, α-synuclein
How to cite this article:
Pan F, Ding H, Dong H, Ye M, Liu W, Cui G, Chen J, Wu Y, Wang H, Dai X, Shi H, Ding X. Association of polymorphism in rs2736990 of the α-synuclein gene with Parkinson's disease in a Chinese population. Neurol India 2013;61:360-4 |
How to cite this URL:
Pan F, Ding H, Dong H, Ye M, Liu W, Cui G, Chen J, Wu Y, Wang H, Dai X, Shi H, Ding X. Association of polymorphism in rs2736990 of the α-synuclein gene with Parkinson's disease in a Chinese population. Neurol India [serial online] 2013 [cited 2023 Jun 8];61:360-4. Available from: https://www.neurologyindia.com/text.asp?2013/61/4/360/117595 |
Fenghua Pan, Haixia Ding, Hairong Dong have contributed equally to this article
| » Introduction | |  |
Parkinson's disease (PD) is one of the most common neurodegenerative disorders of central nervous system and the clinical features include resting tremor, rigidity, bradykinesia and postural instability. PD is characterized by the predominant degeneration of dopaminergic neurons in the substantia nigra and the form of Lewy bodies in the relict dopaminergic neurons. [1] Although the etiology of PD remains unclear, there is growing evidence that genetic abnormalities play a major role in the etiopathogenesis of PD. Recent studies have shown that point mutations and multiplication of α-synuclein (SNCA) were associated with pathogenesis of PD. SNCA gene is located in chromosome 4q22, SNCA protein is encoded by SNCA. Many of the studies suggest that SNCA inclusions cause dysfunction and degeneration of dopaminergic neurons in the substantia nigra. [2] Golbe and Mouradian found that SNCA is the main component of Lewy bodies and cellular inclusions, which are the pathological hallmarks of sporadic PD. [3] The mutations and increased copies of SNCA may enhance the formation of Lewy bodies and inclusions. [4]
From the turn of the century, a multi-marker design highlighting haplotypes became more common in SNCA association studies. Modern methods for genotyping single-nucleotide polymorphisms (SNPs) became more available and facilitated this development. Many studies have found that Rep1 polymorphism, located in the promoter region and commonly referred to as Rep1 (D4S3481), is associated with susceptibility to sporadic PD. [5] This approach also revealed that SNPs in the 5' region contribute to the association signal [6] and SNPs in the 3' block showed the clearest evidence of association with the disease. [7] Besides the mutations mentioned above, variants location in the intron of the SNCA gene was identified and confirmed as a susceptibility gene for sporadic PD. [8] However, these mutations probably account for a small percentage of PD cases in most populations. Therefore, the search for genetic susceptibility risk factors in the vast majority of PD continues to be of scientific interest. A high resolution of whole genome-wide association study (GWAS) of PD was conducted by Edwards et al. in 2010; their results showed that a SNP named rs2736990 within the intron of SNCA was apparently associated with PD in a Caucasian-based population. [9] Recently, Miyake et al. have performed a case-control study and suggest that SNCA SNP rs2736990 is significantly associated with the risk of sporadic PD in Japanese. [10]
Considering of population-specific genetic heterogeneity, we therefore carried out a replicated case-control study to determine whether the polymorphism of SNP rs2736990 could be significantly different between PD patients and healthy controls in a Chinese Han population.
| » Materials and Methods | | |
Subjects
A total of 515 unrelated patients with sporadic PD were recruited consecutively from the Neurology Departments of six hospitals between June 2009 and September 2011. The clinical diagnosis of PD was established by two independent movement disorder specialists according to accepted criteria. If a patient had two signs of the four main signs of PD, i.e. rigidity, tremor at rest, hypokinesis and postural reflex impairment, a diagnosis could be made. [11] Patients with a family history of PD, defined as one or more relatives with the disease, were excluded. This study included 450 healthy control subjects randomly selected from out-patients who underwent regular physical examinations during the same time in the six hospitals. They were free from signs of Parkinsonism More Details, matched to the patients' group in gender, age and ethnicity and had no family history of Parkinsonism. All the subjects were of Han ancestry [Table 1]. The ethical review board at each involved institution approved the study and all participants or their legal surrogates signed informed consent forms. Venous blood samples for deoxyribonucleic acid (DNA) extraction were collected by using standard techniques. | Table 1: Demographic and clinical characteristics of patients and control subjects.
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Polymerase chain reaction analysis and genotyping
Genomic DNA was extracted from leukocyte pellets by UltraPure™ Genome DNA extraction kit (SBS Genetech Technology Co., Ltd, Shanghai, China). The rs2736990 polymorphism was genotyped by the polymerase chain reaction-ligase detection reaction (PCR-LDR) sequencing method. A 267 bp DNA fragment containing the polymorphic site was amplified by PCR using the forward primer 5′-TGGCAGTTGAGAGGAGTATTC-3′ and the reverse primer 5′-GAGCAGGCAGTCCGTGTGATA-3′. The PCR was carried out in a total volume of 15 μl containing 1.5 μl 10 × PCR buffer, 1.5 μl 25 mmol magnesium chloride, 0.25 μl 10 pmol each primer, 0.3 μl deoxyribonucleotide triphosphate, 0.2 μl Taq polymerase (MBI fermentas), 1 μl of genomic DNA and 10 μl H 2 O. The PCR cycling parameters were 35 cycles of 20 s at 94°C, 56°C for 20 s and 72°C for 40 s. LDR was performed in a total volume of 10 μl containing 2 μl PCR product, 1 μl 10 × Taq DNA ligase buffer, 0.125 μl 40 U/μl Taq DNA ligase New England Biolabs, Inc. NEB, 1 μl 10 pmol probes (0.01 μl each of the probe) and 5.875 μl H 2 O. LDR probes were composed of 1 common probe rs2736990-TR P-CTTCTTCCTAAACAGCTCATAAGGT-FAM and 2 discriminating probes, rs2736990-TC 5′-TGCTCCCTGTTACACACATTTACAC-3′ and rs2736990-TT 5′-TTTTGCTCCCTGTTA CACACATTTACAT-3′ (designed by the Shanghai Generay, Biotech Co., Ltd.). Subsequently, LDR products were analyzed by DNA sequencing (Model 377, Applied Biosystems). All assays were conducted blindly without the knowledge of the case or control status. In addition, about 10% of the samples were randomly selected and retested by direct DNA sequencing on a 3730 × l DNA analyzer (Applied Biosystems) and the results were 100% concordant.
Statistical analysis
Categorical data were analyzed using the χ2 test or the Fisher's exact test if appropriate. Differences for continuous variables were evaluated using Student's t-test. Data were expressed as mean ± SD. Hardy-Weinberg mean ± SD Hardy-Weinberg equilibrium (HWE) test, allele and genotype frequencies in the case-control study were calculated using SHEsis program. [12] The Bonferroni test was applied to correct for multiple comparisons. The strength of association between the SNCA gene polymorphism and PD was estimated using odds ratios (OR), with the corresponding 95% confidence intervals (CI). A two-tailed P < 0.05 was considered as significant.
| » Results | | |
In this case-control study, healthy controls (n = 450) were matched with sporadic PD patients (n = 515) in gender, age and ethnicity. We defined early-onset Parkinson's disease (EOPD) as PD with an age at onset <50 years (95 subjects), the remainder (420 subjects) were categorized as late-onset Parkinson's disease patients (LOPD). The mean age of EOPD was 50.85 ± 5.69 years and the mean age at the onset in this group was 45.22 ± 4.63 years (range 30-49). In the LOPD group, the mean age was 67.25 ± 6.78 years and the mean age at onset was 61.49 ± 6.26 years (range 50-76).
The result showed that the frequency of C/T substitutions in SNP rs2736990 was significantly higher in sporadic PD patients than in controls and was much higher in EOPD patients than in healthy controls, based on the genotype frequencies and allele frequencies [Table 2]. In our study, the frequency of allele C of rs2736990 in SNCA gene appeared to be a risk modifier for PD; compared with the controls, it showed a strong correlation in the genotype association test both in the total samples of patients (P = 0.027) and in the EOPD subgroup (P = 0.033), but not in the LOPD subgroup (P = 0.064). In addition, the frequency of the allele C in PD patients was significantly higher than that in controls (P = 0.017, OR = 1.26, 95% CI = 1.04-1.51).When the age of onset was considered, the allele frequency in the EOPD subgroup was also significantly higher than that in the controls (P = 0.007, OR = 1.60, 95% CI = 1.13-2.26). There was no significant difference between LOPD subgroup and controls (P = 0.079) . This frequency analysis was also performed between EOPD subgroup and LOPD subgroup. Neither in genotype frequency (P = 0.144) nor in allele frequency (P = 0.097) showed significant differences. The genotype frequencies of the SNP in patients and controls were in HWE (P = 0.824 and P = 0.099). | Table 2: Genotype and allele frequencies of the SNCA single-nucleotide polymorphism rs 2736990
Click here to view |
| » Discussion | | |
In this hospital-based case-control study, we investigated the association between the risk of PD and SNP rs2736990 in a local Chinese Han ancestry population including 515 patients and 450 healthy controls. Our data showed that the SNP rs2736990, located in the intron region of SNCA gene, was associated with sporadic PD in a Chinese Han population. Several studies on ethnic Chinese populations have found an association between variants in the SNCA gene and the risk of PD. [13],[14] In our study, we provided evidence of an association between allele C of SNP rs2736990 and increased risk of sporadic PD in a region of SNCA gene outside of the promoter and 3′ UTR region.
We found that the allele C could increase the risk for PD approximately 1.26-fold. Our data showed that the frequency of allele C of rs2736990 in patients was significantly higher than that in controls (P = 0.017) and the frequency of the homozygous genotype CC was 44.7% (230 patients), which was significantly higher than that in controls (40.0%, P = 0.027). Our results confirmed that allele C might confer a risk factor in susceptibility to PD. We also found the frequencies of genotype and allele to be significantly higher in the EOPD subgroup than in the control group. However, the results were not found in the LOPD subgroup. Our results suggest that polymorphism in the SNP rs2736990 of SNCA gene may be associated with EOPD, and the pathophysiology of EOPD may be different from that of LOPD.
Simon-Sanchez et al. [15] performed a GWAS in a large-scale European ancestry and highlighted an association between rs2736990 variant in SNCA intron four and common sporadic PD. The same association between PD and rs2736990 polymorphism was replicated in a Japanese population [16] and a Netherlands ancestry. [17] Recently, Ding et al. [18] demonstrated this association in the U.S. population, confirming that this intronic variant, together with the Rep1 SNCA promoter polymorphism [5] and other implicated 5' [6] and 3' [7] variants, is a genetic role for non-coding variants in SNCA in conferring susceptibility to sporadic PD. Our data are consistent with those observations and suggest SNP rs2736990 of SNCA is a major risk locus for PD across different ancestry.
The function of rs2736990 variation in SNCA remains unclear. SNCA is an abundant brain protein, which is located in axon terminals where it may mediate synaptic processes. [19] PD is considered as a synucleinopathy in which aggregations of precipitated filamentous SNCA (which form Lewy bodies) are a common finding in PD brains at autopsy. [20] The causal variant may affect post-transcriptional ribonucleic acid (RNA) processing or RNA stability, is possibly mediated by microRNA binding sites or by alternative splicing. [16] Thus, well-designed studies, phenotypic and further functional assays should be performed to elucidate the underlying mechanisms of PD pathogenesis associated with this genetic variant.
Some possible limitations of our study should be acknowledged. Firstly, selection bias in the study might have affected our results, although the genotype distribution of patients and controls in our study was compatible with the Hardy-Weinberg expectations. Secondly, our sample size was not big enough and our study was performed in a local Chinese Han population. The study should be extrapolated to other regions and ethnic groups cautiously. However, this internally consistent pilot study has provided valuable information for future studies in this area. Finally, the effect of a single gene on susceptibility is limited, whereas interaction between different genes could result in a dramatic modification of susceptibility. Therefore, other genes should be included as a gene-gene interaction model in the etiology of PD. [1]
| » Acknowledgment | | |
We acknowledge Dr. Yusheng Ma and the technical staff of the Generay Biotech for their technical support performing the genotyping.
| » References | | |
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[Table 1], [Table 2]
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