Yanming Xu

LRRK2 Gly2385Arg variant is a risk factor of Parkinson’s disease among Han‐Chinese from mainland China

Mutations in the gene encoding Leucine‐rich repeat kinase 2 (LRRK2) have been recently linked with autosomal‐dominant parkinsonism, and polymorphisms have been commonly associated with sporadic Parkinson’s disease (PD). A p.2385G>R variant has been reported as a risk factor for PD in Taiwan, Singapore and Japan. Herein, we have assessed the frequency of this polymorphism among the ethnic Han‐Chinese population in a case–control study. A total of 600 patients with PD and 334 unrelated healthy controls were genotyped using PCR‐restriction fragment length polymorphism analysis. Hardy–Weinberg equilibrium of each group was calculated, and differences in genotype frequencies between groups were assessed by the Chi‐square test. In the PD cohort, 70 patients (11.7%) were heterozygous and 1 (0.2%) was homozygous for the p.2385G>R variant. This was significantly more frequent than in the controls [3.3%, Odds ratio = 3.9, 95% confidence interval (CI) = 2.1–7.5, P < 0.01]. Clinically, the age of PD onset of the p.2385G>R carriers was lower than the non‐carriers (P = 0.01). Our study indicates that this LRRK2 p.2385G>R substitution contributes to the development of PD in ethnic Han‐Chinese population, which may play important implications for future study on molecular genetics and pathogenesis of PD.

Association studies of MMP-9 in Parkinson's disease and amyotrophic lateral sclerosis.

Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) share several clinical and neuropathologic features, and studies suggest that several gene mutations and polymorphisms are involved in both conditions. Matrix metalloproteinase-9 (MMP-9) is implicated in the pathogenesis of PD and ALS, and the C(−1562)T polymorphism in the MMP-9 gene leads to higher promoter activity. We therefore investigated whether this polymorphism predisposes to both PD and sporadic ALS (sALS). Samples from 351 subjects with PD and 351 healthy controls from two major cities in China were compared, while samples from 226 subjects with sALS were compared to the same number of controls from three centers in China. A possible association between the C(−1562)T polymorphism in the MMP-9 gene and PD or sALS was assessed by restriction fragment length polymorphism (RFLP) analysis. Our results show a significant association between the C(−1562)T polymorphism in the MMP-9 gene and risk of PD (odds ratio = 2.268, 95% CI 1.506–3.416, p<0.001) as well as risk of sALS (odds ratio = 2.163, 95% CI 1.233–3.796, p = 0.006), supporting a role for MMP-9 polymorphism in the risk for PD and sALS.

Association of the glucocerebrosidase N370S allele with Parkinson’s disease in two separate Chinese Han populations of mainland China

Background and purpose:  Mutations in the glucocerebrosidase (GBA) gene have been implicated in the development of Parkinson’s disease (PD). However, recent screenings for GBA mutations in PD subjects from different ethnic populations have yielded contradictory results.

H63D polymorphism in the hemochromatosis gene is associated with sporadic amyotrophic lateral sclerosis in China.

Background and purpose:  The H63D polymorphism in the hemochromatosis (HFE) gene has been reported as a risk factor for amyotrophic lateral sclerosis (ALS) in Europe and America, but no data have been reported for Asia. Here, we investigated the possible association between H63D and sporadic ALS (sALS) in a Chinese Han population.

Lack of evidence for association of a UCH-L1 S18Y polymorphism with Parkinson's disease in a Han-Chinese population.

Mutation in UCH-L1 has been reported as a rare cause of autosomal dominant Parkinsons disease (PD). A S18Y polymorphism in the same gene has been associated with sporadic PD. We investigated the frequency of this polymorphism among the Han-Chinese ethnic population in a case-control study. A total of 600 patients with PD and 334 unrelated healthy controls were genotyped using PCR-restriction fragment length polymorphism analysis. We did not observe any difference in allele or genotype frequencies between the cases and the controls (P>0.05). Our results do not support a role for this variant in sporadic PD.

SNP rs7684318 of the α-synuclein gene is associated with Parkinson's disease in the Han Chinese population

Mutations in the alpha-synuclein (SNCA) gene have been shown to be responsible for a rare familial form of Parkinsons disease (PD). Furthermore, polymorphic variants in multiple regions of the gene have been associated with susceptibility to idiopathic PD in different populations. Previous studies in Japanese have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs7684318, which is located within an intron of the SNCA gene. Our aim was to verify these findings and to further explore the nature of the association in a subset of Han Chinese PD patients. A case-control study of the SNP rs7684318, comprising 332 PD patients and 300 healthy controls, was carried out in Han Chinese populations from two centers in mainland China. The rs7684318 polymorphism was determined by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis. The SNP rs7684318 of the SNCA gene showed a strong association with PD (P<0.01). Among our PD patients, mean age at disease onset and gender did not differ significantly between rs7684318 carriers and non-carriers. Our findings suggested that the SNP rs7684318 (T>C) transition of the SNCA gene contributes to PD susceptibility in Chinese Han population, which is consistent with the earlier study form Japan.

LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China

Common genetic variants that increase the risk for Parkinsons disease (PD) may differentiate patient subgroups and influence future individual therapeutic strategies. Previous studies have found associations between PD and polymorphisms located within the leucine-rich repeat kinase 2 (LRRK2) gene in ethnic Han Chinese from Taiwan and Singapore. Herein, we performed a case-control study and provide evidence supporting the LRRK2 R1628P variant as a risk factor for PD in 2 separate Chinese Han populations from mainland China. A total of 328 PD patients and 300 control individuals were genotyped using PCR-restriction fragment length polymorphism analysis. Differences in genotype frequencies between groups were assessed by the chi-square test. In the PD group, 17 patients (5.2%) were heterozygous for the R1628P variant. This was significantly higher than for the control group [2.0%, P<0.05].No one carrier of the LRRK2 G2385R variant was detected in all the carriers of the R1628P variant. Our results confirm that the LRRK2 R1628P variant contributes to the pathogenesis of PD in Chinese Han populations.

Structural and functional changes mapped in the brains of amyotrophic lateral sclerosis patients with/without dysphagia: A pilot study

The purpose of this study was to explore cerebral structural and functional changes in amyotrophic lateral sclerosis (ALS) patients with or without dysphagia compared with healthy adults. In total, five ALS patients with dysphagia, five ALS patients without dysphagia and 10 healthy controls were evaluated using diffusion tensor magnetic resonance imaging (DTI) and event-related functional magnetic resonance imaging (fMRI) while laryngeal swallow-related movements were recorded. The fMRI data were analysed using the general linear model to gain the differential statistical map (two-sample t-test) for each group. Maps of fractional anisotropy (FA) and mean diffusivity (MD) were calculated within the masks that corresponded to the different statistical functional maps of intergroup comparisons. During the voluntary saliva swallowing, prominent activation of foci corresponded to the primary sensorimotor (SM) cortex in both ALS and controls, while decreased activation of the SM cortex was observed in ALS patients with dysphagia. DTI analysis revealed that FA was significantly reduced and MD was typically increased in the posterior limb of the internal capsule, thalamus, and anterior cingulate gyrus, as well as in the insula of ALS patients compared with controls. However, in ALS patients with dysphagia, FA and MD were more sensitive to these changes than ALS patients without dysphagia. This study highlights the potential of DTI and fMRI for monitoring structural degeneration and functional changes in patients with ALS. This study is the first to demonstrate that cerebral activation map changes correspond to distribution patterns of diffusion abnormalities. Combined non-invasive neuroimaging techniques may be useful tools to assess prognosis and study rehabilitation strategies for dysphagic ALS patients, especially for patients who are MRI-negative by conventional methods.

The transcription factor Pitx3 is a risk modifier for Parkinson’s disease in a Chinese Han population

Background and purpose:  The transcription factor Pitx3 plays a crucial role in the development and survival of midbrain dopaminergic (mDA) neurons, especially the mDA neurons in the substantia nigra pars compacta. The degeneration of these neurons is the pathological hallmark in Parkinson’s disease (PD). Several polymorphisms of the Pitx3 gene have been linked with sporadic and early‐onset forms of PD, but different studies have given conflicting or inconsistent findings. Amongst the polymorphisms studied, the single‐nucleotide polymorphism (SNP) rs3758549, located in the promoter region of Pitx3 gene, is one of the most well‐studied but also one of the most controversial. In order to explore the nature of this association in greater detail and in a new ethnic group, we carried out a case–control study of the SNP rs3758549.

Association of histamine N-methyltransferase Thr105Ile polymorphism with Parkinson's disease and schizophrenia in Han Chinese: a case-control study.

Parkinson’s disease (PD) and schizophrenia (SCZ) are frequent central nervous disorders that have unclear etiologies but that show similarities in their pathogenesis. Since elevated histamine levels in the brain have been associated with PD and SCZ, we wanted to explore whether the Thr105Ile substitution in the histamine N-methyltransferase gene (HNMT-Thr105Ile), which impairs histamine degradation, is associated with either disease. We used the ligase detection reaction to genotype a case-control cohort of Han Chinese patients with PD or SCZ and healthy controls at the HNMT-Thr105Ile locus. The Ile allele was associated with reduced risk of PD (OR 0.516, 95%CI 0.318 to 0.838, p = 0.007) and of SCZ (OR 0.499, 95%CI 0.288 to 0.865, p = 0.011). Genotype frequencies and minor allele frequencies were similar between patients and controls when we compared males with females or early-onset patients with late-onset ones. Genotype and allele frequencies were not significantly different between PD patients with dyskinesia and PD patients without dyskinesia. Our results suggest that the heterozygous Thr/Ile genotype at the HNMT-Thr105Ile locus and the minor Ile105 allele protect against PD and SCZ in Han Chinese.