Jing Xi

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.

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.

Sequencing TMEM230 in Chinese patients with sporadic or familial Parkinson's disease

Taku Hatano, MD, PhD, Nobutaka Hattori, MD, PhD, and Koichi Wakabayashi, MD, PhD Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Japan Department of Pathology, Hirosaki Municipal Hospital, Hirosaki, Japan Department of Neurology, Hirosaki Municipal Hospital, Hirosaki, Japan Department of Neurology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan

Association of the COQ2 V393A Variant with Parkinson's Disease: A Case-Control Study and Meta-Analysis

Both Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases of uncertain etiology, but they show similarities in their pathology and clinical course. The fact that the gene encoding α-synuclein is associated with both diseases also suggests that they share some genetic determinants. Recent studies in Japan associating MSA with a variant in the COQ2 gene led us to question whether variants in the COQ2 gene are associated with PD in Han Chinese in a case-control study. A total of 564 patients with PD were genotyped using the ligase detection rection, together with 484 gender- and age-matched healthy subjects. The M128V and R387X variants of COQ2 were not detected in patients or controls; instead, we detected only the heterozygous V393A variant (CT genotype). The frequency of the CT genotype encoding the V393A mutation was significantly higher in patients PD (4.08%) than in controls (1.86%), corresponding to an odds ratio of 2.24 (95%CI 1.03 to 4.90, p = 0.037). The frequency of the C allele of the V393A variant was significantly higher in patients with PD than in controls (OR 2.22, 95%CI 1.02 to 4.82, p = 0.039), and this was also observed in a meta-analysis of studies from mainland China, Taiwan and Japan. Subgroup analysis of our data showed that the V393A variant was significantly associated with early-onset PD (OR 3.71, 95%CI 1.51 to 9.15, p = 0.002) but not with late-onset disease (OR 1.65, 95%CI 0.69 to 3.95, p = 0.260). Gender was not significantly associated with either genotype or minor allele frequencies. In conclusion, our findings show for the first time that the V393A variant in the COQ2 gene increases risk of PD among the population of east Asia. These results, combined with research on Japanese, lend genetic support to the hypothesis that oxidative stress underlies pathogenesis of both PD and MSA.

Sequence TMEM230 gene in patients with multiple system atrophy in a southwest Chinese population: A pilot study

Both Parkinsons disease (PD) and multiple system atrophy (MSA) areα-synucleinopathies [1] that share clinical characteristics and genetic risk factors [2,3]. Therefore we wanted to investigate whether TMEM230 mutations recently linked to risk of PD may also influence risk ofMSA. Themutation c.422G N T (p.Arg141Leu) has been associated with risk of autosomal dominant PD in a Caucasian family [4], and a study of 433 Caucasian cases of familial PD and 399 Caucasian cases of sporadic PD has linked the mutation c.551A N G (p.*184Trpext*5) with familial disease and themutation c.275A NG (p.Tyr92Cys)with sporadic disease [6]. A fourth mutation, which was a stop codon (c.550_552del TAGinsCCCGGG, p.*184Pro Glyext*5), has been linked to risk of familial PD in a study of seven Han Chinese families [4]. Consistent with these genetic associations, PD has been linked to impaired vesicle trafficking and recycling, and the TMEM230 protein participates in exocytosis, endocytosis and recycling of synaptic vesicles in neurons [4]. Post-mortem and in vivo studies of PD have identified substantially decreased vesicular sequestration of cytoplasmic catecholamines in residual terminals in putamen and heart, leading to accumulation of the toxic dopaminemetabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) [5,6]. Given the similarities between PD and MSA as α-synucleinopathies and a report linkingMSAwith impaired vesicular storage andDOPAL accumulation [7], we sought to determine whether PD-associated TMEM230 polymorphisms, as well as novel TMEM230 variants, might

No evidence of association between polymorphisms in four genes and sporadic amyotrophic lateral sclerosis in Han Chinese

Abstract The four single nucleotide polymorphisms (SNPs) rs34517613, rs3849943, rs8141797 and rs6703183, each located in a different gene, have recently been associated with risk of developing sporadic amyotrophic lateral sclerosis (SALS) in European and northern Chinese populations, but no data are yet available for other ethnic groups. Here we explored the possible association between these four SNPs and SALS in Han Chinese primarily from southern and south-western China. A total of 298 individuals with SALS from three centres in mainland China and 486 unrelated healthy controls were recruited. All subjects were successfully genotyped using the ligase detection reaction (LDR). We found no evidence that any of these SNPs are associated with risk of disease in either heterozygous or homozygous individuals (p > 0.05). Subgroup analysis based on gender showed a similar lack of association. However, subgroup analysis based on spinal- or bulbar-onset SALS revealed significant differences in the genotype distributions (p = 0.009) and minor allele frequencies of rs6703183 (p = 0.004). In conclusion, it may be premature to conclude associations between these four SNPs and SALS, which should be examined in additional ethnic groups.

Absence of association of the Ala58Val (rs17571) CTSD gene variant with Parkinson’s disease or amyotrophic lateral sclerosis in a Han Chinese population

Parkinsons disease (PD), amyotrophic lateral sclerosis (ALS) and Alzheimers disease (AD) are neurodegenerative diseases that may share genetic risk factors. The exon variant Aal58Val (rs17571) in CTSD was recently associated with AD, leading us to examine whether it also affects risk of ALS and PD. The rs17571 variant was genotyped using the ligase detection reaction in 569 Han Chinese patients with PD, 301 patients with ALS, and healthy controls age- and gender-matched to each patient group. The frequencies of genotypes and alleles were similar between each disease group and its respective control group. Similar results were obtained when patients were stratified by gender, age at disease onset or type of symptoms at disease onset. These results suggest that the CTSD rs17571 variant may not be associated with risk of ALS or PD in Han Chinese.

Sequence CLCN1 and SCN4A in patients with Nondystrophic myotonias in Chinese populations: Genetic and pedigree analysis of 10 families and review of the literature

ABSTRACT Myotonia congenita (MC), paramyotonia congenita (PC) and sodium channel myotonias(SCM) were belonged to Non-dystrophic myotonias, in which muscle relaxation is delayed after voluntary or evoked contraction. These diseases can not be simply distinguished only based on symptoms and signs but also on genetics: more than 100 mutations in the CLCN1 gene have been associated with MC, while at least 20 mutations in the SCN4A gene have been associated with PC and SCM. Most of these genetics studies have been conducted outside China, only several MC, PC, and SCM families accepted gene scan were reported in China. Therefore we analyzed genetic mutations in CLCN1 and SCN4A in 10 Chinese families clinically diagnosed with Non-dystrophic myotonias. Our result revealed 12 potential disease-causing mutations(3 mutations were novel) that were present in the probands and affected family members. We also reviewed all available literature on mutations linked to these 3 disease in Chinese populations. Our results may help identify genetic determinants as well as clarify genotype-phenotype relationships.