Sijia Tian

Association of the functional SNP rs2275294 in ZNF512B with risk of amyotrophic lateral sclerosis and Parkinson's disease in Han Chinese.

The single nucleotide polymorphism (SNP) rs2275294 of the ZNF512B gene has been reported to be associated with a risk of ALS in the Japanese population. Here we conducted a case-control study examining the possible association of rs2275294 with risk of sporadic ALS and PD in Han Chinese. Our study included 301 patients with ALS and 457 age- and gender-matched controls, as well as 555 patients with PD and 473 age- and gender-matched controls. Subjects were genotyped at rs2275293 using the ligase detection reaction. The genotype distribution of rs2275294 shows significant difference between patients with ALS and the control group according to the dominant model (OR 1.518, 95% CI 1.074–2.145, p = 0.018) and based on alleles (OR 1.249, 95% 1.016–1.534, p = 0.035). Stratification analysis showed a significant difference between females with ALS and female controls based on the dominant model (OR 3.285, 95% CI 1.856–5.815, p < 0.001) or alleles (OR 1.697, 95% CI 1.208–2.383, p = 0.002). In contrast, no significant differences were identified between rs2275294 and patients with PD. In conclusion, our case-control study suggests that the CC genotype and C allele at rs2275294 are associated with increased risk of ALS in Han Chinese, particularly females.

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

HLA-DRA/HLA-DRB5 polymorphism affects risk of sporadic ALS and survival in a southwest Chinese cohort

INTRODUCTION Frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Parkinsons disease (PD) are neurodegenerative diseases that share common genetic risk factors. A recent genome-wide association study has linked risk of FTD with polymorphisms in the HLA-DRA/HLA-DRB5 gene (rs9268877, rs9268856), BTNL2 gene (rs1980493), and RAB38/CTSC gene (rs302668). METHODS We used the SNPscan™ Kit to genotype these variants in 400 Chinese patients with sporadic ALS, 554 with sporadic PD and 634 healthy controls. RESULTS The AA genotype at rs9268856 increased risk of ALS (P=0.005). Mean survival time was significantly shorter in patients with the AA genotype (24.8±16.2months) than in patients with other genotypes (36.9±19.9months; P<0.001). Kaplan-Meier curves and Cox analysis indicated significantly lower survival probability for patients carrying the AA genotype (P<0.001). CONCLUSION Our results suggest that the AA genotype at rs9268856 is an independent risk factor and prognostic factor for ALS in Han Chinese from southwest China.

Mutational analysis of CHCHD2 in Chinese patients with multiple system atrophy and amyotrophic lateral sclerosis

CHCHD2, which encodes a regulator of mitochondrial metabolism, has been linked to Parkinsons disease (PD) in a Japanese population. Since PD and two other neurodegenerative diseases, multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS), are associated with mitochondrial dysfunction, we wanted to know whether CHCHD2 mutations may be linked to MSA and sporadic ALS in Chinese patients. All four CHCHD2 exons were Sanger-sequenced in 89 patients with MSA, 424 patients with sporadic ALS and 594 unrelated healthy Han Chinese. Four exonic variants were detected in six patients with sporadic ALS: Pro2Leu (rs142444896), Ala32Thr (rs145190179), Ser85Arg (rs182992574), and Tyr99ArgfsX42 (rs778030300). No exonic variants were detected in patients with MSA. Pro2Leu was not significantly associated with risk of ALS in our cohort, and no variants in untranslated or flanking regions of CHCHD2 were associated with risk of MSA or ALS. Our results suggest that genetic variants of CHCHD2 may not be a frequent cause of MSA or ALS in our Chinese population.

Polymorphism in MIR4697 but not VPS13C, GCH1, or SIPA1L2 is associated with risk of Parkinson’s disease in a Han Chinese population

A large meta-analysis recently identified six new loci associated with risk of PD, but subsequent studies have given discrepant results. Here we conducted a case-control study in a Han Chinese population in an attempt to clarify risk associations in Chinese. Among the four single-nucleotide polymorphisms (SNPs) that we examined - VPS13C-rs2414739, MIR4697-rs329648, GCH1-rs11158026, and SIPA1L2- rs10797576 we detected a significant association between rs329648 and risk of developing PD in a recessive model. This association remained significant after adjusting for gender and age (OR 1.87, 95%CI 1.295-2.694, p=8.21×10-4) or Bonferroni correction. The T allele of rs329648 occurred significantly more frequently among patients with PD than among healthy controls (OR 1.22, 95%CI 1.033-1.443, p=0.02), while there was no statistic significant after Bonferroni correction. Subgroup analysis showed a significant association specifically among males in a recessive model (OR 1.943, 95%CI 1.200-3.147, p=0.007). In contrast, genotye and allele frequencies at rs329648 did not differ significantly between female patients with PD and healthy female controls, or between patients with early-onset or late-onset PD. Our results suggest that rs329648 is associated with risk of developing PD in the Han Chinese population. Our findings should be verified in further studies, and they highlight the need for functional studies of MIR4697.

Festination Correlates with SNCA Polymorphism in Chinese Patients with Parkinson’s Disease

The genetic basis of festination, a common motor symptom in Parkinsons disease (PD), remains unclear. Since polymorphism in the alpha-synuclein (SNCA) gene is associated with PD phenotype, we examined whether such polymorphism is also associated with festination. SNCA polymorphisms rs11931074 and rs894278 were genotyped in a consecutive series of 258 patients with PD, of whom 122 (47.3%) suffered festination. Univariate analysis revealed significant differences in genotype and minor allele frequencies at rs11931074 or rs894278 between patients with festination and those without it (all p < 0.05). Based on logistic regression, a GG or GT genotype at rs11931074 was associated with higher risk of festination among patients with PD (OR 2.077, 95% CI 1.111–3.883, p = 0.022), as was the TT genotype at rs894278 (OR 2.271, 95% CI 1.246–4.139, p = 0.007). Therefore, we conclude that festination is associated with polymorphism at rs11931074 or rs894278 among patients with PD.

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

Association between a heme oxygenase-2 genetic variant and risk of Parkinson’s disease in Han Chinese

Studies have reported conflicting results about possible associations between variants in heme oxygenase (HMOX) genes and risk of Parkinsons disease (PD) in Caucasians, and little is known about these associations in Asians. We genotyped the single-nucleotide polymorphisms (SNPs) rs2071746 and rs2071747 in HMOX1 and rs1051308 in HMOX2 in 583 Han Chinese with PD and 627 healthy controls using a customized 2×48-Plex SNP Scan™ kit. Frequencies of genotypes and minor alleles were similar between patients and controls for rs2071746 and rs2071747, but different for rs1051308(P=0.004, OR 1.705, 95%CI 1.191-2.442 for genotypes; P=0.009, OR 1.249, 95%CI 1.037-1.476 for alleles). Our results suggest that rs1051308 is associated with risk of developing PD in Han Chinese, and further studies involving various ethnicities are needed to validate the association.

Association between gene polymorphism and depression in Parkinson's disease: A case-control study

OBJECTIVE To investigate possible associations of Parkinsons disease (PD) with polymorphism in depression-related genes and in the alpha-synuclein (SNCA) gene. METHODS A consecutive series of patients with PD were divided into those with depression and those without it. Patients (330) were genotyped at four single-nucleotide polymorphisms (SNPs) in four genes previously associated with depression, as well as four SNPs in the PD-associated SNCA gene. RESULTS Of 330 patients, 125 (37.9%) had depression and 205 (62.1%) did not. Univariate analysis revealed significant differences between the two groups in minor allele frequency at the SNP rs1545843 in the SLC6A15 gene (p<0.05), as well as in frequencies of genotypes and minor alleles at rs78162420 in the TPH2 gene (all p<0.05). Logistic regression identified the following risk factors for depression among patients with PD: Hoehn and Yahr stage>2 (OR 1.759, 95%CI 1.035-2.989, p=0.037), AA genotype at rs1545843 (OR 1.866, 95%CI 1.017-3.426, p=0.044), and AC genotype at rs78162420 (OR 5.036, 95%CI 1.451-17.484, p=0.011). CONCLUSIONS Among patients with PD, depression is associated with polymorphism at rs78162420 and rs1545843, both previously linked with depression. Our results may help clarify the pathogenesis of depression in PD.

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.