Zhen-hua Liu

The relationship between the phenotype of Parkinson's disease and levodopa-induced dyskinesia

Levodopa has been demonstrated to be an effective medication for Parkinsons disease (PD), but its long-term use is complicated by the subsequent development of dyskinesias. Few studies have distinguished distinct PD subtypes associated with the occurrence of Levodopa-Induced Dyskinesia (LID). Therefore, we performed a retrospective analysis to determine if the specific phenotype of PD and other epidemiological factors are associated with the development of LID. Of 367 PD patients taking levodopa, 101 of them developed LID. Multivariate logistic regression analysis demonstrated that initial tremor-dominant manifestation was associated with a reduced risk of LID, independent of other risk factors, such as age at the onset of PD, the duration and dose of levodopa.

The rs3756063 polymorphism is associated with SNCA methylation in the Chinese Han population.

Parkinsons disease (PD) is the second most common neurodegenerative disorder. Genome-wide association studies have confirmed the association of single nucleotide polymorphisms (SNPs) located in the SNCA gene with the risk of PD. While hypomethylation of the SNCA intron-1 was observed in patients with sporadic PD, an association between SNCA SNPs and SNCA methylation levels has been identified. To investigate whether these SNPs are associated with the level of SNCA methylation in the Chinese population, we genotyped SNCA SNPs and analyzed the relationship between SNCA SNPs and SNCA DNA methylation status from peripheral blood mononuclear cells of Chinese Han PD patients. Our results revealed that the rs3756063 polymorphism could contribute to the risk of PD in the Chinese Han population and confirmed the effect of this polymorphism on SNCA DNA methylation. Further studies will be needed to gain a better understanding of the mechanisms underlying the associations between SNPs, methylation and PD pathogenesis.

Analysis of EIF4G1 in ethnic Chinese.

BackgroundEukaryotic translation initiation factor 4-gamma 1 (EIF4G1) gene mutations have recently been reported in autosomal dominant, late-onset Parkinson’s disease (LOPD). We carried out genetic analysis to determine the prevalence of EIF4G1 variants in an ethnic Chinese population and to better understand the association between EIF4G1 and PD.MethodsWe conducted a comprehensive genetic analysis of EIF4G1 in a cohort of 29 probands of autosomal dominant, LOPD families. Polymerase chain reaction (PCR) analysis and sequencing was carried out of the entire EIF4G1 exonic regions and exon-intron boundaries. Specific mutation and exonic variants were chosen for further sequencing in a case–control study including 503 sporadic PD and 508 healthy controls. Statistical significance was analyzed by the Chi-square test.ResultsOur analysis revealed three exonic variants (rs2230571, rs13319149 and rs2178403) and eight intronic variants across the entire EIF4G1 gene. No reported mutations were detected in EIF4G1 exonic regions. The synonymous coding variant rs2230571 in exon 27 and the eight intronic variants were not used for further sequencing, but the specific mutation c.3614G > A (p.R1205H) and the two nonsynonymous variants (rs13319149 and rs2178403) were chosen for further analysis in a case–control study. None of the 503 sporadic PD or 508 healthy controls carried p.R1205H, and there was no statistical significance in rs2178403 genotype or allele frequencies in EIF4G1 between the PD cases and the healthy controls (p = 0.184 and p = 0.774, respectively; Chi-square test). The rs13319149 genotype in all PD cases and healthy controls was GG.ConclusionsOur data indicate that in an ethnic Chinese population, the pathogenic mutation p.R1205H in EIF4G1 is not common and that EIF4G1 exonic variants rs2178403 and rs13319149 are not associated with PD. EIF4G1 does not appear to be a frequent cause of PD in this ethnic Chinese population.

Lack of association between IL-10 and IL-18 gene promoter polymorphisms and Parkinson’s disease with cognitive impairment in a Chinese population

Inflammatory processes have been implicated in the pathogenesis of Parkinson’s disease (PD), including the development of PD-associated cognitive impairment. Whether genetic variants of inflammatory cytokine genes influence the risk of cognitive impairment in PD is unknown. In this study, we investigated single nucleotide polymorphisms (SNPs) in the IL-10 promoter (rs1800871 and rs1800872) and in the IL-18 promoter (rs1946518 and rs187238) in a Han Chinese cohort (N = 933). PD patients (N = 460) and controls (N = 473) were genotyped. Additionally, 268 PD patients were divided into three subgroups [cognitively normal (PD-NC), mild cognitive impairment (PD-MCI), and with dementia (PD-D)] on the basis of their performance on a battery of neuropsychological tests. No associations were found between the aforementioned polymorphisms and cognitive impairment in PD; thus no confirmatory evidence for the hypothesis of IL-10 and IL-18 alleles modulating the risk of cognitive impairment in Chinese PD patients was obtained.

LRRK2 A419V variant is a risk factor for Parkinson's disease in Asian population

Recently, LRRK2 A419V (rs34594498) was reported associating with Parkinsons disease (PD) in Asian population; yet the conclusion is still unobvious. We conducted a case-control study to determine the potential associations between A419V and PD in Chinese population. Five hundred PD patients and 574 health controls were genotyped. Our results showed, A419V has a significantly higher frequency among PD patients than the controls (p = 0.025, odds ratio [OR] = 2.57, 95% confidence interval [CI] [1.13-5.86]), especially in early-onset PD (p = 0.027, OR = 10.40, 95% CI [1.31-82.89]). And PD patients who carried A419V have a lower Minimum-Mental State Examination scores than PD patients who did not (p = 0.04). We also conducted a meta-analysis on A419V. In Asian population, A419V was detected at a significantly higher frequency among PD patients in contrast to controls: Z = 2.47, p = 0.01, OR = 2.11, 95% CI [1.17-3.82]. When only considering the Chinese population, the difference was more obvious with Z = 3.41, p = 0.0007, OR = 2.07, 95% CI [1.36-3.14]. The results suggest LRRK2 A419V appears to be a risk factor for PD in Asian, especially in early-onset patients. Finally, larger sample with centering on young or cognitive impairment PD patients in Asian would be preferable for further confirmation.

Assessment of RIT2 rs12456492 association with Parkinson's disease in Mainland China

A recent meta-analysis of genome-wide association studies in Parkinsons disease (PD) has identified the rs12456492 variant in RIT2 as a new susceptibility loci. Because the characteristics of this locus in a Han Chinese population from mainland China was still unknown, we performed a case-control replication study in this population and investigated RIT2 rs12456492 variant in a large cohort of Chinese Han individuals. In total, 933 subjects comprising 460 PD patients and 473 control subjects were genotyped. We found a significant difference in the distributions of genotype and allele between PD and control groups (genotype p = 0.008, allele p = 0.007, odds ratio = 1.296, 95% confidence interval = 1.075-1.563). This study replicates the association between rs12456492 variant and risk of developing PD in a Han Chinese population.

A neurophysiological profile in Parkinson’s disease with mild cognitive impairment and dementia in China

Mild cognitive impairment (MCI) and dementia (D) are frequent features of Parkinsons disease (PD) but widely disparate criteria have been used. Our understanding of the prevalence and cognitive profile of Chinese PD patients remains limited. In order to determine the frequency and pattern of cognitive dysfunction and identify risk factors for cognitive dysfunction in the Chinese Han PD population we performed a cross-sectional study in a cohort of 330 PD patients and 163 healthy controls. Five cognitive domains (executive function, attention, praxis and visuospatial function, memory, and language) and mood/behavior were evaluated. According to the Movement Disorder Society Task Force consensus criteria, up to 29.1% of PD patients were classified as PD-MCI and 32.1% as PD-D. Impairments occur in a range of cognitive domains with dysexecutive profile predominating. Healthy controls also outperformed cognitively preserved PD patients in tasks of executive function and attention. Logistic regression indicated that PD-MCI may be predicted by lower educational level and apathy. Additionally, later disease onset, longer disease duration, more severe motor symptoms and higher neuropsychiatric inventory score were associated with a faster transition from PD-MCI to PD-D. These findings suggest that all PD patients should undergo routine cognitive screening. For high-risk patients early recognition and therapeutic intervention is imperative.

The single nucleotide polymorphism Rs12817488 is associated with Parkinson's disease in the Chinese population

A recent meta-analysis of datasets from five of the published Parkinsons disease (PD) genome-wide association studies implicated the single nucleotide polymorphism (SNP) rs12817488 in coiled-coil domain containing 62 (CCDC62)/huntingtin interacting protein 1 related (HIP1R) as a risk factor for PD. We conducted a case-control study to evaluate the possible association between rs12817488 and PD in Chinese people. All patients (515 PD patients and 518 age and sex-matched controls) were successfully genotyped using polymerase chain reaction restriction fragment length polymorphism analysis. We observed that the rs12817488 polymorphism is associated with PD (p=0.003) and that the genotype and allele frequencies showed a difference between late-onset PD patients and male controls (p=0.025 and p=0.007, respectively). However, there was no difference in the early-onset PD patients and controls. We found a difference in the genotype and allele frequencies between the male PD patients and the male controls (p=0.034 and p=0.017, respectively). However, there was no difference in females. Patients with the A allele were susceptible to PD in both dominant (GA+AA versus GG; odds ratio [OR] 1.365, 95% confidence interval [CI] 1.041-1.788) and recessive (AA versus GG+GA; OR 1.606, 95% CI 1.194-2.158) models. Therefore, our findings support the conclusion that the rs12817488 in CCDC62/HIP1R polymorphism may increase the risk of PD in the Chinese Han population.

Analysis of several loci from genome-wide association studies in Parkinson’s disease in mainland China

Large-scale meta-analyses of genome-wide association studies in Parkinsons disease (PD) have identified a number of susceptibility loci in sporadic PD. Since the characteristics of those loci in a Han Chinese population from mainland China were unknown, we performed a case-control replication study in this population and evaluated several single nucleotide polymorphisms (SNPs) identified in a recent GWAS-meta-analysis. In total, 933 subjects comprised of 460 PD patients and 473 controls were genotyped. We found strong evidence of an association for rs708723 in RAB7L1 in the total sample (genotype p=0.01, allele p=0.01, OR=0.78, 95% CI=0.65-0.94). With rs156429 in GPNMB, there was a significant difference in genotype and allele distribution between male PD patients and the control subgroup (genotype p=0.01, allele p=0.01, OR=0.67, 95% CI=0.49-0.92). However, we did not observe any significant difference in genotype or allele distribution between PD and control for rs34016896 in NMD3 and rs6812193 in STBD1.

Relationship between Alzheimer's disease GWAS-linked top hits and risk of Parkinson's disease with or without cognitive decline: a Chinese population-based study

Alzheimers disease (AD), Parkinsons disease (PD), and cognitive impairment in PD have overlapping clinical and pathological features. To examine whether there is a genetic link for these diseases, we performed a case-control study in Chinese population to evaluate the association of AD genome-wide association studies top hits with both PD and cognitive function in PD, investigating 13 single-nucleotide polymorphisms in 9 genes (BIN1, CLU, ABCA7, CR1, PICALM, MS4A6A, CD33, MS4A4E, and CD2AP). A total of 454 controls and 442 PD patients were genotyped, including 75 mild cognitive impairment and 99 dementia. As a result, no significant association of the AD-susceptibility loci was identified in PD cases, PD-dementia, or PD-mild cognitive impairment. Our findings imply that the 13 single-nucleotide polymorphisms from AD genome-wide association studies may not play major role in the genetic predisposition with PD and cognitive function in PD in a Chinese population.