Meng-Ling Chen

Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease

Common genetic variants that increase the risk for Parkinsons disease may differentiate patient subgroups and influence future individualized therapeutic strategies. Herein we show evidence for leucine‐rich repeat kinase 2 (LRRK2) c.4883G>C (R1628P) as a risk factor in ethnic Chinese populations. A study of 1,986 individuals from 3 independent centers in Taiwan and Singapore demonstrates that Lrrk2 R1628P increases risk for Parkinsons disease (odds ratio, 1.84; 95% confidence interval, 1.20–2.83; p = 0.006). Haplotype analysis suggests an ancestral founder for carriers approximately 2,500 years ago. These findings support the importance of LRRK2 variants in sporadic Parkinsons disease. Ann Neurol 2008

Novel ATP13A2 variant associated with Parkinson disease in Taiwan and Singapore.

Objectives: To assess the association of ATP13A2 gene mutation among patients with early onset Parkinson disease (EOPD, onset < 50 years) in ethnic Chinese population. Methods: Among 771 subjects, we studied 182 patients with EOPD and familial PD and 589 matched controls from two cohorts of Han Chinese in Taiwan and Singapore. The entire ATP13A2 coding region and intron-exon boundaries were sequenced in 71 probands and 70 controls in Taiwanese/ethnic Chinese. An additional 111 index patients with PD in Singapore and 589 controls were later screened to validate possible mutations that were found in the first set of study subjects. Results: We identified one novel missense variant, AL746Thr, in a single heterozygous state in three patients (two were from Taiwan and one was from Singapore) (1.7% in EOPD). The variant was not observed in 589 ethnicity matched controls. The frequency of this variant was significantly higher in PD cases than controls (p = 0.01, relative risk 4.3, 95% CI 1.9–4.3). The clinical phenotype and 18F-dopa PET image of ATP13A2 Ala78Thr carriers are similar to that seen in idiopathic PD. The variant is located between the highly conserved phosphorylation region and the fifth transmembrane domain of the ATP13A2 protein. Conclusions: A rare variant of the ATP13A2 was associated with an increased risk of Parkinson disease among ethnic Chinese in Asia. Further studies are needed to clarify the functional role of this genetic risk factor. GLOSSARY: cDNA = complementary DNA; EOPD = early onset Parkinson disease; ER = endoplasmic reticulum; RT-PCR = reverse-transcriptase PCR; SNP = single nucleotide polymorphism.

Vitamin D receptor genetic variants and Parkinson's disease in a Taiwanese population

Patients with Parkinsons disease (PD) have hypovitaminosis D status and genetic variants of vitamin D receptor (VDR) gene are recently shown to be associated with PD in a large-scale genome-wide association study in a Caucasian population. Few studies examined VDR genetic variants in large-scale Asian patients with PD. We therefore genotyped 6 VDR genetic variants in a total of 1492 Taiwanese subjects, including 700 patients with PD and 792 age and/or gender matched control subjects. We did not observe any significant associations between the studied genetic variants of VDR and the risk of PD. Our data suggest that genetic variations of the VDR gene did not play a major role in a Taiwanese PD population. Further studies of VDR and its interaction with serum vitamin D levels are warranted to clarify the potential role of vitamin D in PD pathogenesis.

Association of candidate genetic variants with restless legs syndrome in end stage renal disease: a multicenter case−control study in Taiwan

Recent genome‐wide association studies have shown associations between multiple genetic variants and primary restless legs syndrome (RLS). Their roles in end stage renal disease (ESRD) related secondary RLS are not clear and studies in Asian populations are scarce. The association between candidate genetic variants and uremic RLS was investigated in a large cohort of Taiwanese dialysis patients.

RIT2 variant is not associated with Parkinson's disease in a Taiwanese population

Recent genome-wide association studies of Parkinsons disease (PD) have identified the rs12456492 variant of the novel susceptibility loci, RIT2, as being associated with disease risk in a large white population. Studies among Asians are scarce. We genotyped RIT2 rs12456492 variant in a total of 1000 participants, comprising 500 patients with PD and 500 control subjects in a Taiwanese population. The frequency of GA/AA genotype was slightly higher in PD patients compared with controls, but was without statistical significance (odds ratio = 1.03, 95% confidence interval = 0.73-1.46, p = 0.86). We failed to replicate the RIT2 rs12456492 variant as a genetic risk factor for PD in our population.

A novel neuropsychiatric phenotype of KCNJ2 mutation in one Taiwanese family with Andersen-Tawil syndrome.

Andersen–Tawil syndrome (ATS) is a rare familial potassium channelopathy characterized by the clinical triad of periodic paralysis, cardiac arrhythmia and dysmorphic facial/skeletal features. The majority of ATS patients are caused by mutations of the KCNJ2 gene, which encodes the inward-rectifying potassium channel protein Kir2.1. However, the effects of the KCNJ2 mutation on the central nervous system are rarely studied. In this report, we describe a heterozygous missense mutation (p.Thr192Ile) in the KCNJ2 gene, which segregates with the disease phenotype in an ATS family. It is noted that in addition to the classical clinical phenotypes of ATS, the index patient exhibited major depression and pyramidal tract signs with diffuse periventricular white matter lesions without contrast enhancement. This mutation and the unusual clinical manifestations observed underscore the phenotypic complexity underlying ATS. Our observations expand the current knowledge of the phenotypic variability of ATS caused by the KCNJ2 mutation. Patients with ATS, especially those carrying the KCNJ2 mutations, should be monitored for their potential neuropsychiatric system involvement.

Mutational analysis of FBXO7 gene in Parkinson's disease in a Taiwanese population.

Mutations in the FBXO7 gene cause an autosomal-recessive early-onset parkinsonism with pyramidal tract signs. Its role in typical Parkinsons disease (PD) without pyramidal features is unclear. We assayed FBXO7 gene in 900 participants comprising 448 PD patients and 452 age- and sex-matched control subjects from Taiwan. The entire FBXO7 coding region and intron-exon boundaries were sequenced. We identified 2 novel missense substitutions, p.Ile87Thr and p.Asp328Arg, in a single heterozygous state in 2 early-onset PD patients individually (1.1% early-onset PD). These 2 variants were not observed in control subjects with a total of 904 normal alleles. Additionally, we also found 1 noncoding variant, exon 1 IVS-329C>T, modestly associated with PD. The frequency of the CT/TT genotype was higher in PD patients compared with control subjects (odds ratio, 1.43; 95% confidence interval, 1.02-2.01; p = 0.04). The clinical phenotypes of genetic variant carriers are similar to that seen in idiopathic PD. We conclude that FBXO7 gene contributes little to typical PD in our population. Further studies in other ethnic cohorts will be important to address its potential pathophysiological role in PD.

BST1 rs11724635 interacts with environmental factors to increase the risk of Parkinson's disease in a Taiwanese population

A recently published genome-wide association study in Caucasian and Asian populations showed a significant association between the bone marrow stromal cell antigen 1 (BST1) SNP rs11724635 and increased risk for Parkinsons disease (PD). To investigate whether BST1 rs11724635 increases the risk of PD, either by itself or in combination with environmental factors, we performed an association analysis of BST1 rs11724635 in a large cohort of Taiwanese patients with PD and age matched controls. The study used TaqMan genotyping, logistic regression, and haplotype methods. The genotype distribution of rs11724635 in PD patients (N = 468; p = 0.50) and control subjects (N = 487; p = 0.44) was consistent with Hardy-Weinberg equilibrium. Compared with the AA genotype, the frequency of both CA and CC genotypes was not significantly different between the patient and control groups. The adjusted odd ratios (ORs) for CA and CC were not statistically significant (CA: OR = 0.962, 95% CI = 0.643-1.439, p = 0.850; CC: OR = 0.992, 95% CI = 0.654-1.503, p = 0.969). Of note, ever use of well water before the onset of PD symptoms had an impact on the occurrence of PD through interactions with BST1 rs11724635 AC (OR = 1.453, p = 0.024) and CC (OR = 1.623, p = 0.008). Our results show that the BST1 rs11724635 polymorphism alone is not associated with the development of PD, but it can interact with well water drinking to increase the risk of PD in this Taiwanese population.

Reaffirmation of GAK, But Not HLA-DRA, as a Parkinson's Disease Susceptibility Gene in a Taiwanese Population

Recent genome‐wide association studies of Parkinsons disease (PD) in Caucasian populations have identified two new susceptibility loci, GAK and HLA‐DRA; however, only limited information exists regarding the involvement of these genes in PD risk in other ethnic groups. Here, we examined whether these genetic effects were consistent in a Taiwanese PD population. In a total 900 participants, including 448 PD patients and 452 control subjects, we genotyped the rs11248051 and rs1564282 variants of GAK, and the rs3129882 variant of HLA‐DRA. Logistic regression analysis was used to test for associations between genotype and PD under an additive model, adjusting for age and gender. Subjects with CT/TT genotypes of GAK rs11248051 had a modestly increased association with PD compared to those with CC genotype (OR = 1.37; 95% CI = 1.09, 1.87; P = 0.03). Carriers and non‐carriers exhibited indistinguishable phenotypes in regards to clinical presentation and onset age. We observed no association between PD risk and GAK rs1564282 or HLA‐DRA rs3129882 variant. The different genetic effects between Taiwanese and Caucasian populations may come from differences in population structure and geographic region‐specific genetic–environmental interactions. In conclusion, our results supported the association between the rs11248051 variant in GAK and PD risk in a Taiwanese population. Future functional studies of GAK in neuronal degeneration are warranted to unravel its role in the pathogenetic mechanism of PD.

Clinical heterogeneity of LRRK2 p.I2012T mutation

INTRODUCTION Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinsons disease (PD). However, only few cases carrying LRRK2 mutations have been reported in Taiwanese PD patients. METHODS We used targeted next generation sequencing (NGS), covering 24 candidate genes involved in neurodegenerative disorders, to analyze 40 probands with familial PD, and 10 patients with mixed neurodegenerative disorders. Sanger sequencing of the identified mutation in the first set of the study was performed in additional 270 PD patients, including 139 familial PD and 131 early-onset PD (onset age less than 50 years old), and 300 age/gender matched control subjects. RESULTS We found a missense variant, p.I2012T, in the LRRK2 gene in one sporadic patient having early-onset frontotemporal dementia with parkinsonism and dystonia. Sanger sequencing this substitution in additional 270 PD patients in the second set of the study revealed two additional variant carriers: one having autosomal-dominant familial PD, and one with sporadic PD. The p.I2012T substitution was absent in 300 normal control subjects. Analyzing family members of the proband with p.I2012T revealed co-segregation of the variant and parkinsonism. Clinical presentations, levodopa responses, and Tc99mTRODAT-SPECT imaging findings of this index family were similar to idiopathic PD. CONCLUSIONS Our results revealed clinical heterogeneity of the LRRK2 p.I2012T substitution, and demonstrated the use of targeted NGS for genetic diagnosis in multiplex families with PD or mixed neurodegenerative disorders.