G2385R Variant Research Articles

Penetrance of LRRK2 G2385R and R1628P is modified by common PD-associated genetic variants

Variants in the LRRK2 gene are well-characterized genetic predisposing factors for PD worldwide, and LRRK2-associated PD is often indistinguishable from idiopathic PD (IPD). However, considerable heterogeneity of LRRK2-PD suggests the existence of additional genetic and/or environmental modifiers for LRRK2 carriers, which have yet to be confirmed by large-scale human studies. In a Chinese cohort consisting of 2013 sporadic PD patients and 1971 controls, we investigated the modification of the two Asian-specific LRRK2 variants, G2385R and R1628P, by variants of five other PD-associated genes/loci (SNCA, MAPT, GBA, BST1, PARK16). Of all the PD patients, 13.1% carried LRRK2 G2385R and/or R1628P variant. Among these carriers, a total of 15 different polygenic genotypes were detected representing different combination patterns between LRRK2 variants and those of the other genes/loci, which, alone or in combination, significantly modified the LRRK2-related risk for PD and the patients’ ages at onset (AAOs). These results not only represent the largest replication data affirming the association between PD and all the six genes/loci in Chinese, but for the first time suggest that multiple PD-associated genetic factors modify both the penetrance and AAO of LRRK2 parkinsonism. This finding may have important implications for elucidating pathophysiologic mechanisms relevant to both LRRK2-associated and idiopathic PD. However, testing interactions among multiple genes by genetic association studies is still challenging. Future studies with much larger sample sizes are needed to confirm our findings.

Contribution of glucocerebrosidase mutation in a large cohort of sporadic Parkinson’s disease in Taiwan

The association between glucocerebrosidase (GBA) mutations and Parkinson's disease (PD) is attracting increased attention worldwide. In patients of Chinese ethnicity, other than the common L444P mutation, a few mutations have been reported. However, the contribution of GBA to PD can be answered only by a thorough investigation of its mutations in a unique large population. We enrolled 1747 participants: 967 PD patients and 780 healthy individuals. We screened entire GBA coding regions and exon-intron boundaries in 30 randomly chosen PD patients, followed by testing five variants (L444P, D409H, R120W, L174P, and Q497R) in all participants. The G2385R and R1628P in LRRK2 had been previously studied in almost all participants. In total, 36 patients (3.72%) carried a heterozygous mutant GBA allele (27 L444P, 7 RecNciI, and 2 D409H). Only two controls (0.26%) carried heterozygous GBA mutation (1 L444P and 1 RecNciI). In PD group, the mean age at onset in carriers was younger than in non-carriers. The difference in percentage of mutation frequencies between patients and controls was highly significant for the L444P mutation (P < 0.0001). One L444P carrier was also associated with LRRK2 G2385R variant, but no atypical Parkinsonism was observed. The present study ascertains that L444P mutation in GBA gene may contribute to an earlier onset of development of PD in Han/Chinese population. Following LRRK2 variants, GBA is the second most frequent mutations indicated for sporadic PD development in the Han/Chinese population. These GBA carriers are associated with an earlier onset of Parkinsonism.

The LRRK2 G2385R variant is a risk factor for sporadic Parkinson's disease in the Korean population

The G2385R (SNP accession no. rs34778348) and R1628P (rs33949390) variants of leucine-rich repeat kinase 2 ( LRRK2, PARK8) are emerging as an important risk factor for Parkinson's disease (PD) in the ethnic Chinese and Japanese populations. The purpose of this study was to investigate whether these variants are a genetic risk factor in sporadic PD patients in the Korean population. A total of 923 patients and 422 healthy subjects were included. The variants were screened by a SNaPshot assay. The LRRK2 G2385R variant was detected in 82 PD patients (8.9%, two homozygous and 80 heterozygous) and in 21 normal controls (5.0%, all heterozygous). The frequency of the LRRK2 G2385R variant in PD was significantly higher than in normal controls (adjusted odds ratio 1.83, p = 0.0170, 95% confidence interval 1.11–3.00). There were no differences in the mean age at onset or gender between the G2385R carriers and the non-carriers in PD patients. The LRRK2 R1628P variant was very rare (0.78% in patients versus 0.26% in controls) in the tested 384 patient–control pairs, and was not a significant risk factor. This study supports that the LRRK2 G2385R variant may be a genetic risk factor for sporadic PD in the Korean population.

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

Common genetic variants that increase the risk for Parkinson's 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.

Essential tremor and the common LRRK2 G2385R variant

Co-existence of Parkinson's disease (PD) and essential tremor (ET) suggests a possible overlapping pathophysiology between these two conditions. PD patients with leucine-rich repeat kinase-2 ( LRRK2) mutations have been reported to present initially with ET. A common LRRK2 Gly2385Arg variant has been widely shown to be associated with a two fold increased risk of PD in various Asian populations. We analyzed the Gly2385Arg variant in a cohort of ET and controls. A total of 419 subjects comprising of 172 ET and 247 controls were included. The mean age, age at onset of ET, and age of controls were 52.1 ± 19.6, 41.8 ± 21.6, and 62.2 ± 11.6 years, comprising of 53.0% and 54.3% men, respectively. The Gly2385Arg variant was demonstrated in 5/172 (2.9%) ET patients compared to 10/247 (4.0%) of controls (odds ratio = 0.72, 95% CI 0.24, 2.1, p = 0.6). All the Gly2385Arg carriers were heterozygotes. The LRRK2 Gly2385Arg variant is not a significant risk factor for ET in our population.

The role of common genetic risk variants in Parkinson disease

Despite the discovery of at least five pathogenic genes in Parkinson disease (PD), the genetic etiology in the vast majority of PD remains to be clarified. Common genetic variants could act as susceptibility risk factors. Our previous meta-analysis of PD genetic association studies, over a 30-year period yielded four genes (N-acetylcysteine 2, monoamine oxidase B, glutathione transferase, and mitochondrial tRNA), as their common variants were found to be associated with PD. More recently, international collaborative studies and meta-analysis have identified the S18Y variant of ubiquitin carboxy-terminal hydrolase L1, Rep 1 variant of alpha-synuclein and tau H1 haplotype to be genetic susceptibility risk/protective factors. However, the most significant, common genetic risk factor in PD has been its association with the leucine-rich repeat kinase-2 (LRRK2) G2385R variant. We conducted an analysis of independent studies involving 2205 PD and 1817 controls and found the average carrier rate of G2385R variant to be about 9% in PD and 4% in controls (p < 0.001; odds ratio: 2.27; 95% confidence interval: 1.78-2.9). A higher frequency of G2385R carriers has been observed in familial PD when compared with sporadic patients. Based on current evidence, certain common genetic variants are likely to modulate the risk of PD.

Leucine-Rich Repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population

To assess the effect of genetic factors on sporadic Parkinson disease, we performed a case-control study of a variant (G2385R) in Leucine-Rich Repeat kinase 2 among the Japanese population. The G2385R (c.7153G>A) variant was reported as a risk factor for sporadic Parkinson disease in the Chinese population from Taiwan and Singapore. Genotyping was conducted in 448 Parkinson disease patients and 457 healthy controls. The frequency of A allele in Parkinson disease was significantly higher than in the control (P=1.24x10(-4), odds ratio 2.63, 95% confidence interval 1.56-4.35). Our results suggest that the G2385R variant is a risk factor for sporadic Parkinson disease in the Asian population.

A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan

BackgroundParkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized clinically by resting tremor, bradykinesia, postural instability and rigidity. The prevalence of PD is approximately 2% of the population over 65 years of age and 1.7 million PD patients (age ≥ 55 years) live in China. Recently, a common LRRK2 variant Gly2385Arg was reported in ethnic Chinese PD population in Taiwan. We analyzed the frequency of this variant in our independent PD case-control population of Han Chinese from Taiwan.Methods305 patients and 176 genetically unrelated healthy controls were examined by neurologists and the diagnosis of PD was based on the published criteria. The region of interest was amplified with standard polymerase chain reaction (PCR). PCR fragments then were directly sequenced in both forward and reverse directions. Differences in genotype frequencies between groups were assessed by the X2 test, while X2 analysis was used to test for the Hardy-Weinberg equilibrium.ResultsOf the 305 patients screened we identified 27 (9%) with heterozygous G2385R variant. This mutation was only found in 1 (0.5%) in our healthy control samples (odds ratio = 16.99, 95% CI: 2.29 to 126.21, p = 0.0002). Sequencing of the entire open reading frame of LRRK2 in G2385R carriers revealed no other variants.ConclusionThese data suggest that the G2385R variant contributes significantly to the etiology of PD in ethnic Han Chinese individuals. With consideration of the enormous and expanding aging Chinese population in mainland China and in Taiwan, this variant is probably the most common known genetic factor for PD worldwide.