Genetic Variants of LRRK2 in Taiwanese Parkinson’s Disease

Abstract

Genetic variants of leucine-rich repeat kinase 2 (LRRK2) were reported to alter the risk for Parkinson’s disease (PD). However, the genetic spectrum of LRRK2 variants has not been clearly disclosed yet in Taiwanese population. Herein, we sequenced LRRK2 coding region in 70 Taiwanese early onset PD patients (age at onset ≤ 50), and found six amino acid-changing single nucleotide polymorphisms (SNPs, N551K, R1398H, R1628P, S1647T, G2385R and M2397T), one reported (R1441H) and 2 novel missense (R767H and S885N) mutations. We examined the frequency of identified LRRK2 variants by genotyping 573 Taiwanese patients with PD and 503 age-matched control subjects. The results showed that PD patients demonstrated a higher frequency of G2385R A allele (4.6%) than control subjects (2.1%; odds ratio = 2.27, 95% confidence interval: 1.38–3.88, P = 0.0017). Fewer PD patients (27.7%) carried the 1647T-2397T haplotype as compared with the control subjects (33.0%; odds ratio = 0.80, 95% confidence interval: 0.65–0.97, P = 0.0215). However, the frequency of 1647T-2385R-2397T haplotype (4.3%) in PD patients was still higher than in control subjects (1.9%, odds ratio: 2.15, 95% confidence interval: 1.27–3.78, P = 0.0058). While no additional subject was found to carry R767H and R1441H, one more patient was observed to carry the S885N variant. Our results indicate a robust risk association regarding G2385R and a new possible protective haplotype (1647T-2397T). Gene-environmental interaction and a larger cohort study are warranted to validate our findings. Additionally, two new missense mutations (R767H and S885N) regarding LRRK2 in PD patients were identified. Functional studies are needed to elucidate the effects of these LRRK2 variants on protein function.

Confirmation of the association between LRRK2 R1628P variant and susceptibility to Parkinson's disease in the Thai population

“…Interestingly, Wu et al recently described that a LRRK2 p.S1647T-p.M2397T haplotype appeared to have a protective effect against PD in a large Taiwanese cohort [12]. Although the protective haplotype was not able to counteract with genetic effect on the PD risk of the p.G2385R, it seemed to decrease in risk of developing PD of the other carriers (OR ¼ 0.8, 95%CI ¼ 0.65e0.97) including carriers of the p.R1628P [12]. Our finding was quite different; all Thai carriers of the p.R1628P had p.S1647T-p.M2397T haplotype, and they were still more susceptible to develop PD than the non-carrier group.…”

“…As mention earlier, the negative studies were likely to result from inadequate sample sizes in relation to a paucity of the variant in the population studied. Interestingly, Wu et al recently described that a LRRK2 p.S1647T-p.M2397T haplotype appeared to have a protective effect against PD in a large Taiwanese cohort [12]. Although the protective haplotype was not able to counteract with genetic effect on the PD risk of the p.G2385R, it seemed to decrease in risk of developing PD of the other carriers (OR ¼ 0.8, 95%CI ¼ 0.65e0.97) including carriers of the p.R1628P [12].…”

Association of LRRK2 R1628P variant with Parkinson’s disease in Ethnic Han-Chinese and subgroup population

“…Totally, 14 studies711131520212223242526272829 were included from across all the ethnic Han-Chinese population that mainly located in Mainland China, Singapore and Taiwan. Process of searching for and screening studies was showed in Figure S1.…”

“…Only 2 studies722 in ethnic Han-Chinese with familial PD and 11 studies711152021232425262728 in ethnic Han-Chinese with sporadic PD were analyzed to evaluate the overall level for association between familial (Fig. 4A) or sporadic (Fig.…”

“…In addition, G2019S variant was rarely among India8, but not detected in Chinese population1012, Haplotype analysis suggested LRRK2 R1628P variant is more recent than G2385R variant, approximately 2,500 years and 4,000 years ago respectively1314. Interesting, the R1628P variant of LRRK2 has been discovered as a genetic risk factor for PD in ethnic Han-Chinese population from Taiwan, Singapore, and Mainland China1516. However, this variant was very rare or absent in Malay (2.3%), Korean (0.8%), Indian (not detected), Japanese (not detected) and Caucasian (0.1%) Parkinsonism51718.…”