BioMed Research International

BioMed Research International / 2014 / Article
Special Issue

Familial Parkinson’s Disease/Parkinsonism

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Research Article | Open Access

Volume 2014 |Article ID 867321 | 4 pages | https://doi.org/10.1155/2014/867321

LRRK2 G2385R and R1628P Mutations Are Associated with an Increased Risk of Parkinson’s Disease in the Malaysian Population

Academic Editor: Hiroyuki Tomiyama
Received23 May 2014
Accepted24 Jul 2014
Published28 Aug 2014

Abstract

The LRRK2 gene has been associated with both familial and sporadic forms of Parkinson’s disease (PD). The G2019S variant is commonly found in North African Arab and Caucasian PD patients, but this locus is monomorphic in Asians. The G2385R and R1628P variants are associated with a higher risk of developing PD in certain Asian populations but have not been studied in the Malaysian population. Therefore, we screened the G2385R and R1628P variants in 1,202 Malaysian subjects consisting of 695 cases and 507 controls. The G2385R and R1628P variants were associated with a 2.2-fold () and 1.2-fold () increased risk of PD, respectively. Our data concur with other reported findings in Chinese, Taiwanese, Singaporean, and Korean studies.

1. Introduction

Parkinson’s disease (PD) is an age-related illness, and, as populations age, the proportion of people with this neurodegenerative disease will continue to rise. It is projected that, by the year 2030, 9.3 million individuals above the age of 50 will suffer from PD and these cases will be concentrated outside the western world [1]. Studies have implicated exposure to environmental toxins and trauma as aetiological factors for PD [2]. Genetic variations also play a role, especially in cases where there is a family history of PD, which account for around 10–20% of all PD cases [3]. However, studies have shown that even late-onset sporadic PD may also have a genetic contribution [4].

One of the genes commonly implicated in both familial and sporadic PD is the leucine-rich repeat kinase 2 (LRRK2) gene. Several variants of LRRK2 such as R1441C, G2019S, and I2020T have been well established as risk factors for PD [3]. Interestingly, there appear to be population-specific variants in LRRK2; for example, the G2019S variant is prevalent among the Ashkenazi Jews and North African Arabs (occurring in approximately 20% and 40% of PD patients in these groups, respectively [5]) but is absent in Asian populations (Chinese, Indian, Korean, and Japanese) [6, 7]. In Asian (Chinese, Taiwanese, Singaporean, and Japanese) populations, the G2385R variant is a more established risk variant but conversely is not found in Caucasian or Jewish patients with PD [812]. The R1628P is another common risk variant in Asian PD populations (Chinese, Taiwanese, and Singaporean) [13].

Given the lack of data regarding how these variants contribute to PD in Malaysian patients, we sought to investigate the prevalence of G2385R and R1628P in a Malaysian PD cohort. We found that G2385R was significantly associated with PD and R1628P showed a trend towards being a risk factor.

2. Methodology

A total of 1,202 subjects participated in this study. Six hundred and ninety-five PD patients were diagnosed by neurologists based on the United Kingdom PD Brain Bank Criteria and 507 controls who did not suffer from any neurological or movement disorders were recruited. Ethics approval and written consent from subjects were obtained. DNA was extracted from lymphocytes that were obtained from venous blood using the phenol-chloroform method. The G2385R (rs34778348) and R1628P (rs33949390) genotyping was done by Taqman allelic discrimination assay on a 7500 Fast Real-Time PCR machine. A subset of 20 individuals was sequenced to determine the error rate. The allele and genotype frequencies in PD cases and controls were compared with Fisher’s exact test. Statistical analyses were performed using an open-source software (OpenEpi).

3. Results and Discussion

The mean age at PD diagnosis was years and the mean age of controls was years. Sixty percent of PD patients and 51% of controls were male. Results of the G2385R and R1628P genotyping are summarised in Table 1. The error rate of the assay was 0% in the subset of 20 individuals. Fifty-five patients (7.9%) had early-onset PD (onset < 40 years). Four patients were compound heterozygous for G2385R and R1628P; two of these patients had a family history of PD and developed PD before the age of 50, while the other two patients had no family history and had a later age of onset (>55).


SNPPD (MAF)Controls (MAF)OR (95% confidence interval)

G2385R (c.7153G>A), rs34778348
Wild type (G)1354 (0.974)1002 (0.999)OR 2.22 (1.15–4.29)
Variant (A)36 (0.026)12 (0.001)

R1628P (c.4883G>C), rs33949390
Wild type (G)1347 (0.969)996 (0.982)OR 1.23 (1.039–1.448)
Variant (C)43 (0.031)18 (0.018)

The G2385R variant was associated with PD, with an odds ratio (OR) of 2.22 (), while the R1628P variant had an OR of 1.23 with a trend towards significance (). Interestingly, the G2385R mutation was present in control subjects as well (MAF = 0.001), although it was less frequently present than in the PD cohort (MAF = 0.026).

Our findings are in keeping with other published reports on G2385R, where this variant is associated with an increased risk of developing PD by approximately twofold (Chinese, Taiwanese, Singaporean, and Japanese populations) (Table 2). The G2385R variant is located within the WD40 domain of LRRK2, which is responsible for a variety of functions including signal transduction, pre-mRNA processing, and cytoskeleton assembly, and cells carrying the G2385R variant are more susceptible to oxidative stress and apoptosis [14].


StudyAsian countrySample sizeResults

G2385R (c.7153G>A), rs34778348
Di Fonzo et al., 2006 [9]Taiwan608 PD, 373 controlsOR 2.24

Fung etal., 2006 [20]Taiwan305 PD, 176 controlsOR 17.00

Farrer et al., 2007 [21]Taiwan410 PD, 335 controlsOR 2.24
Tan et al., 2007 [14]Singapore495 PD, 494 controlsOR 2.14

Tan et al., 2007 [16]Non-Chinese Asian (Malays and Indians)98 PD, 173 controls
66 PD, 133 controls
Malays
OR 1.78
Indians-monomorphic

An et al., 2008 [11]Mainland China600 PD, 334 controlsOR 3.94

Funayama et al., 2007 [10]Japan448 PD, 457 controlsOR 2.60

Zabetian et al., 2009 [7]Japan601 PD, 1,628 controlsOR 1.96

Miyake et al., 2010 [22]Japan229 PD, 358 controlsOR 2.06

Kim et al., 2010 [12]Korea923 PD, 422 controls
119 YOPD
814 LOPD
Combined
OR 1.83
YOPD
OR 2.28
LOPD
OR 1.81

Ross et al., 2011 [19]AsianTaiwanese
369 PD, 300 controls
Korean
844 PD, 587 controls
Japanese
173 PD, 95 controls
Combined
1,386 PD, 982 controls
OR 1.62
* value not stated
OR 1.87
* value not stated
OR 1.44
* value not stated
OR 1.73

Current study Malaysia695 PD, 507 controlsOR 2.22

R1628P(c.4883G>C), rs33949390
Mata et al., 2005 [15]Europe, Asia, and North America100 PD probands with family history of parkinsonism,
300 controls
MAF 0.01

Lu et al., 2008 [18]Taiwan834 PD, 543 controlsOR 2.13

Tan et al., 2008 [16]Singapore246 PD, 243 controlsOR 2.5

Tan et al., 2008 [23]Non-Chinese Asian (Malays and Indians)132 PD, 160 controls
60 PD, 105 controls
OR 0.61
Indians-monomorphic

Ross et al., 2008 [13]Taiwan, SingaporeWu RM
484 PD, 341 controls
Wu YR
345 PD, 316 controls
EK Tan
250 PD, 250 controls
Combined
1079 PD, 907 controls
OR 2.15
OR 1.39
OR 2.20

OR 1.84

Zabetian et al., 2009 [7]Japanese631 PD, 320 controlsMonomorphic

Yu et al., 2009 [24]Mainland China328 PD, 300 controlsOR 2.68

Zhang et al., 2009 [25]Mainland China600 PD, 459 controlsOR 3.14

Kim et al., 2010 [12]Korea384 PD, 384 controlsOR 2.98

Pulkes et al., 2011 [17]Thai154 PD, 156 controlsOR 3.25

Ross et al., 2011 [19] AsianTaiwanese
(369 PD, 300 controls)
OR 0.56
Korean
(844 PD, 587 controls)
OR 2.47
Japanese
(173 PD, 95 controls)
Monomorphic
Combined
(1,386 PD, 982 controls)
OR 0.62

Current study Malaysian695 PD, 507 controlsOR 1.23

The R1628P variant was first identified by Mata et al. [15]. Subsequently, Ross et al. reported this variant to be the second common genetic risk factor for PD in the ethnic Chinese (Taiwanese and Singaporean) population, with an OR of 1.84 () [13]. Other independent studies carried out by Tan et al., Pulkes et al., and Lu et al. in Singapore, Thailand, and China showed a similar trend with OR values of 2.5, 3.3, and 2.1, respectively [1618]. However, this was not observed in a Japanese cohort where the locus was found to be monomorphic [7]. This mutation alters a highly conserved amino residue within the “COR” domain of the LRRK2 protein [18]. The substitution of a highly basic polar arginine (R) with a neutral nonpolar proline (P) is likely to cause a conformational change in the protein secondary structure, thus altering the function of the protein. We note however that a recent multicentre study by Ross et al. involving 1386 Asian PD cases and 982 Asian controls did not find an association with R1628P (OR 0.62, 95% CI 0.36–1.07, ) [19]. Whilst the findings in their Japanese and Korean subsets were consistent with previously published data, their Taiwanese cohort did not show a risk association, but rather a trend in the opposite direction (i.e., protective, with an OR of 0.56, 95% CI 0.32–1.01, ).

In conclusion, our data concur with other reports in the Chinese, Taiwanese, Singaporean, and Korean populations. The G2385R variant is significantly associated with an increased risk of developing PD, while the R1628P variant is predicted to have a more modest effect. These data together with others can lead to a better understanding of the pathogenetic pathways leading to cell dysfunction and death in PD, with the ultimate hope that more specific drugs can be developed to treat this disabling disease.

Conflict of Interests

The authors declare that they have no conflict of interests regarding the publication of this paper.

Acknowledgments

This study was supported by an FRGS Grant (FP017-2013B, awarded to AAA) and a Malaysian Ministry of Higher Education Grant for High Impact Research (HIR) (E000033, awarded to SYL).

References

  1. E. R. Dorsey, R. Constantinescu, J. P. Thompson et al., “Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030,” Neurology, vol. 68, no. 5, pp. 384–386, 2007. View at: Publisher Site | Google Scholar
  2. P. Lee, Y. Bordelon, J. Bronstein, and B. Ritz, “Traumatic brain injury, paraquat exposure, and their relationship to Parkinson disease,” Neurology, vol. 79, no. 20, pp. 2061–2066, 2012. View at: Publisher Site | Google Scholar
  3. L. M. Bekris, F. M. Ignacio, and C. P. Zabetian, “The genetics of Parkinson disease,” Journal of Geriatric Psychiatry and Neurology, vol. 23, no. 4, pp. 228–242, 2010. View at: Publisher Site | Google Scholar
  4. W. Satake, Y. Nakabayashi, I. Mizuta et al., “Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease,” Nature Genetics, vol. 41, no. 12, pp. 1303–1307, 2009. View at: Publisher Site | Google Scholar
  5. L. J. Ozelius, G. Senthil, R. Saunders-Pullman et al., “LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews,” New England Journal of Medicine, vol. 354, no. 4, pp. 424–425, 2006. View at: Publisher Site | Google Scholar
  6. E. K. Tan, H. Shen, L. C. S. Tan et al., “The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson's disease patients,” Neuroscience Letters, vol. 384, no. 3, pp. 327–329, 2005. View at: Publisher Site | Google Scholar
  7. C. P. Zabetian, M. Yamamoto, A. N. Lopez et al., “LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease,” Movement Disorders, vol. 24, no. 7, pp. 1034–1041, 2009. View at: Publisher Site | Google Scholar
  8. M. Toft, K. Haugarvoll, O. A. Ross, M. J. Farrer, and J. O. Aasly, “LRRK2 and Parkinson's disease in Norway,” Acta Neurologica Scandinavica, vol. 115, no. 187, pp. 72–75, 2007. View at: Publisher Site | Google Scholar
  9. A. Di Fonzo, Y. H. Wu-Chou, C. S. Lu et al., “A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan,” Neurogenetics, vol. 7, no. 3, pp. 133–138, 2006. View at: Publisher Site | Google Scholar
  10. M. Funayama, Y. Li, H. Tomiyama et al., “Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population,” NeuroReport, vol. 18, no. 3, pp. 273–275, 2007. View at: Publisher Site | Google Scholar
  11. X.-K. An, R. Peng, T. Li et al., “LRRK2 Gly2385Arg variant is a risk factor of Parkinson's disease among Han-Chinese from mainland China,” European Journal of Neurology, vol. 15, no. 3, pp. 301–305, 2008. View at: Publisher Site | Google Scholar
  12. J. M. Kim, J. Y. Lee, H. J. Kim et al., “The LRRK2 G2385R variant is a risk factor for sporadic Parkinson's disease in the Korean population,” Parkinsonism and Related Disorders, vol. 16, no. 2, pp. 85–88, 2010. View at: Publisher Site | Google Scholar
  13. O. A. Ross, Y. Wu, M. Lee et al., “Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease,” Annals of Neurology, vol. 64, no. 1, pp. 88–92, 2008. View at: Publisher Site | Google Scholar
  14. E. K. Tan, Y. Zhao, L. Skipper et al., “The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence,” Human Genetics, vol. 120, no. 6, pp. 857–863, 2007. View at: Publisher Site | Google Scholar
  15. I. F. Mata, J. M. Kachergus, J. P. Taylor et al., “Lrrk2 pathogenic substitutions in Parkinson's disease,” Neurogenetics, vol. 6, no. 4, pp. 171–177, 2005. View at: Publisher Site | Google Scholar
  16. E. K. Tan, L. C. Tan, H. Q. Lim et al., “LRRK2 R1628P increases risk of Parkinson's disease: replication evidence,” Human Genetics, vol. 124, no. 3, pp. 287–288, 2008. View at: Publisher Site | Google Scholar
  17. T. Pulkes, C. Papsing, S. Mahasirimongkol, M. Busabaratana, K. Kulkantrakorn, and S. Tiamkao, “Frequencies of LRRK2 variants in Thai patients with Parkinson's disease: evidence for an R1628P founder,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 82, no. 10, pp. 1179–1180, 2011. View at: Publisher Site | Google Scholar
  18. C. Lu, Y. Wu-Chou, M. Van Doeselaar et al., “The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in the Chinese population,” Neurogenetics, vol. 9, no. 4, pp. 271–276, 2008. View at: Publisher Site | Google Scholar
  19. O. A. Ross, A. I. Soto-Ortolaza, M. J. Heckman et al., “Association of LRRK2 exonic variants with susceptibility to Parkinsons disease: a casecontrol study,” Lancet Neurology, vol. 10, pp. 898–908, 2011. View at: Google Scholar
  20. H. C. Fung, C. M. Chen, J. Hardy, A. B. Singleton, and Y. R. Wu, “A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan,” BMC Neurology, vol. 6, article 47, 2006. View at: Publisher Site | Google Scholar
  21. M. J. Farrer, J. T. Stone, C. Lin et al., “Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia,” Parkinsonism and Related Disorders, vol. 13, no. 2, pp. 89–92, 2007. View at: Publisher Site | Google Scholar
  22. Y. Miyake, Y. Tsuboi, M. Koyanagi et al., “LRRK2 Gly2385Arg polymorphism, cigarette smoking, and risk of sporadic Parkinson's disease: a case-control study in Japan,” Journal of the Neurological Sciences, vol. 297, no. 1-2, pp. 15–18, 2010. View at: Publisher Site | Google Scholar
  23. E. Tan, M. Tang, L. C. Tan et al., “Lrrk2 R1628P in non-Chinese Asian races,” Annals of Neurology, vol. 64, no. 4, pp. 472–473, 2008. View at: Publisher Site | Google Scholar
  24. L. Yu, F. Hu, X. Zou et al., “LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China,” Brain Research, vol. 1296, pp. 113–116, 2009. View at: Publisher Site | Google Scholar
  25. Z. Zhang, J. Burgunder, X. An et al., “LRRK2 R1628P variant is a risk factor of Parkinson's disease among Han-Chinese from mainland China,” Movement Disorders, vol. 24, no. 13, pp. 1902–1905, 2009. View at: Publisher Site | Google Scholar

Copyright © 2014 Aroma Agape Gopalai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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