Genetic Analysis of LRRK2 R1628P in Parkinson's Disease in Asian Populations

Yuan Zhang, Qiying Sun, Minhan Yi, Xun Zhou, Jifeng Guo, Qian Xu, Beisha Tang, Xinxiang Yan, Yuan Zhang, Qiying Sun, Minhan Yi, Xun Zhou, Jifeng Guo, Qian Xu, Beisha Tang, Xinxiang Yan

Abstract

Although the etiology of Parkinson's disease (PD) remains unclear, there is increasing evidence of genetic factors contributing to the onset of PD. Various mutations and risk variants of the gene LRRK2 have been reported, but the association between LRRK2 R1628P and PD is still inconsistent. Thus, we conducted a meta-analysis to determine the potential relationship between R1628P and PD. Our study sample was an aggregate of 17 publications, which in total consisted of 9,275 PD patients and 8,114 controls. All of these articles are of high quality according to NOS, and there was no obvious reporting bias or heterogeneity. In a general Asian population, the pooled OR of the risk genotype contrasts was 1.83 (95% CI: 1.57, 2.13). When stratified by ethnicity, the pooled ORs were 1.84 (95% CI: 1.56, 2.18) in a Chinese population and 1.79 (95% CI: 1.27, 2.52) in a non-Chinese population. Our study suggests that LRRK2 R1628P appears to be a risk factor for PD in Asian populations, both Chinese and non-Chinese.

Figures

Figure 1
Figure 1
Flow chart of included publications.
Figure 2
Figure 2
Forest plot of R1628P in PD.
Figure 3
Figure 3
Funnel plot of R1628P in PD.

References

    1. Kalia L. V., Lang A. E. Parkinson's disease. The Lancet. 2015;386(9996):896–912. doi: 10.1016/S0140-6736(14)61393-3.
    1. Dächsel J. C., Farrer M. J. LRRK2 and Parkinson disease. Archives of Neurology. 2010;67(5):542–547. doi: 10.1001/archneurol.2010.79.
    1. Di Fonzo A., Tassorelli C., De Mari M., et al. Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease. European Journal of Human Genetics. 2006;14(3):322–331. doi: 10.1038/sj.ejhg.5201539.
    1. Paisán-Ruíz C., Nath P., Washecka N., Gibbs J. R., Singleton A. B. Comprehensive analysis of LRRK2 in publicly available Parkinson's disease cases and neurologically normal controls. Human Mutation. 2008;29(4):485–490. doi: 10.1002/humu.20668.
    1. Lesage S., Dürr A., Tazir M., et al. LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. The New England Journal of Medicine. 2006;354(4):422–423. doi: 10.1056/nejmc055540.
    1. Hulihan M. M., Ishihara-Paul L., Kachergus J., et al. LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study. The Lancet Neurology. 2008;7(7):591–594. doi: 10.1016/S1474-4422(08)70116-9.
    1. Peeraully T., Tan E. K. Genetic variants in sporadic parkinson's disease: East vs west. Parkinsonism & Related Disorders. 2012;18(supplement 1):S63–S65.
    1. Farrer M. J., Stone J. T., Lin C.-H., et al. Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism & Related Disorders. 2007;13(2):89–92. doi: 10.1016/j.parkreldis.2006.12.001.
    1. Di Fonzo A., Wu-Chou Y. H., Lu C. S., et al. A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. neurogenetics. 2006;7(3):133–138. doi: 10.1007/s10048-006-0041-5.
    1. Gopalai A. A., Lim S.-Y., Chua J. Y., et al. LRRK2 G2385R and R1628P Mutations Are Associated with an Increased Risk of Parkinson's Disease in the Malaysian Population. BioMed Research International. 2014;2014 doi: 10.1155/2014/867321.867321
    1. Pulkes T., Papsing C., Thakkinstian A., et al. Confirmation of the association between LRRK2 R1628P variant and susceptibility to Parkinson's disease in the Thai population. Parkinsonism & Related Disorders. 2014;20(9):1018–1021. doi: 10.1016/j.parkreldis.2014.06.013.
    1. Wu-Chou Y.-H., Chen Y.-T., Yeh T.-H., et al. Genetic variants of SNCA and LRRK2 genes are associated with sporadic PD susceptibility: a replication study in a Taiwanese cohort. Parkinsonism & Related Disorders. 2013;19(2):251–255. doi: 10.1016/j.parkreldis.2012.10.019.
    1. Fu X., Zheng Y., Hong H., et al. LRRK2 G2385R and LRRK2 R1628P increase risk of Parkinson's disease in a Han Chinese population from Southern Mainland China. Parkinsonism & Related Disorders. 2013;19(3):397–398. doi: 10.1016/j.parkreldis.2012.08.007.
    1. Ross O. A., Soto-Ortolaza A. I., Heckman M. G., et al. Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study. The Lancet Neurology. 2011;10(10):898–908.
    1. Kim J. M., Lee J. Y., Kim H. J., et al. The LRRK2 G2385R variant is a risk factor for sporadic Parkinson's disease in the Korean population. Parkinsonism & Related Disorders. 2010;16(2):85–88. doi: 10.1016/j.parkreldis.2009.10.004.
    1. Zhou Y., Luo X., Li F., et al. Association of Parkinson's disease with six single nucleotide polymorphisms located in four PARK genes in the northern Han Chinese population. Journal of Clinical Neuroscience. 2012;19(7):1011–1015. doi: 10.1016/j.jocn.2011.09.028.
    1. Lu C.-S., Wu-Chou Y.-H., van Doeselaar M., et al. The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in the Chinese population. Neurogenetics. 2008;9(4):271–276. doi: 10.1007/s10048-008-0140-6.
    1. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European Journal of Epidemiology. 2010;25(9):603–605. doi: 10.1007/s10654-010-9491-z.
    1. Ross O. A., Wu Y.-R., Lee M.-C., et al. Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease. Annals of Neurology. 2008;64(1):88–92. doi: 10.1002/ana.21405.
    1. Tan E. K., Tang M., Tan L. C., et al. Lrrk2 R1628P in non-Chinese Asian races. Annals of Neurology. 2008;64(4):472–473. doi: 10.1002/ana.21467.
    1. Tan E. K., Tan L. C., Lim H. Q., et al. LRRK2 R1628P increases risk of Parkinson's disease: replication evidence. Human Genetics. 2008;124(3):287–288. doi: 10.1007/s00439-008-0544-2.
    1. Zhang Z., Burgunder J.-M., An X., et al. LRRK2 R1628P variant is a risk factor of Parkinson's disease among Han-Chinese from mainland China. Movement Disorders. 2009;24(13):1902–1905. doi: 10.1002/mds.22371.
    1. Yu L., Hu F., Zou X., et al. LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China. Brain Research. 2009;1296:113–116. doi: 10.1016/j.brainres.2009.08.047.
    1. Zabetian C. P., Yamamoto M., Lopez A. N., et al. LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease. Movement Disorders. 2009;24(7):1034–1041. doi: 10.1002/mds.22514.
    1. Pulkes T., Papsing C., Mahasirimongkol S., Busabaratana M., Kulkantrakorn K., Tiamkao S. Frequencies of LRRK2 variants in Thai patients with Parkinson's disease: evidence for an R1628P founder. Journal of Neurology, Neurosurgery & Psychiatry. 2011;82(10):1179–1180. doi: 10.1136/jnnp.2009.194597.
    1. Cai J., Lin Y., Chen W., et al. Association between G2385R and R1628P polymorphism of LRRK2 gene and sporadic Parkinson's disease in a Han-Chinese population in south-eastern China. Neurological Sciences. 2013;34(11):2001–2006. doi: 10.1007/s10072-013-1436-3.
    1. Wu Y.-R., Chang K.-H., Chang W.-T., et al. Genetic variants of LRRK2 in Taiwanese Parkinson's disease. PLoS ONE. 2013;8(12) doi: 10.1371/journal.pone.0082001.e82001
    1. Guo J.-F., Li K., Yu R.-L., et al. Polygenic determinants of Parkinson's disease in a Chinese population. Neurobiology of Aging. 2015;36(4):1765.e1–1765.e6. doi: 10.1016/j.neurobiolaging.2014.12.030.
    1. Bosgraaf L., van Haastert P. J. M. Roc, a Ras/GTPase domain in complex proteins. Biochimica et Biophysica Acta. 2003;1643(1–3):5–10. doi: 10.1016/j.bbamcr.2003.08.008.
    1. Zimprich A., Biskup S., Leitner P., et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44(4):601–607. doi: 10.1016/j.neuron.2004.11.005.
    1. Saiki S., Sato S., Hattori N. Molecular pathogenesis of Parkinson's disease: update. Journal of Neurology, Neurosurgery & Psychiatry. 2012;83(4):430–436. doi: 10.1136/jnnp-2011-301205.
    1. Chan S. L., Angeles D. C., Tan E.-K. Targeting leucine-rich repeat kinase 2 in Parkinson's disease. Expert Opinion on Therapeutic Targets. 2013;17(12):1471–1482. doi: 10.1517/14728222.2013.842978.
    1. Berg D., Postuma R. B., Bloem B., et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease. Movement Disorders. 2014;29(4):454–462. doi: 10.1002/mds.25844.
    1. Berg D., Postuma R. B., Adler C. H., et al. MDS research criteria for prodromal Parkinson's disease. Movement Disorders. 2015;30(12):1600–1611. doi: 10.1002/mds.26431.
    1. Nalls M. A., McLean C. Y., Rick J., et al. Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: A population-based modelling study. The Lancet Neurology. 2015;14(10, article no. 123):1002–1009. doi: 10.1016/S1474-4422(15)00178-7.
    1. Tan E. K., Peng R., Teo Y. Y., et al. Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study. Human Mutation. 2010;31(5):561–568. doi: 10.1002/humu.21225.
    1. Wang C., Cai Y., Zheng Z., et al. Penetrance of LRRK2 G2385R and R1628P is modified by common PD-associated genetic variants. Parkinsonism & Related Disorders. 2012;18(8):958–963. doi: 10.1016/j.parkreldis.2012.05.003.

Source: PubMed

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