LRRK2  N551K and R1398H variants are protective in Malays and Chinese in Malaysia: A case–control association study for Parkinson's disease

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Abstract

Background

The LRRK2 gene is associated with Parkinson's disease (PD) as a number of mutations within the gene have been shown to be susceptibility factors. Studies on various global populations have determined that mutations such as G2019S, G2385R, and R1628P in LRRK2 increase the risk of developing PD while the N551K‐R1398H haplotype is associated with conferring protection against developing PD. Here we report a study looking at the N551K and R1398H variants for the first time in the Malaysian population.

Methods

Cases (523) which conformed to the United Kingdom PD Brain Bank Criteria for PD were recruited through trained neurologists and age‐ and ethnically matched controls (491) were individuals free of any neurological disorder. The N551K and R1398H mutations were genotyped using the Taqman SNP genotyping assay.

Results

A significant protective association for N551K was found in those of Malay ancestry, with a protective trend seen for R1398H. A meta‐analysis of Chinese individuals in this cohort with other published cohorts of Chinese ancestry indicated a significant protective role for N551K and R1398H.

Conclusion

This study reports that the N551K‐R1398H haplotype is also relevant to the Malaysian population, with a significant protective effect found in those of Malay and Chinese ancestries.

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Most cited references 16

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Kinase activity of mutant LRRK2 mediates neuronal toxicity.

Wanli W. Smith, Zhong Pei, Haibing Jiang … (2006)

Mutations in the the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson disease and some cases of sporadic Parkinson disease. Here we found that LRRK2 kinase activity was regulated by GTP via the intrinsic GTPase Roc domain, and alterations of LRRK2 protein that reduced kinase activity of mutant LRRK2 correspondingly reduced neuronal toxicity. These data elucidate the pathogenesis of LRRK2-linked Parkinson disease, potentially illuminate mechanisms of sporadic Parkinson disease and suggest therapeutic targets.

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LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews.

Christine Klein, Shanda Hunt, Neil Risch … (2006)

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Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study.

Alexis Elbaz, Barbara Jasinska-Myga, Nobutaka Hattori … (2011)

Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012). The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. Michael J Fox Foundation and National Institutes of Health. Copyright © 2011 Elsevier Ltd. All rights reserved.

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Author and article information

Contributors

Azlina Ahmad Annuar:

ORCID: https://orcid.org/0000-0001-6329-4366

azlina_aa@um.edu.my

Journal

Journal ID (nlm-ta): Mol Genet Genomic Med

Journal ID (iso-abbrev): Mol Genet Genomic Med

Journal ID (doi): 10.1002/(ISSN)2324-9269

Journal ID (publisher-id): MGG3

Title: Molecular Genetics & Genomic Medicine

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2324-9269

Publication date (Electronic): 05 September 2019

Publication date Collection: November 2019

Volume: 7

Issue: 11 ( doiID: 10.1002/mgg3.v7.11 )

Electronic Location Identifier: e604

Affiliations

[ ¹ ] Faculty of Medicine, Department of Biomedical Science University of Malaya Kuala Lumpur Malaysia

[ ² ] Health Services Research Singapore General Hospital Singapore Singapore

[ ³ ] Centre for Quantitative Medicine Duke‐NUS Medical School Singapore Singapore

[ ⁴ ] Department of Clinical Translational Research Singapore General Hospital Singapore Singapore

[ ⁵ ] Island Hospital George Town Malaysia

[ ⁶ ] Department of Neurology Hospital Pulau Pinang Penang Malaysia

[ ⁷ ] Department of Neurology Hospital Kuala Lumpur Kuala Lumpur Malaysia

[ ⁸ ] Hospital University Kebangsaan Malaysia Kuala Lumpur Malaysia

[ ⁹ ] Department of Medicine Hospital Sultanah Nur Zahirah Kuala Terengganu Malaysia

[ ¹⁰ ] Faculty of Medicine, Department of Medicine University of Malaya Kuala Lumpur Malaysia

[ ¹¹ ] Faculty of Medicine, Division of Neurology and the Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders University of Malaya Kuala Lumpur Malaysia

[ ¹² ] Department of Neurology Singapore General Hospital Singapore Singapore

[ ¹³ ] National Neuroscience Institute and Duke‐NUS Graduate Medical School Singapore Singapore

Author notes

[*] [* ] Correspondence

Azlina Ahmad Annuar, Faculty of Medicine, Department of Biomedical Science, University of Malaya, Kuala Lumpur, Malaysia

Email: azlina_aa@ 123456um.edu.my

Author information

Shanthi Viswanathan https://orcid.org/0000-0002-0094-0540

Azlina Ahmad Annuar https://orcid.org/0000-0001-6329-4366

Article

Publisher ID: MGG3604

DOI: 10.1002/mgg3.604

PMC ID: 6825847

PubMed ID: 31487119

SO-VID: ef32a82c-6d72-47a0-9793-f118d1ccda12

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 26 October 2018

Date revision received : 06 January 2019

Date accepted : 09 January 2019

Page count

Figures: 2, Tables: 2, Pages: 6, Words: 3654

Funding

Funded by: National Medical Research Council

Funded by: University of Malaya High‐Impact Research (HIR) grant

Funded by: Singapore Millennium Foundation

Funded by: Fundamental Research Grant Scheme (Malaysia)

Custom metadata

source-schema-version-number 2.0

component-id mgg3604

cover-date November 2019

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:03.11.2019

LRRK2 N551K and R1398H variants are protective in Malays and Chinese in Malaysia: A case–control association study for Parkinson's disease

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Abstract

Background

Methods

Results

Conclusion

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Karger: Neurology and Neuroscience

Most cited references 16

Kinase activity of mutant LRRK2 mediates neuronal toxicity.

LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews.

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study.

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