Interactive Association Between Intronic Polymorphism (rs10506151) of the LRRK2 Gene and Type 2 Diabetes on Neurodegenerative Diseases

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Abstract

Purpose

We investigated the interactive effect of rs10506151 polymorphism of the Leucine-rich repeat kinase 2 (LRRK2) gene and type 2 diabetes (T2D) on neurodegenerative disease (ND) risk.

Materials and Methods

Data of 17, 927 participants in the Taiwan Biobank (TWB) assessed between 2008 and 2015 were linked to healthcare records in the National Health Insurance Research Database (NHIRD). The odd ratios (ORs) and 95% confidence intervals (CIs) for NDs were determined using logistic regression analysis.

Results

There were 145 cases with NDs, and 28.28% (n = 41) of these individuals had T2D. Associations of neurodegenerative disorders with LRRK2 rs10506151 variant and T2D were not significant. The corresponding ORs (95% CI) for NDs were 1.06 (0.75–1.49) in CA/AA compared to CC individuals and 0.93 (0.63–1.39) in those with T2D compared to non-diabetic participants. However, we found evidence of a significant interaction between rs10506151 and T2D (p = 0.0073). After stratification by genotypes of rs10506151, the OR for NDs was 0.37 (CI, 0.17–0.82) in CA/AA individuals with T2D and 1.41 (0.88–2.27) in their CC counterparts. When CA/AA individuals with T2D represented the reference group, the OR (95% CI) was 1.74 (0.81–3.73) in CC individuals with no T2D, 2.47 (CI, 1.14–5.38) in CA/AA individuals with no T2D, and 2.34 (CI, 1.07–5.11) in CC individuals with T2D.

Conclusion

Our data indicated that the risk of NDs was significantly lower among diabetic individuals with combined CA/AA of the LRRK2 rs10506151 variant in Taiwan.

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Most cited references 29

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Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study.

S Jick, Patrick Imfeld, C Meier … (2012)

To explore the risk of developing Alzheimer's disease (AD) in individuals with diabetes mellitus treated with metformin or other antidiabetic drugs. Case-control study. The United Kingdom-based General Practice Research Database (GPRD), a well-established primary care database. Seven thousand eighty-six individuals aged 65 and older with an incident diagnosis of AD identified between 1998 and 2008 and the same number of matched controls without dementia. Matching criteria were age, sex, general practice, calendar time, and years of history in the database. Comparison of previous use of metformin or other antidiabetic drugs between cases and controls and calculation of corresponding odds ratios (ORs) with 95% confidence intervals (CIs), using conditional logistic regression. Risk estimates were stratified according to duration of use and adjusted for potential confounders. As compared with nonusers, long-term users of 60 or more metformin prescriptions were at greater risk of developing AD (adjusted OR (AOR) = 1.71, 95% CI = 1.12-2.60), but there was no consistent trend with increasing number of prescriptions. Long-term use of other antidiabetic drugs such as sulfonylureas (AOR = 1.01, 95% CI = 0.72-1.42), thiazolidinediones (AOR = 0.87, 95% CI = 0.31-2.40), or insulin (AOR = 1.01, 95% CI = 0.58-1.73) was not related to an altered risk of developing AD. Long-term use of sulfonylureas, thiazolidinediones, or insulin was not associated with an altered risk of developing AD. There was a suggestion of a slightly higher risk of AD in long-term users of metformin. © 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.

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Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer’s disease and Parkinson’s disease

Gargi Ganguly, Sasanka Chakrabarti, Uttara Chatterjee … (2017)

Alzheimer’s disease and Parkinson’s disease are two common neurodegenerative diseases of the elderly people that have devastating effects in terms of morbidity and mortality. The predominant form of the disease in either case is sporadic with uncertain etiology. The clinical features of Parkinson’s disease are primarily motor deficits, while the patients of Alzheimer’s disease present with dementia and cognitive impairment. Though neuronal death is a common element in both the disorders, the postmortem histopathology of the brain is very characteristic in each case and different from each other. In terms of molecular pathogenesis, however, both the diseases have a significant commonality, and proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction and oxidative stress are the cardinal features in either case. These three damage mechanisms work in concert, reinforcing each other to drive the pathology in the aging brain for both the diseases; very interestingly, the nature of interactions among these three damage mechanisms is very similar in both the diseases, and this review attempts to highlight these aspects. In the case of Alzheimer’s disease, the peptide amyloid beta (Aβ) is responsible for the proteinopathy, while α-synuclein plays a similar role in Parkinson’s disease. The expression levels of these two proteins and their aggregation processes are modulated by reactive oxygen radicals and transition metal ions in a similar manner. In turn, these proteins – as oligomers or in aggregated forms – cause mitochondrial impairment by apparently following similar mechanisms. Understanding the common nature of these interactions may, therefore, help us to identify putative neuroprotective strategies that would be beneficial in both the clinical conditions.

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Diabetes and Risk of Parkinson’s Disease

Qun Xu, Yikyung Park, Xuemei Huang … (2011)

OBJECTIVE To investigate the relationship between diabetes and future risk of Parkinson’s disease (PD) among older U.S. adults. RESEARCH DESIGN AND METHODS A prospective study of self-reported diabetes in 1995 and 1996 in relation to PD diagnosed after 1995 among 288,662 participants of the National Institutes of Health-AARP Diet and Health Study. Multivariate odds ratio (OR) and 95% CI were derived from logistic regression models. RESULTS A total of 1,565 participants with PD diagnosed after 1995 were included in the analysis. After adjustment for potential confounders, PD risk was ∼40% higher (OR = 1.41 [95% CI 1.20–1.66]) among diabetic patients than among participants without diabetes. Further analysis showed that the risk elevation was largely limited to individuals who had diabetes for more than 10 years at the time of baseline survey (1.75 [1.36–2.25]). The association with diabetes was seen for both participants with PD diagnosed between 1995 and 1999 and participants with PD diagnosed after 2000. In addition, similar results were obtained after excluding participants with stroke, heart disease, cancers, or poor or fair health status and in subgroup analyses by age, sex, smoking status, and coffee consumption. CONCLUSIONS This large study showed that diabetes was associated with a higher future risk of PD and the nature of this association warrants further investigation.

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Author and article information

Journal

Journal ID (nlm-ta): Pharmgenomics Pers Med

Journal ID (iso-abbrev): Pharmgenomics Pers Med

Journal ID (publisher-id): pgpm

Journal ID (pmc): ppm

Title: Pharmacogenomics and Personalized Medicine

Publisher: Dove

ISSN (Electronic): 1178-7066

Publication date (Electronic): 13 July 2021

Publication date Collection: 2021

Volume: 14

Pages: 839-847

Affiliations

[1 ]Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University , Taichung, 40402, Taiwan

[2 ]Department of Biomedical Sciences, Chung Shan Medical University , Taichung, Taiwan

[3 ]Division of Allergy, Department of Pediatrics, Chung Shan Medical University Hospital , Taichung, Taiwan

[4 ]Department of Public Health and Institute of Public Health, Chung Shan Medical University , Taichung, 40201, Taiwan

[5 ]Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University , Taichung, 40402, Taiwan

[6 ]Department of Medical Research, China Medical University Hospital , Taichung, 40447, Taiwan

[7 ]Brain Diseases Research Center, China Medical University , Taichung, 40402, Taiwan

[8 ]Department of Medical Imaging, Chung Shan Medical University Hospital , Taichung City, 40201, Taiwan

Author notes

Correspondence: Yung-Po Liaw Department of Public Health and Institute of Public Health, Chung Shan Medical University , No. 110, Sec. 1 Jianguo N. Road, Taichung City, 40201, TaiwanTel +886-4-24730022 ext.11838Fax +886-4-23248179 Email Liawyp@csmu.edu.tw

Yuan-Shiun Chang Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University , Taichung, 40402, TaiwanTel +886-4-22053366 ext. 5502Fax +886-4-22083362 Email yschang@mail.cmu.edu.tw

Author information

Yung-Po Liaw http://orcid.org/0000-0003-2046-4964

Article

Publisher ID: 316158

DOI: 10.2147/PGPM.S316158

PMC ID: 8286148

SO-VID: c70a61d3-e640-4d3a-82d7-252d9b07cef7

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 16 April 2021

Date accepted : 16 June 2021

Page count

Figures: 1, Tables: 15, References: 29, Pages: 9

Funding

Funded by: the Ministry of Science and Technology;

This study was supported by the Ministry of Science and Technology (MOST 109-2121-M-040-002). The funder hand no role in the collection, analysis, and interpretation of data and in writing the manuscript.

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Interactive Association Between Intronic Polymorphism (rs10506151) of the LRRK2 Gene and Type 2 Diabetes on Neurodegenerative Diseases

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Karger: Endocrinology

Most cited references 29

Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study.

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer’s disease and Parkinson’s disease

Diabetes and Risk of Parkinson’s Disease

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