Objective: To determine if subjects with DM and carriers of LRKK2 risk variant (R1628P) have an increased risk of PD compared to

non-carriers without DM.

Background: Diabetes mellitus (DM) may predispose to neurodegeneration and an increased risk of Parkinson’s

disease (PD), a common neurodegenerative disease. A polymorphic LRRK2 gain of function coding

variant (R1628P) has been linked to PD and leprosy. We hypothesized that diabetic carriers of

R1628P may have a much higher risk compared to non-diabetic and non-gene carriers to develop PD.

Method: A case-control study (PD patients and controls) was conducted prospectively at tertiary referral

centers in Singapore. Clinical diagnosis was based on the United Kingdom PD brain bank criteria and

information on age, PD onset, gender and family history were collected. Subjects who were on anti-

diabetic drugs and given a medical diagnosis of DM were defined as having DM. DNA was extracted

and genotyping of the R1628P carried out. All participants gave informed consent and the study

received institution ethics approval. Difference between categories of PD was tested using 2-sample

t-test and Fisher’s exact test for continuous and categorical variables respectively. Univariate and

multivariable binary logistic regression models were used to determine the association between PD

and covariates. Risk association was expressed as odds ratio (OR) with 95% confidence intervals

(95%CI). P-value<0.05 was considered statistically significant and all tests used in this study were

two-sided.

Results: A total of 2085 PD patients [58.8% male; age at onset 62.4) years] and 3019 controls [54.8% male;

53.0(+11.88) years]. Multivariate regression analysis demonstrated that presence of DM was

associated with a 4.48 times increased risk of developing PD [OR(95% CI) = 4.477 (3.648,5.494),

p<0.0001]. However when R1628P was included in the multivariate model, the risk of diabetics

developing PD increased by two fold [OR(95% CI) = 9.609 (3.317,27.836), p<0.0001]. Diabetic R1628P

carriers had a 9.6 times higher risk compared to subjects without DM and were non-R1628P carriers.

Conclusion: Concurrent presence of Diabetes Mellitus and LRRK2 risk variant significantly increases the risk of PD, compared to

non diabetic non carriers and to diabetes alone.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/additive-effect-of-diabetes-mellitus-and-genetic-risk-variant-in-parkinsons-disease/