Objective: To determine if LRRK2 variants are able to reduce the diabetes associated risk in Parkinsons disease

Background: Leucine-rich repeat kinase 2 (LRRK2) mutations are common cause of familial and sporadic Parkinsons disease (PD). Diabetes mellitus (DM) can increase the risk of PD. However, LRRK2 polymorphic variants N551K and R1398H confer up to 20% reduction of PD risk. It is unclear if these variants interact with DM and able to reduce the risk of DM in PD.

Method: We recruited subjects with PD and healthy controls at tertiary referral centres in Singapore. PD was diagnosed using UK PD brain bank criteria and healthy controls were screened for presence of neurodegenerative disorders. Demographic data and comorbidities were collected. Written informed consent was taken from all study subjects and the study received institution ethics approval. Outcome PD variable status was categorized as binary variable with “PD” and “non-PD”; all co-variables summarized were based on PD status. Difference between categories of PD was tested using 2-sample t-test and Fisher’s exact test for continuous and categorical variables respectively. Statistical significance was defined at p-value<0.05. Analysis was done using SAS 9.4 software.

Results: A total of 2085 (40.9%) PD [58.8% male;66.7(10.17) years] and 3019 controls [54.8% male;53.0(11.88) years] were included. Multivariate regression analysis demonstrated that diabetes [OR(95%CI): 1.79(1.43-2.24); p<0.0001] was  associated with the greatest risk (1.79 times) of developing PD among the co-variables analyzed. Compared to R1398H carriers without DM, diabetic carriers had a 3.9 times increased risk (95%CI:2.552-6.099;p<0.0001) but this risk increased to 6.4 times (95%CI:4.907-8.457;p<0.0001) in diabetic non-R1398H carriers. This trend was also observed for the N551K protective variant, where diabetic non-carriers had a 6 times risk (95%CI:4.609-7.944;p<0.0001) and diabetic carriers 3.7 times risk (95%CI:2.394-5.589;p<0.0001) compared to non diabetic carriers.

Conclusion: LRRK2 variants (R1398H, N551K) can reduce about half the PD risk conferred by diabetes mellitus. Further functional studies to unravel pathophysiologic clues will be of interest.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-risk-factors-reduce-the-risk-of-diabetes-mellitus-in-parkinsons-disease/