Loss of Function Variants in LRRK1 and LRRK2 Not Linked to Parkinson Disease

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Kinase inhibition or allele-specific targeting of mutant LRRK2 may still be a meaningful target for therapeutic development.
Kinase inhibition or allele-specific targeting of mutant LRRK2 may still be a meaningful target for therapeutic development.

Research published in JAMA Neurology suggests that haploinsufficiency of LRRK1 or LRRK2 is not a cause of or protective against the development of Parkinson disease (PD), suggesting that kinase inhibition or allele-specific targeting of mutant LRRK2 may still be a meaningful target for therapeutic development in a subset of patients with PD.  

Next-generation sequencing data from a case-control cohort of >23,000 individuals were analyzed for loss of function (LOF) variants in LRRK1 and LRRK2, in order to establish the prevailing mechanism of LRRK-mediated disease. Data were generated at 5 different sites and 5 different datasets, which included both patients with clinically diagnosed PD (n=11,095) and neurologically normal controls (n=12,615). All data were gathered between 2012 and 2017. The main outcome measures was the frequency of LRRK1 and LRRK2 LOF variants in the general population, as well as a comparison of the frequency among cases vs controls.

Of 11,095 patients with PD and 12,615 controls, LRRK1 LOF variants were identified in 0.205% vs 0.139%, respectively (odds ratio [OR] 1.48; 95% CI, 0.45-4.44; P =.49). In contrast, LRRK2 LOF variants were detected in 0.117% vs 0.087%, respectively (OR 1.48; 95% CI, 0.63-3.50; P =.36). Testing suggested a lack of association between LRRK1 or LRRK2 variants and PD. According to the findings, there was no significant enrichment in LRRK1 and LRKR2 LOF variants found in patients with PD (0.205% and 0.117%, respectively) compared with controls (0.139% vs 0.087%, respectively).

Additional analysis of lymphoblastoid cell lines from several LOF variant carriers demonstrated that, as anticipated, LRRK2 protein levels are decreased by approximately half compared with wild-type alleles.

The investigators concluded that the presence of LRRK1 and LRRK2 LOF variants does not increase an individual's risk for PD. The results of this analysis support the expansion of these studies in clinical trials and in cells from LRRK2 variant carriers.

Reference

Blauwendraat C, Reed X, Kia DA, et al; COURAGE-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease) Consortium, the French Parkinson's Disease Consortium, and the International Parkinson's Disease Genomics Consortium (IPDGC). Frequency of loss of function variants in LRRK2 in Parkinson disease [published online July 23, 2018]. JAMA Neurol.
doi:10.1001/jamaneurol.2018.1885

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