The LRRK2 Gene is a Shared Genetic Regulator among Three Clinically Divergent Common Inflammatory Disorders
1. Program in Immunology and Infectious Diseases in Global Health, Research Institute of the McGill University Health Centre, and 2. The McGill International TB Centre, Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada; 3. Hospital for Dermato-Venerology, Ho Chi Minh City, Vietnam; 4. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale; 5. University Paris Descartes, Imagine Institute, and 6. St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York. 7. Centre d’Investigation Clinique, Unité de Recherche Clinique, Necker and Cochin Hospitals, Paris, France
LRRK2 (formerly PARK8) is a large multi-domain protein that is highly expressed in immune cells. Coding variants of LRRK2 have been associated with Parkinson’s Disease (PD) and Crohn’s Disease (CD). Moreover, non-coding variants of LRRK2 were associated with leprosy susceptibility and LRRK2 directly interacts with PARK2, a well-established leprosy susceptibility gene. Recently, we demonstrated that a previously reported association between leprosy and the TNFSF15/TNFSF8 genes (also a CD susceptibility locus) was most likely due to patients suffering from type-1 reactions (T1R). This prompted us to investigate if LRRK2 variants were primarily associated with T1R rather than leprosy.
We tested the preferential LRRK2 association with T1R over leprosy in a family-based design. For this, we matched two samples of 229 families each with divergent T1R affection status in their offspring. In set 1, patients suffered from leprosy and T1R while in set 2 patients only suffered from leprosy. By formally comparing the T1R-affected versus the T1R-free subset we were able to address the association of genetic markers with the T1R endophenotype. We genotyped 156 SNPs in a 500kb window overlapping the LRRK2 and MUC19 genes. Of the 156 variants, 36 were significantly associated in the T1R-affected subset (P < 0.05) and 20 of these showed significant evidence for heterogeneity between T1R and leprosy. The “M” allele of the M2397T coding variant was significantly associated with T1R only (P = 0.008, P het =0.01). The same allele is a risk factor for CD (P = 2.6 e-15). A second SNP, rs7970326, significantly associated with T1R (P = 0.03, P het =0.006) is a risk factor for PD (P = 1.1 e-6) with the same direction of association. Next, we quantified LRRK2 mRNA expression in a whole blood assay of 54 leprosy cases in presence and absence of stimulation with Mycobacterium leprae antigen. Among the SNPs associated with T1R, we identified a series of eQTLs in unstimulated but not in stimulated blood.
Our results link the LRRK2 gene to the pathogenesis of three clinically distinct common inflammatory disorders of medical importance. This suggests LRRK2 as a prime candidate for host directed therapy in inflammatory disorders irrespective of their aetiologies and anatomical sites.
* Supported by the fellowship 9074/11-2. CAPES Foundation, Ministry of Education of Brazil, Brasilia, Brazil.
# Supported by a Canadian Institutes of Health research postdoctoral fellowship