Association of the LRRK2 genetic polymorphisms with leprosy in Han Chinese from Southwest China

Abstract

Leprosy is a chronic infectious and neurological disease that is caused by infection of Mycobacterium leprae (M. leprae). A recent genome-wide association study indicated a suggestive association of LRRK2 genetic variant rs1873613 with leprosy in Chinese population. To validate this association and further identify potential causal variants of LRRK2 with leprosy, we genotyped 13 LRRK2 variants in 548 leprosy patients and 1078 healthy individuals from Yunnan Province and (re-)analyzed 3225 Han Chinese across China. Variants rs1427267, rs3761863, rs1873613, rs732374 and rs7298930 were significantly associated with leprosy per se and/or paucibacillary leprosy (PB). Haplotype A-G-A-C-A was significantly associated with leprosy per se (P=0.018) and PB (P=0.020). Overexpression of the protective allele (Thr2397) of rs3761863 in HEK293 cells led to a significantly increased nuclear factor of activated T-cells' activity compared with allele Met2397 after lipopolysaccharides stimulation. Allele Thr2397 could attenuate 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced autophagic activity in U251 cells. These data suggest that the protective effect of LRRK2 variant p.M2397T on leprosy might be mediated by increasing immune response and decreasing neurotoxicity after M. leprae loading. Our findings confirm that LRRK2 is a susceptible gene to leprosy in Han Chinese population.

Common variants in the PARL and PINK1 genes increase the risk to leprosy in Han Chinese from South China

“…We also found a significantly increased mtDNA copy number in lepromatous leprosy patients11 compared with controls. The mitochondrial outer membrane protein, LRRK2, has been identified by a genome-wide association study (GWAS) as one of the leprosy susceptibility genes in Han Chinese population12, and this was confirmed by our recent case-control study13 and other studies1415, although the associated LRRK2 SNPs or their effects were different in these studies. Most recently, we provided solid evidence to show that the OPA1 gene, encoding an mitochondrial inner membrane protein, was associated with leprosy susceptibility possibly by affecting mitochondrial function and antimicrobial pathways16.…”

“…Although there was no positive interaction among PARL, PINK1, OPA1 and LRRK2 SNPs (Table S6) based on our recently reported data1316 and current data, the positive associations of these four genes with leprosy suggested that mitochondrial related genes should play active roles in leprosy. The protein interaction network analysis supported this speculation, as we found that the other mitochondrial genes ( MCCD1, SDHD, SNCA , and VARS2 ) could interact with the reported leprosy susceptibility genes (Table S5).…”

“…It is therefore reasonable to believe that genes involved in mitochondrial function would affect the host response to microbe infection. Indeed, we recently provided evidence that genetic variants of the mitochondrial genes, like LRRK2 and OPA1 were associated with leprosy1316, although three mitochondrial-related antimicrobial/antiviral immune genes ( MAVS, MITA and MFN2 ) showed no evidence to be associated with leprosy49. In this study, we found that two mitochondrial genes, PARL and PINK1 , conferred genetic susceptibility to leprosy per se and/or multibacillary leprosy.…”

“…In our recent studies, we identified an association of two mitochondrial genes ( LRRK2 and OPA1 ) with leprosy1316. Although there was no positive interaction among PARL, PINK1, OPA1 and LRRK2 SNPs (Table S6) based on our recently reported data1316 and current data, the positive associations of these four genes with leprosy suggested that mitochondrial related genes should play active roles in leprosy.…”

The LRRK2 signalling system

“…Intriguingly, variation at the LRRK2 locus has also been connected by genome-wide association with immune diseases such as systemic lupus erythematosus (Zhang et al 2017), Crohn’s disease (Barrett et al 2008) and inflammatory bowel disease (Liu et al 2011) and with susceptibility to multibacillary leprosy (Wang et al 2015; Fava et al 2016). LRRK2 has also been linked to cancer, with the PD G2019S mutation associated with specific cancers such as non-skin and hormonal cancers (Agalliu et al 2015) and the R1441C mutation linked to increased risk of colon cancer (Tacik et al 2016).…”