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.
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References
Britton WJ, Lockwood DN . Leprosy. Lancet 2004; 363: 1209–1219.
WHO. Leprosy update 2011 Wkly Epidemiol Rec 2011; 86: 389–399.
Scollard DM, Adams LB, Gillis TP, Krahenbuhl JL, Truman RW, Williams DL . The continuing challenges of leprosy. Clin Microbiol Rev 2006; 19: 338–381.
Worobec SM . Treatment of leprosy/Hansen's disease in the early 21st century. Dermatol Ther 2009; 22: 518–537.
Johnson CM, Lyle EA, Omueti KO, Stepensky VA, Yegin O, Alpsoy E et al. Cutting edge: a common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J Immunol 2007; 178: 7520–7524.
Zhang FR, Huang W, Chen SM, Sun LD, Liu H, Li Y et al. Genomewide association study of leprosy. N Engl J Med 2009; 361: 2609–2618.
Misch EA, Berrington WR, Vary JC Jr ., Hawn TR . Leprosy and the human genome. Microbiol Mol Biol Rev 2010; 74: 589–620.
Yang D, Song H, Xu W, Long H, Shi C, Jing Z et al. Interleukin 4-590T/C polymorphism and susceptibility to leprosy. Genet Test Mol Biomarkers 2011; 15: 877–881.
Sousa AL, Fava VM, Sampaio LH, Martelli CM, Costa MB, Mira MT et al. Genetic and immunological evidence implicates interleukin 6 as a susceptibility gene for leprosy type 2 reaction. J Infect Dis 2012; 205: 1417–1424.
Cardoso CC, Pereira AC, Brito-de-Souza VN, Duraes SM, Ribeiro-Alves M, Nery JA et al. TNF -308G>A single nucleotide polymorphism is associated with leprosy among Brazilians: a genetic epidemiology assessment, meta-analysis, and functional study. J Infect Dis 2011; 204 :: 1256–63.
Sapkota BR, Macdonald M, Berrington WR, Misch EA, Ranjit C, Siddiqui MR et al. Association of TNF, MBL, and VDR polymorphisms with leprosy phenotypes. Hum Immunol 2010; 71: 992–998.
Alter A, de Léséleuc L, Van Thuc N, Thai VH, Huong NT, Ba NN et al. Genetic and functional analysis of common MRC1 exon 7 polymorphisms in leprosy susceptibility. Hum Genet 2010; 127: 337–348.
Cardoso CC, Pereira AC, Brito-de-Souza VN, Dias-Baptista IM, Maniero VC, Venturini J et al. IFNG +874 T>A single nucleotide polymorphism is associated with leprosy among Brazilians. Hum Genet 2010; 128: 481–490.
Wang D, Feng J-Q, Li Y-Y, Zhang D-F, Li X-A, Li QW et al. Genetic variants of the MRC1 gene and the IFNG gene are associated with leprosy in Han Chinese from Southwest China. Hum Genet 2012; 131: 1251–1260.
Zhang D-F, Huang X-Q, Wang D, Li Y-Y, Yao Y-G . Genetic variants of complement genes ficolin-2, mannose-binding lectin and complement factor H are associated with leprosy in Han Chinese from Southwest China. Hum Genet 2013; 132: 629–640.
Zhang D-F, Wang D, Li Y-Y, Yao Y-G . Mapping genetic variants in the CFH gene for association with leprosy in Han Chinese. Genes Immun 2014; 15: 506–510.
Gardet A, Benita Y, Li C, Sands BE, Ballester I, Stevens C et al. LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol 2010; 185: 5577–5585.
Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA . LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci 2006; 29: 286–293.
Paisán-RuĂz C, Jain S, Evans EW, Gilks WP, SimĂłn J, van der Brug M et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004; 44: 595–600.
Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004; 44: 601–607.
Recchia A, Debetto P, Negro A, Guidolin D, Skaper SD, Giusti P . Alpha-synuclein and Parkinson's disease. FASEB J 2004; 18: 617–626.
Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008; 40: 955–962.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G et al. Patterns of somatic mutation in human cancer genomes. Nature 2007; 446: 153–158.
Tong Y, Giaime E, Yamaguchi H, Ichimura T, Liu Y, Si H et al. Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol Neurodegener 2012; 7: 2.
Plowey ED, Cherra SJ 3rd, Liu YJ, Chu CT . Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 2008; 105: 1048–1056.
Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ . The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol 2011; 12: 1063–1070.
Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG, DeSilva TM et al. LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 2012; 32: 1602–1611.
Bi R, Zhao L, Zhang C, Lu W, Feng J-Q, Wang Y et al. No association of the LRRK2 genetic variants with Alzheimer's disease in Han Chinese individuals. Neurobiol Aging 2014; 35: 444. e5–e9.
Li X, Zhang W, Zhang C, Gong W, Tang J, Yi Z et al. No association between genetic variants of the LRRK2 gene and schizophrenia in Han Chinese. Neurosci Lett 2014; 566: 210–215.
Zhu JH, Horbinski C, Guo F, Watkins S, Uchiyama Y, Chu CT . Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Am J Pathol 2007; 170: 75–86.
Bravo-San Pedro JM, Niso-Sántano M, Gómez-Sánchez R, Pizarro-Estrella E, Aiastui-Pujana A, Gorostidi A et al. The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway. Cell Mol Life Sci 2013; 70: 121–136.
Marcinek P, Jha AN, Shinde V, Sundaramoorthy A, Rajkumar R, Suryadevara NC et al. LRRK2 and RIPK2 variants in the NOD 2-mediated signaling pathway are associated with susceptibility to Mycobacterium leprae in Indian populations. PLoS One 2013; 8: e73103.
Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB et al. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci USA 2005; 102: 18676–18681.
Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O et al. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 2009; 18: 4022–4034.
Saha S, Guillily MD, Ferree A, Lanceta J, Chan D, Ghosh J et al. LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci 2009; 29: 9210–9218.
Lewis PA, Manzoni C . LRRK2 and human disease: a complicated question or a question of complexes? Sci Signal 2012; 5: pe2.
Watson SR, Morrison NE, Collins FM . Delayed hypersensitivity responses in mice and guinea pigs to Mycobacterium leprae Mycobacterium vaccae, and Mycobacterium nonchromogenicum cytoplasmic proteins. Infect Immun 1979; 25: 229–236.
Wang HY, Liu JH, Ye SZ, Yu LC, Shi MQ, Sang HG . Preliminary observations on experimental leprosy in tupaias (Tupaia belangeri yunalis. Leprosy Rev 1990; 61: 12–18.
Wang D, Su L-Y, Zhang A-M, Li YY, Li XA, Chen LL et al. Mitochondrial DNA copy number, but not haplogroup, confers a genetic susceptibility to leprosy in Han Chinese from Southwest China. PLoS One 2012; 7: e38848.
Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 2013; 16: 394–406.
Manzoni C, Mamais A, Dihanich S, Abeti R, Soutar MP, Plun-Favreau H et al. Inhibition of LRRK2 kinase activity stimulates macroautophagy. Biochim Biophys Acta 2013; 1833: 2900–2910.
Zhu Y, Wang C, Yu M, Cui J, Liu L, Xu Z . ULK1 and JNK are involved in mitophagy incurred by LRRK2 G2019S expression. Protein Cell 2013; 4: 711–721.
Bandopadhyay R, de Belleroche J . Pathogenesis of Parkinson's disease: emerging role of molecular chaperones. Trends Mol Med 2010; 16: 27–36.
Wong AS, Lee RH, Cheung AY, Yeung PK, Chung SK, Cheung ZH et al. Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease. Nat Cell Biol 2011; 13: 568–579.
Jorgensen ND, Peng Y, Ho CC, Rideout HJ, Petrey D, Liu P et al. The WD40 domain is required for LRRK2 neurotoxicity. PLoS One 2009; 4: e8463.
Sheng D, Qu D, Kwok KH, Ng SS, Lim AY, Aw SS et al. Deletion of the WD40 domain of LRRK2 in Zebrafish causes Parkinsonism-like loss of neurons and locomotive defect. PLoS Genet 2010; 6: e1000914.
Li Y-Y, Li X-A, He L, Wang D, Chen WY, Chen L et al. Trends in new leprosy case detection over 57 years (1952-2008) in Yuxi, Yunnan Province of Southwest China. Leprosy Rev 2011; 82: 6–16.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.
Gauderman WJ . Sample size requirements for matched case-control studies of gene-environment interaction. Stat Med 2002; 21: 35–50.
Acknowledgements
We are grateful to all the participants in this study. We thank Mr Jia-Qi Feng and Dr Yue-Mei Feng for technical assistance. This study was supported by the National Natural Science Foundation of China (31271346 and 30925021) and the Ministry of Science and Technology of China (2011CB910902). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Wang, D., Xu, L., Lv, L. et al. Association of the LRRK2 genetic polymorphisms with leprosy in Han Chinese from Southwest China. Genes Immun 16, 112–119 (2015). https://doi.org/10.1038/gene.2014.72
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DOI: https://doi.org/10.1038/gene.2014.72
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