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Susceptibility to leprosy is associated with PARK2 and PACRG

Abstract

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year1. It has long been thought that leprosy has a strong genetic component2, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25–q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5′ regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.

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Figure 1: High-density SNP analysis.
Figure 2: Expression of PARK2 and PACRG.

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Acknowledgements

We thank all patients, their families and population controls that participated in this study; J. L. Casanova for support, suggestions and critical reading of the manuscript; T. H. M. Ottenhoff for his help and support in the Schwann cell work; and A. Sammak, C. Darmond-Zwaig, Y. Renaud, M. Girard, N. Martin, A. Villeneuve, D. Frappier and A. Verville for technical assistance. This study was supported by a grant from the Canadian Institutes of Health Research to E.S. The genotyping core at the McGill University and Genome Québec Innovation Centre is supported by the Canadian Genetic Diseases Network and Genome Québec, and the Schwann cell work in Leiden is supported by the Netherlands Leprosy Foundation. M.T.M. is supported by a graduate fellowship of the Brazilian Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES). A.A. and L.A. are supported in part by grants from Fondation Banque Nationale de Paris–Paribas, Fondation pour la Recherche Médicale and Fondation Schlumberger. T.J.H. and E.S. are Canadian Institutes of Health Research Investigators.Authors' contributions L.A. and E.S. share senior authorship.

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Correspondence to Laurent Abel or Erwin Schurr.

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The authors declare that they have no competing financial interests.

Supplementary information

41586_2004_BFnature02326_MOESM1_ESM.xls

Supplementary Web Table 1: This file lists all oligonucleotides used for genotyping. Indicated are the method of genotyping, the lab name of the oligonucleotide, the nucleotide sequence, the type of nucleotide change, and the minor allele frequency observed among the Vietnamese families. ni: MAF < 5%, failed: genotyping assay did not produce reliable results. (XLS 106 kb)

41586_2004_BFnature02326_MOESM2_ESM.xls

Supplementary Web Table 2: This file lists all SNPs discovered by comparative sequencing of the 80 kb LD block in 12 unrelated individuals. Indicated are the SNP ID, the chromosome 6 position of a specific SNP on the July 2003 map, and the corresponding genotypes for each of the 12 individuals. (XLS 57 kb)

Supplementary Methods: This file gives more detail about the laboratory and analytical methods employed. (DOC 40 kb)

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Mira, M., Alcaïs, A., Van Thuc, N. et al. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427, 636–640 (2004). https://doi.org/10.1038/nature02326

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