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Stepwise replication identifies a low-producing lymphotoxin-α allele as a major risk factor for early-onset leprosy

Nature Genetics volume 39, pages 517–522 (2007)Cite this article

Abstract

Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning1,2. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan1, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-α (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.

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Figure 1: High-density SNP association scan of a 10.4-Mb region on chromosome 6p21 in 194 Vietnamese trios.
Figure 2: Fine linkage disequilibrium mapping of a 90-kb interval in the HLA class III region in 194 Vietnamese trios.
Figure 3: Age-dependence of the LTA+80 A allele effect on leprosy susceptibility.

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Acknowledgements

We thank all affected individuals, their families and population controls for participating in this study. We thank T.J. Hudson, P. Lepage, E.N. Sarno and J.L. Casanova for helpful comments and discussions; A. Montpetit and A. Belisle for assistance with high-throughput genotyping; S. Caillat-Zucman for help in HLA genotyping and L. Simkin for technical assistance. This study was supported by a grant from the Canadian Institutes of Health Research (CIHR) to E.S. A. Alter holds a graduate studentship from the Natural Science and Engineering Research Council of Canada (NSERC). A. Alter and M.O. are supported by the CIHR Strategic Training Centre in the Integrative Biology of Infectious Diseases and Autoimmunity. G.A. is supported by Fondation pour la Recherche Médicale. E.S. is a Chercheur National of the Fonds de Recherche en Santé du Québec and an International Research Scholar of the Howard Hughes Medical Institute. A. Alcaïs and L.A. are supported by the Assistance Publique-Hopitaux de Paris, Programme de Recherche Fondamentale en Microbiologie Maladies Infectieuses et Parasitaires and the Agence Nationale de la Recherche of the Ministère Français de l'Education Nationale de la Recherche et de la Technologie. Requests for materials should be addressed to L.A. (abel@necker.fr) or E.S. (erwin.schurr@mcgill.ca).

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Author notes

  1. Alexandre Alcaïs, Andrea Alter and Guillemette Antoni: These authors contributed equally to this work and are listed in alphabetical order.

Authors and Affiliations

  1. Laboratoire de Génétique Humaine des Maladies Infectieuses, Institut National de la Santé et de la Recherche Médicale, U550, Paris, 75015, France

    Alexandre Alcaïs, Guillemette Antoni & Laurent Abel

  2. Université Paris René Descartes, Faculté Médecine Necker, Paris, 75015, France

    Alexandre Alcaïs & Laurent Abel

  3. McGill Centre for the Study of Host Resistance and Departments of Human Genetics, Medicine and Biochemistry, McGill University, 1650 Cedar Avenue, Montreal, H3G1A4, Quebec, Canada

    Andrea Alter, Marianna Orlova & Erwin Schurr

  4. Hospital for Dermato-Venereology, Nguyen Thong Street, District 3, Ho Chi Minh City, Vietnam

    Nguyen Van Thuc, Vu Hong Thai, Ngyuen Thu Huong & Nguyen Ngoc Ba

  5. Department of Transplant Immunology and Immunogenetics, All-India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Meenakshi Singh & Narinder Mehra

  6. Tropical Medicine Department, Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, CEP 21040-900, Brazil

    Patrícia R Vanderborght & Milton Moraes

  7. Central JALMA Institute of Leprosy and Other Infectious Diseases, Taj Ganj, Agra, 282001, India

    Kiran Katoch

  8. Centro de Ciências Biológicas e da Saúde, Pontifícia Universidade Católica do Paraná, Rua Imaculada Conceição, 1155, Curitiba, CEP 80215-901, Paraná, Brasil

    Marcelo T Mira

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  1. Alexandre Alcaïs
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Contributions

Genotyping and SNP selection were performed by A. Alter, G.A., M.O., M.S. P.R.V. and M.T.M. Statistical analysis was performed by A. Alcais, A. Alter and G.A. Clinical analyses and phenotype assessment were performed by N.V.T., K.K., V.H.T., N.T.H., N.N.B. and M.M. A. Alcais, M.M., N.M., E.S. and L.A. designed the study. A. Alcais, A. Alter, E.S. and L.A. wrote the paper. E.S. and L.A. share senior authorship of this work.

Corresponding authors

Correspondence to Erwin Schurr or Laurent Abel.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Characterization of 418 SNPs used in the primary scan of 10.4-Mb interval on human chromosome region 6p21 in 388 unrelated Vietnamese individuals. (PDF 185 kb)

Supplementary Table 2

Family-based association scan of the 10.4-Mb region on chromosome 6p21 in 194 Vietnamese trios. (PDF 200 kb)

Supplementary Table 3

rs2071590, rs3128961, rs937662 and rs707928 are associated with leprosy independently of the two PARK2/PACRG SNPs. (PDF 13 kb)

Supplementary Table 4

Bin structure of 33 informative SNPs spanning the 90-kb target interval in the HLA class III region, analyzed in the Vietnamese sample. (PDF 30 kb)

Supplementary Table 5

Characterization of 31 SNPs used in the linkage disequilibrium mapping of a 0.82-MB interval covering the whole HLA class III region in 54 unrelated Vietnamese individuals. (PDF 26 kb)

Supplementary Table 6

Characterization of HLA class I alleles in 37 unrelated Vietnamese individuals. (PDF 15 kb)

Supplementary Table 7

Multivariate analysis in the Indian sample. (PDF 14 kb)

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Alcaïs, A., Alter, A., Antoni, G. et al. Stepwise replication identifies a low-producing lymphotoxin-α allele as a major risk factor for early-onset leprosy. Nat Genet 39, 517–522 (2007). https://doi.org/10.1038/ng2000

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