Human Genetics

, Volume 132, Issue 1, pp 107–116

Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy

Authors

  • Andrea Alter
    • McGill Centre for the Study of Host ResistanceResearch Institute of the McGill University Health Centre
    • Departments of Medicine and Human GeneticsMcGill University
  • Vinicius Medeiros Fava
    • McGill Centre for the Study of Host ResistanceResearch Institute of the McGill University Health Centre
    • Departments of Medicine and Human GeneticsMcGill University
  • Nguyen Thu Huong
    • Hospital for Dermato-Venereology
  • Meenakshi Singh
    • Department of Transplant Immunology and ImmunogeneticsAll India Institute of Medical Sciences
  • Marianna Orlova
    • McGill Centre for the Study of Host ResistanceResearch Institute of the McGill University Health Centre
    • Departments of Medicine and Human GeneticsMcGill University
  • Nguyen Van Thuc
    • Hospital for Dermato-Venereology
  • Kiran Katoch
    • Central JALMA Institute of Leprosy and Other Infectious Diseases
  • Vu Hong Thai
    • Hospital for Dermato-Venereology
  • Nguyen Ngoc Ba
    • Hospital for Dermato-Venereology
  • Laurent Abel
    • Laboratory of Human Genetics of Infectious Diseases, Necker BranchInstitut National de la Santé et de la Recherche Médicale
    • University Paris DescartesSorbonne Paris Cité, Necker Medical School
    • Saint Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchThe Rockefeller University
  • Narinder Mehra
    • Department of Transplant Immunology and ImmunogeneticsAll India Institute of Medical Sciences
  • Alexandre Alcaïs
    • Laboratory of Human Genetics of Infectious Diseases, Necker BranchInstitut National de la Santé et de la Recherche Médicale
    • University Paris DescartesSorbonne Paris Cité, Necker Medical School
    • Saint Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchThe Rockefeller University
    • CIC-0901, Cochin-Necker
    • Unité de Recherche Clinique, AP-HP, Hôpital Tarnier
    • McGill Centre for the Study of Host ResistanceResearch Institute of the McGill University Health Centre
    • Departments of Medicine and Human GeneticsMcGill University
    • Montreal General Hospital Research Institute
Original Investigation

DOI: 10.1007/s00439-012-1227-6

Cite this article as:
Alter, A., Fava, V.M., Huong, N.T. et al. Hum Genet (2013) 132: 107. doi:10.1007/s00439-012-1227-6

Abstract

One of the persistent challenges of genetic association studies is the replication of genetic marker-disease associations across ethnic groups. Here, we conducted high-density association mapping of PARK2/PACRG SNPs with leprosy and identified 69 SNPs significantly associated with leprosy in 198 single-case Vietnamese leprosy families. A total of 56 associated SNPs localized to the overlapping promoter regions of PARK2/PACRG. For this region, multivariate analysis identified four SNPs belonging to two major SNP bins (rs1333955, rs7744433) and two single SNP bins (rs2023004, rs6936895) that capture the combined statistical evidence (P = 1.1 × 10−5) for association among Vietnamese patients. Next, we enrolled a case–control sample of 364 leprosy cases and 370 controls from Northern India. We genotyped all subjects for 149 SNPs that capture >80 % of the genetic variation in the Vietnamese sample and found 24 SNPs significantly associated with leprosy. Multivariate analysis identified three SNPs (rs1333955, rs9356058 and rs2023004) that capture the association with leprosy (P < 10−8). Hence, two SNPs (rs1333955 and rs2023004) were replicated by multivariate analysis between both ethnic groups. Marked differences in the linkage disequilibrium pattern explained some of the differences in univariate analysis between the two ethnic groups. In addition, the strength of association for two promoter region SNP bins was significantly stronger among young leprosy patients in the Vietnamese sample. The same trend was observed in the Indian sample, but due to the higher age-at-diagnosis of the patients the age effect was less pronounced.

Supplementary material

439_2012_1227_MOESM1_ESM.pdf (102 kb)
Supplementary material 1 (PDF 102 kb)
439_2012_1227_MOESM2_ESM.pdf (80 kb)
Supplementary material 2 (PDF 79 kb)

Copyright information

© Springer-Verlag 2012