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Genetic analysis of multicase families of visceral leishmaniasis in northeastern Brazil: no major role for class II or class III regions of HLA

Genes & Immunity volume 3, pages 350–358 (2002)Cite this article

Abstract

Familial aggregation, high relative risk to siblings, and segregation analysis, suggest genetic control of visceral leishmaniasis in Brazil. Class II gene effects in mice, and high circulating tumour necrosis factor α in humans, provide reasons to target HLA. Fifteen polymorphic markers across 1.03 Mb (DQB1 to TNFa) were genotyped (87 multicase families; 638 individuals). Model-based parametric analyses using single-point combined segregation and linkage in COMDS, or multi-point linkage in ALLEGRO, failed to detect linkage. Model-free nonparametric affected sibling pair (SPLINK) or NPLall score (ALLEGRO) analyses also failed to detect linkage. Information content mapping confirmed sufficient marker information to detect linkage. Analysis of simulated data sets demonstrated that these families had 100% power to detect NPLall scores of 5 to 6 (>LOD4; P < 0.00001) over the range (7% to 61%) of age-related penetrances for a disease susceptibility gene. The extended transmission disequilibrium test (TDT) showed no consistent allelic associations between disease and the 15 loci. TDT also failed to detect significant associations between extended haplotypes and disease, consistent with failure to detect significant linkage disequilibrium across the region. Linkage disequilibrium between adjacent groups of markers (HLADQ/DR; 82–1/82–3/-238bpTNFA; LTA/62/TNFa) was not accompanied by significant global haplotype TDT associations with disease. The data suggest that class II/III regions of HLA do not contain major disease gene(s) for visceral leishmaniasis in Brazil.

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Authors and Affiliations

  1. Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2XY, UK

    C S Peacock & J M Blackwell

  2. Department of Molecular Medicine, Karolinska Hospital, CMM L8:03, Stockholm, S171 76, Sweden

    C B Sanjeevi

  3. School of Biology, University of Leeds, Leeds, LS2 9JT, UK

    M-A Shaw

  4. Human Genetics, Duthie Building (808), Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK

    A Collins

  5. MRC HGMP Resource Centre, Hinxton, CB10 1SA, Cambridge, UK

    R D Campbell

  6. Research & Development Genetics Department, Zeneca Pharmaceuticals, Alderly Park, Macclesfield, Cheshire, SK10 4TG, UK

    R March

  7. Instituto Evandro Chagas, Caixa Postal 3, Belem, 66.001, Brazil

    F Silveira & J J Shaw

  8. Departamento de Patologica, Universidade de Federal do Maranho, São Luis, Maranhão, Brazil

    J Costa & M D Nascimento

  9. Departamento de Parasitologia, Universidade de Piaui, Terasina, Piaui, Brazil

    C H Coste

  10. London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

    R Siddiqui

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  1. C S Peacock
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Correspondence to J M Blackwell.

Additional information

This work was supported by grants from The Wellcome Trust, Heather Cordell (CIMR) provided valuable advice on power calculations for linkage. We would also like to thank the people of northeastern Brazil for their hospitality and for their contribution to this study.

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Peacock, C., Sanjeevi, C., Shaw, MA. et al. Genetic analysis of multicase families of visceral leishmaniasis in northeastern Brazil: no major role for class II or class III regions of HLA. Genes Immun 3, 350–358 (2002). https://doi.org/10.1038/sj.gene.6363852

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