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

C.S. Peacock, C.B. Sanjeevi, M.A. Shaw, A. Collins, R.D. Campbell, R. March, F. Silveira, J. Costa, C.H. Coste, M.D. Nascimento, R. Siddiqui, J.J. Shaw, Jenefer Blackwell

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23 Citations (Scopus)

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 a 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 ALLEGPO, failed to detect linkage. Model-free nonparametric affected sibling pair (SPLINK) or NPLall score (ALLEGPO) 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.
Original languageEnglish
Pages (from-to)350-358
JournalGenes and Immunity
Volume3
Issue number6
DOIs
Publication statusPublished - 2002

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