Genetic analysis of multicase families of visceral leishmaniasis in northeastern Brazil: no major role for class II or class III regions of HLA
Peacock, C.S., Sanjeevi, C.B., Shaw, M.-A., Collins, A., Campbell, R.D., March, R., Silveira, F., Costa, J., Coste, C.H., Nascimento, M.D., Siddiqui, R., Shaw, J.J. and Blackwell, J.M. (2002) Genetic analysis of multicase families of visceral leishmaniasis in northeastern Brazil: no major role for class II or class III regions of HLA. Genes and Immunity, 3, (6), 350-358. (doi:10.1038/sj.gene.6363852).
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Description/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 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.
| Item Type: | Article |
|---|---|
| ISSNs: | 1466-4879 (print) |
| Related URLs: | |
| Keywords: | role, brazil, linkage disequilibrium, risk, necrosis,visceral, animals, antigens, lod score, genetics,alpha, histocompatibility antigens class ii, non-u.s.gov't, humans, human, research, family, analysis, disease susceptibility, mice, immunology, haplotypes, genetic predisposition to disease, genetic markers, research support, disease, leishmania donovani, leishmaniasis |
| Subjects: | R Medicine > RB Pathology Q Science > QH Natural history > QH426 Genetics |
| Divisions: | University Structure - Pre August 2011 > School of Medicine > Human Genetics |
| Item ID: | 24899 |
| Date Deposited: | 06 Apr 2006 |
| Last Modified: | 01 Apr 2012 02:07 |
| Contributors: | Peacock, C.S. (Author) Sanjeevi, C.B. (Author) Shaw, M.-A. (Author) Collins, A. (Author) Campbell, R.D. (Author) March, R. (Author) Silveira, F. (Author) Costa, J. (Author) Coste, C.H. (Author) Nascimento, M.D. (Author) Siddiqui, R. (Author) Shaw, J.J. (Author) Blackwell, J.M. (Author) |
| Date: | 2002 |
| Status: | Published |
| URI: | http://eprints.soton.ac.uk/id/eprint/24899 |
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