Genetic epidemiology of visceral leishmaniasis in northeastern Brazil.
Familial clustering of disease, racial differences in asymptomatic:disease ratios, and studies of mice all point to a genetic component for disease susceptibility in visceral leishmaniasis. Analysis of 87 multi-case pedigrees (824 individuals; 138 nuclear families) from a region of northeastern Brazil endemic for Leishmania chagasi demonstrates a high relative risk ratio (lambda(2S) = 34) to further siblings of affected sibling pairs. Complex segregation analysis using POINTER and COMDS show that all single locus models, as well as polygenic and multifactorial models, provide a significantly (P < 0.001) better fit to the data than a sporadic model. Of the genetic models, the general single locus model was not significantly different from additive or dominant single locus models, all of which gave a gene frequency for the putative disease susceptibility allele of approximately 0.002. The general single locus model was strongly favored (P < 0.001) over a recessive single gene model. Using POINTER, polygenic and multifactorial models were clearly rejected (P < 0.001 in all cases) in favor of the general single locus model. Using COMDS, the analysis was extended to consider two locus models. Results under a general two-locus model did not differ significantly from the dominant, additive, or general single locus models. Under this model, one locus was estimated at a gene frequency of 0.0017, i.e., in the same range as the disease susceptibility locus for the most favored single gene models, with the second locus at a much lower frequency of 0.0002. Hence, the data support the hypothesis that a single major gene may be important in determining disease susceptibility in this population. To identify the gene(s) involved, a genome scan with replication using two subsets of these larger pedigrees with power to detect linkage is in progress.
Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, University of Cambridge Clinical School, Addenbrooke's Hospital, Cambridge, United Kingdom.
C S
CS
Peacock
A
A
Collins
M A
MA
Shaw
F
F
Silveira
J
J
Costa
C H
CH
Coste
M D
MD
Nascimento
R
R
Siddiqui
J J
JJ
Shaw
J M
JM
Blackwell
D000293:Adolescent; D000328:Adult; D001938:Brazil / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D003627:Data Interpretation, Statistical; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007898:Leishmaniasis, Visceral / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D010375:Pedigree