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.
Peacock
C S
CS
Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, University of Cambridge Clinical School, Addenbrooke's Hospital, Cambridge, United Kingdom.
Collins
A
A
Shaw
M A
MA
Silveira
F
F
Costa
J
J
Coste
C H
CH
Nascimento
M D
MD
Siddiqui
R
R
Shaw
J J
JJ
Blackwell
J M
JM
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