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 su sceptibility in visceral leishmaniasis. Analysis of 87 multi-case pedigrees (824 individuals; 138 nuclear families) from a region of northeastern Braz il endemic for Leishmania chagasi demonstrates a high relative risk ratio ( lambda (2S) = 34) to further siblings of affected sibling pairs. Complex se gregation analysis using POINTER and COMDS show that all single locus model s, 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 mo dels, the general single locus model was not significantly different from a dditive or dominant single locus models, all of which gave a gene frequency for the putative disease susceptibility allele of <similar to>0.002. The g eneral 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 l ocus model. Using COMDS, the analysis was extended to consider two locus mo dels. Results under a general two-locus model did not differ significantly from the dominant, additive, or general single locus models. Under this mod el, one locus was estimated at a gene frequency of 0.0017, i.e., in the sam e range as the disease susceptibility locus for the most favored single gen e 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 g ene(s) involved, a genome scan with replication using two subsets of these larger pedigrees with power to detect linkage is in progress. (C) 2001 Wile y-Liss, Inc.