EVIDENCE FOR A MAJOR GENE CONTROLLING SUSCEPTIBILITY TO TEGUMENTARY LEISHMANIASIS IN A RECENTLY EXPOSED BOLIVIAN POPULATION

Tegumentary leishmaniasis due to Leishmania braziliensis is a parasiti c disease that occurs in two stages after the infected sandfly bite: ( 1) a primary cutaneous lesion followed by (2) a secondary mucosal invo lvement generally resulting in severe facial deformities. In order to investigate the genetic and environmental factors involved in the deve lopment of the cutaneous lesion, a familial study was performed in a r egion of Bolivia in which the disease is endemic. Complete selection o f 118 nuclear families (703 subjects, with 241 patients), each with at least one cutaneous affected subject, was achieved; 41 families were of native origin, and 77 (herein designated ''migrant'') recently had settled in the area. For the analysis, the trait under study was the t ime to onset of the primary cutaneous lesion. The start of the follow- up was birth, for native population, or date of arrival in the endemic area, for migrant population. Segregation analysis was performed by u se of a model based on survival analysis methods that allows joint est imation of genetic and environmental effects and accounts for gene x c ovariate interactions. A significant effect of gender, home-forest dis tance, and forest-related activity was found. in the 77 migrant famili es there was evidence for a recessive major gene controlling the onset of the primary cutaneous lesion, with residual familial dependences a nd age x genotype interaction. Penetrance estimations show that young subjects are genetically more susceptible than older subjects, suggest ing that this genetic component could concern mechanisms involved in t he development of individual protection during childhood. There was al so a significant genetic heterogeneity of the sample according to the native/migrant origin of the families, and no major-gene effect was fo und in the native subsample.