A Major Susceptibility Locus on Chromosome 22q12 Plays a Critical Role in the Control of Kala-Azar

Abstract

Kala-azar (KA) is a life-threatening protozoal disease caused by Leishmania parasites (L. donovani, L. chagasi, and L. infantum). The disease, which is also called "visceral leishmaniasis," is prevalent in Africa, South America, Asia, and the Mediterranean basin. Epidemics occur periodically, killing a large number of infected individuals. Factors determining whether a patient remains asymptomatic or develops KA are still largely unknown. In a previous study that was performed during an outbreak of KA in a village on the Ethiopian-Sudanese border, we showed that KA was more frequent in certain families and ethnic groups, thereby suggesting that host genetic factors play an important role in the development of the disease. Here, we report the results of a genomewide linkage study performed on 63 Sudanese families selected from the most affected ethnic group and including 169 children with KA. Significant linkage (LOD score 3.50 [P=3x10-5] in all patients; LOD score 3.90 [P=10-5] in patients who were affected early in the outbreak) was obtained with markers on chromosome 22q12. These results are the first evidence of a major genetic effect on the development of human KA. They may lead to identification of genes critical in the pathogenesis of this disease and to new therapeutic interventions against this parasite, which is developing resistance to available drugs.

Human genetic basis of interindividual variability in the course of infection

“…It taught us more about the impact of infections on the genome of human populations than about the genetic determinism of infectious diseases. In this regard, the work of my colleague Laurent Abel and his collaborators, first detecting major genes by segregation studies (142)(143)(144)(145)(146) and then mapping these genes for conditions such as schistosomiasis, leishmaniasis, leprosy, and tuberculosis, has bridged the gap between population-based and patient-based studies of infectious diseases (147)(148)(149)(150)(151)(152)(153)(154). Interestingly, the effect of most major genes decreases with age.…”

Identification of a novel G245R polymorphism in the IL-2 receptor β membrane proximal domain associated with human visceral leishmaniasis

“…13 Noteworthy, this suppression can be reversed in vitro, both in mice 14 and human, 15 by the addition of IL-2, thus suggesting that the T-cell anergic state is in part mediated by a defect in IL-2/IL-2R signalling. 16 Interestingly, the IL2RB gene coding the IL2Rb-chain is located on chromosome 22q12 in a region for which we found a highly significant genetic linkage by a genome-wide linkage study of VL susceptibility in multicase families of Eastern Sudan 17 affected by a severe outbreak of VL (1996)(1997)(1998)(1999)(2000). 18,19 This prompts us to investigate whether genetic polymorphisms of the IL2RB gene were associated with resistance/susceptibility to VL in this population.…”

“…17 All non-synonymous variants were included in this analysis as well as four non-coding SNPs for which the minor allele was at least observed on three of the 14 sequenced chromosomes. All SNPs were in Hardy-Weinberg equilibrium in our population.…”

“…The family set used for this study has been described elsewhere. 17 It was composed of 59 nuclear families comprising 2-5 affected sibs and parents. Primer sequences and genotyping conditions for the SNPs are available upon request.…”

Major histocompatibility complex and its importance towards controlling infection

“…[21][22][23][24][25][26][27] Other linkage studies to identify genes causing rare, monogenic susceptibility phenotypes have been reported, though the causative variation identified are rare mutations rather than polymorphisms and the identified genes rarely, if ever, relevant to common variation in susceptibility. 28,29 Thus, it is an area of intense interest that has been mainly focused on susceptibility to malaria, human immunodeficiency virus (HIV)/acquired immunodeficiency disease syndrome (AIDS) and mycobacterial infection; but other bacterial, viral and parasitic diseases are receiving increasing attention.…”