Karplus Theresa M, Jeronimo Selma M B, Chang Haeok, Helms Bethany K, Burns Trudy L, Murray Jeffrey C, Mitchell Adele A, Pugh Elizabeth W, Braz Regina F S, Bezerra Fabiana L, Wilson Mary E
Department of Internal Medicine, University of Iowa, Iowa City 52242, USA.
Infect Immun. 2002 Dec;70(12):6919-25. doi: 10.1128/IAI.70.12.6919-6925.2002.
A periurban outbreak of visceral leishmaniasis (VL) caused by the protozoan Leishmania chagasi is ongoing outside Natal, northeast Brazil. Manifestations range from asymptomatic infection to disseminated visceral disease. Literature reports suggest that both genetic and environmental factors influence the outcome of infection. Due to the association of the tumor necrosis factor (TNF) locus with other infectious diseases, we examined whether polymorphic alleles at this locus are associated with the outcome of L. chagasi infection. Neighborhoods with ongoing transmission were identified through patients admitted to local hospitals. Altogether, 1,024 individuals from 183 families were classified with the following disease phenotypes: (i) symptomatic VL, (ii) asymptomatic infection (positive delayed-type hypersensitivity [DTH+]), or (iii) no evidence of infection (DTH-). Genotypes were determined at a microsatellite marker (MSM) upstream of the TNFB gene encoding TNF-beta and at a restriction fragment length polymorphism (RFLP) at position -307 in the promoter of the TNFA gene encoding TNF-alpha. Analyses showed that the distribution of TNFA RFLP alleles (TNF1 and TNF2) and the TNF MSM alleles (TNFa1 to TNFa15) differed between individuals with VL and those with DTH+ phenotypes. TNF1 was transmitted more frequently than expected from heterozygous parents to DTH+ offspring (P = 0.0006), and haplotypes containing TNF2 were associated with symptomatic VL (P = 0.0265, transmission disequilibrium test). Resting serum TNF-alpha levels were higher in TNF1/2 heterozygotes than in TNF1/1 homozygotes (P < 0.05). These data led us to hypothesize that an individual's genotype at the TNF locus may be associated with whether he or she develops asymptomatic or symptomatic disease after L. chagasi infection. The results preliminarily suggest that this may be the case, and follow-up with larger populations is needed for verification.
巴西东北部纳塔尔市郊外正在发生由恰加斯利什曼原虫引起的城市周边内脏利什曼病（VL）疫情。其表现从无症状感染到播散性内脏疾病不等。文献报道表明，遗传因素和环境因素都会影响感染的结果。由于肿瘤坏死因子（TNF）基因座与其他传染病有关联，我们研究了该基因座的多态性等位基因是否与恰加斯利什曼原虫感染的结果相关。通过当地医院收治的患者确定正在发生传播的社区。总共对来自183个家庭的1024人进行了如下疾病表型分类：（i）有症状的VL，（ii）无症状感染（迟发型超敏反应阳性[DTH+]），或（iii）无感染证据（DTH-）。在编码TNF-β的TNFB基因上游的微卫星标记（MSM）以及编码TNF-α的TNFA基因启动子中-307位的限制性片段长度多态性（RFLP）处确定基因型。分析表明，VL患者和DTH+表型患者之间TNFA RFLP等位基因（TNF1和TNF2）以及TNF MSM等位基因（TNFa1至TNFa15）的分布存在差异。TNF1从杂合子父母向DTH+后代的传递频率高于预期（P = 0.0006），并且含有TNF2的单倍型与有症状的VL相关（P = 0.0265，传递不平衡检验）。TNF1/2杂合子的静息血清TNF-α水平高于TNF1/1纯合子（P < 0.05）。这些数据使我们推测，个体在TNF基因座的基因型可能与恰加斯利什曼原虫感染后是否发展为无症状或有症状疾病有关。结果初步表明可能是这种情况，需要对更多人群进行随访以进行验证。
