Weirather Jason L, Duggal Priya, Nascimento Eliana L, Monteiro Gloria R, Martins Daniella R, Lacerda Henio G, Fakiola Michaela, Blackwell Jenefer M, Jeronimo Selma M B, Wilson Mary E
Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, USA.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Ann Hum Genet. 2017 Jan;81(1):41-48. doi: 10.1111/ahg.12180. Epub 2017 Jan 4.
Genetic risk factors contribute to asymptomatic versus symptomatic visceral leishmaniasis (VL) outcomes following infection with Leishmania infantum. We therefore carried out a family-based (n = 918 post-quality control fully genotyped and phenotyped individuals) candidate gene study for symptomatic VL or asymptomatic delayed-type hypersensitivity (DTH) skin test phenotypes in highly endemic neighborhoods of northeast Brazil. A total of 248 SNPs were genotyped in 42 genes selected as candidates on the basis of prior genetic, immunological, and transcriptional profiling studies. The most significant association with the VL phenotype was with SNP rs6785358 (P = 5.7e-04; p = 0.026) 3.8 kb upstream of TGFBR2, the gene encoding the type 2 receptor for transforming growth factor beta (TGFβ). A second inhibitory member of the TGBβ superfamily signaling pathway, SMAD7, was associated with the DTH phenotype (SNP rs7238442: P = 0.001; p = 0.051). The most significant association for the DTH phenotype was with SNP rs10800309 (P = -8.4e-06; p = 3.9e-04) situated 3.1 kb upstream of FCGR2A, the gene encoding the low-affinity IIa receptor for the Fc fragment of IgG. Overall, our results imply a role for IgG-mediated inflammation in determining DTH associated with asymptomatic infection and contribute to growing evidence that the TGFβ pathway is important in the immunopathogenesis of VL.
遗传风险因素在婴儿利什曼原虫感染后导致无症状与有症状内脏利什曼病（VL）结局方面发挥作用。因此，我们在巴西东北部高度流行地区开展了一项基于家庭的（n = 918名经过质量控制且已完全进行基因分型和表型分型的个体）候选基因研究，以探究有症状VL或无症状迟发型超敏反应（DTH）皮肤试验表型。基于先前的遗传、免疫和转录谱研究，从42个基因中选择了候选基因，并对其中总共248个单核苷酸多态性（SNP）进行了基因分型。与VL表型最显著的关联是与位于转化生长因子β（TGFβ）2型受体（TGFBR2）编码基因上游3.8 kb处的SNP rs6785358（P = 5.7×10⁻⁴；p = 0.026）相关。TGBβ超家族信号通路的另一个抑制成员SMAD7与DTH表型相关（SNP rs7238442：P = 0.001；p = 0.051）。与DTH表型最显著的关联是与位于编码IgG Fc片段低亲和力IIa受体的基因（FCGR2A）上游3.1 kb处的SNP rs10800309（P = -8.4×10⁻⁶；p = 3.9×10⁻⁴）相关。总体而言，我们的结果表明IgG介导的炎症在决定与无症状感染相关的DTH中起作用，并进一步证明TGFβ通路在VL的免疫发病机制中很重要。
