■利什曼病继续在全球97个国家造成巨大的健康负担。利什曼原虫感染的进展和转归受多种因素影响,包括细胞因子环境,感染部位的皮肤微生物群,涉及的特定利什曼原虫物种,宿主的遗传背景,和寄生虫的负荷。在利什曼病的流行地区,只有一小部分受感染的人真正患上了这种疾病。IL-13在天然抗性C57BL/6小鼠中的过表达使得它们对L.主要感染易感。从沿着染色体片段的几个单核苷酸变体(SNV)构建的单倍型可以提供对可能与遗传关联研究中的表型真正相关的片段附近的任何SNV的了解。
■我们调查了9个SNV(SNV1rs1881457A>C,SNV2rs1295687C>G,SNV3rs2069744C>T,SNV4rs2069747C>T,SNV5rs20541A>G,SNV6rs1295685A>G,SNV7rs848A>C,SNV8rs2069750G>C,和SNV9rs847T>C)跨越古阳乳杆菌皮肤利什曼病(Lg-CL)患者的整个IL13基因。
■我们的分析未揭示SNV与Lg-CL发展的易感性/保护之间的任何显著关联。然而,单倍型分析,由于次要等位基因频率低,不包括SNV4rs2069747和SNV8rs2069750,显示单倍型CCCTAAC的携带者发生Lg-CL的可能性降低了93%。同样,单倍型ACCCGCT(ORadj=0.02[95%CI0.00-0.07];p值,6.0×10-19)和AGCTAAC(ORadj=0.00[95%CI0.00-0.00];p值2.7×10-12)似乎可以防止Lg-CL的发展。相反,单倍型ACCTGCC携带者发展Lg-CL的可能性增加190%(ORadj=2.9[95CI1.68-5.2];p值,2.5×10-6)。同样,单倍型ACCCAAT(ORadj=2.7[95CI1.5-4.7];p值,3.2×10-5)和单倍型AGCCGCC与Lg-CL发展的易感性相关(ORadj=1.7[95CI1.04-2.8];p值,0.01).在我们的调查中,我们还发现Lg-Cl患者rs2069744,rs20541,rs1295685,rs847和rs848基因型与血浆IL-5水平之间存在相关性.此外,rs20541与Lg-Cl患者血浆IL-13水平相关,rs2069744和rs848与同一组血浆IL-4水平相关。
■总的来说,我们的研究确定了与疾病发展抗性相关的三种IL13单倍型和与易感性相关的三种单倍型.这些发现表明,基因区域之外的变异可能有助于,与其他基因结合,易感性差异和部分病理学差异。
Leishmaniasis continues to pose a substantial health burden in 97 countries worldwide. The progression and outcome of Leishmania infection are influenced by various factors, including the cytokine milieu, the skin microbiota at the infection site, the specific Leishmania species involved, the genetic background of the host, and the parasite load. In endemic regions to leishmaniasis, only a fraction of individuals infected actually develops the disease. Overexpression of IL-13 in naturally resistant C57BL/6 mice renders them susceptible to L. major infection. Haplotypes constructed from several single nucleotide variant (SNV) along a chromosome fragment may provide insight into any SNV near the fragment that may be genuinely associated with a phenotype in genetic association studies.
We investigated nine SNVs (SNV1rs1881457A>C, SNV2rs1295687C>G, SNV3rs2069744C>T, SNV4rs2069747C>T, SNV5rs20541A>G, SNV6rs1295685A>G, SNV7rs848A>C, SNV8rs2069750G >C, and SNV9rs847T>C) spanning the entire IL13 gene in patients with L. guyanensis cutaneous leishmaniasis (Lg-CL).
Our analysis did not reveal any significant association between the SNVs and susceptibility/protection against Lg-CL development. However, haplotype analysis, excluding SNV4rs2069747 and SNV8rs2069750 due to low minor allele frequency, revealed that carriers of the haplotype CCCTAAC had a 93% reduced likelihood developing Lg-CL. Similarly, the haplotypes ACCCGCT (ORadj=0.02 [95% CI 0.00-0.07]; p-value, 6.0×10-19) and AGCTAAC (ORadj=0.00[95% CI 0.00-0.00]; p-value 2.7×10-12) appeared to provide protection against the development of Lg-CL. Conversely, carriers of haplotype ACCTGCC have 190% increased likelihood of developing Lg-CL (ORadj=2.9 [95%CI 1.68-5.2]; p-value, 2.5×10-6). Similarly, haplotype ACCCAAT (ORadj=2.7 [95%CI 1.5-4.7]; p-value, 3.2×10-5) and haplotype AGCCGCC are associated with susceptibility to the development of Lg-CL (ORadj=1.7[95%CI 1.04-2.8]; p-value, 0.01). In our investigation, we also found a correlation between the genotypes of rs2069744, rs20541, rs1295685, rs847, and rs848 and plasma IL-5 levels among Lg-Cl patients. Furthermore, rs20541 showed a correlation with plasma IL-13 levels among Lg-Cl patients, while rs2069744 and rs848 showed a correlation with plasma IL-4 levels among the same group.
Overall, our study identifies three haplotypes of IL13 associated with resistance to disease development and three haplotypes linked to susceptibility. These findings suggest the possibility of a variant outside the gene region that may contribute, in conjunction with other genes, to differences in susceptibility and partially to the pathology.