Sánchez-Maldonado Jose Manuel, Moñiz-Díez Ana, Ter Horst Rob, Campa Daniele, Cabrera-Serrano Antonio José, Martínez-Bueno Manuel, Garrido-Collado María Del Pilar, Hernández-Mohedo Francisca, Fernández-Puerta Laura, López-Nevot Miguel Ángel, Cunha Cristina, González-Sierra Pedro Antonio, Springer Jan, Lackner Michaela, Alcazar-Fuoli Laura, Fianchi Luana, Aguado José María, Pagano Livio, López-Fernández Elisa, Clavero Esther, Potenza Leonardo, Luppi Mario, Moratalla Lucia, Solano Carlos, Sampedro Antonio, Cuenca-Estrella Manuel, Lass-Flörl Cornelia, Canzian Federico, Loeffler Juergen, Li Yang, Einsele Hermann, Netea Mihai G, Vázquez Lourdes, Carvalho Agostinho, Jurado Manuel, Sainz Juan
Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain.
Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain.
J Fungi (Basel). 2020 Dec 23;7(1):4. doi: 10.3390/jof7010004.
Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the and loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the genotype had a significantly increased risk of developing IA ( = 0.00022). We also found that carriers of the allele showed decreased serum levels of TNFSF14 protein ( = 0.0027), and that their macrophages had a decreased fungicidal activity ( = 0.048). In addition, we observed that each copy of the allele increased the risk of IA by 60% ( = 0.0017), whereas each copy of the allele was estimated to decrease the risk of developing the disease ( = 0.0029). Mechanistically, we found that carriers of the risk allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood ( = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin ( = 0.00097). Finally, we also found that carriers of the protective allele had decreased numbers of CD27-IgM-IgD- B cells ( = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells ( = 0.00018 and 0.00023). Altogether, these results suggest a role of the genes in determining IA risk.
在此，我们评估了[相关基因]位点内的36个单核苷酸多态性（SNP）是否会影响侵袭性曲霉病（IA）的发病风险。我们进行了一项两阶段病例对照研究，纳入了911例通过aspBIOmics联盟确诊的血液系统恶性肿瘤高危患者。对发现队列和验证队列的荟萃分析显示，[特定基因型]的携带者发生IA的风险显著增加（P = 0.00022）。我们还发现，[特定等位基因]的携带者血清TNFSF14蛋白水平降低（P = 0.0027），且其巨噬细胞的杀真菌活性降低（P = 0.048）。此外，我们观察到[特定等位基因]的每个拷贝会使IA风险增加60%（P = 0.0017），而[另一个特定等位基因]的每个拷贝估计会降低患该病的风险（P = 0.0029）。从机制上讲，我们发现携带风险[等位基因]的携带者血液中CD38 + IgM - IgD - 浆母细胞数量增加（P = 0.00086），而携带该等位基因两个拷贝的携带者胸腺基质淋巴细胞生成素的血清浓度降低（P = 0.00097）。最后，我们还发现携带保护性[等位基因]的携带者CD27 - IgM - IgD - B细胞数量减少（P = 0.00087），CD14 + 和CD14 + CD16 - 细胞数量显著减少（P分别为0.00018和0.00023）。总之，这些结果表明[相关基因]在决定IA风险中发挥作用。
