Maestri Alvino, Sortica Vinicius Albuquerque, Tovo-Rodrigues Luciana, Santos Mirleide Cordeiro, Barbagelata Luana, Moraes Milene Raiol, Alencar de Mello Wyller, Gusmão Leonor, Sousa Rita Catarina Medeiros, Emanuel Batista Dos Santos Sidney
Laboratory of Human and Medical Genetics, Federal University of Pará, Belém, Pará, Brazil.
Center of Cancer Studies, Federal University of Pará, Belém, Pará, Brazil.
PLoS One. 2015 Oct 5;10(10):e0139681. doi: 10.1371/journal.pone.0139681. eCollection 2015.
Different host genetic variants may be related to the virulence and transmissibility of pandemic Influenza A(H1N1)pdm09, influencing events such as binding of the virus to the entry receptor on the cell of infected individuals and the host immune response. In the present study, two genetic variants of the ST3GAL1 gene, which encodes the Siaα2-3Galβ1- receptor to which influenza A(H1N1)pdm09 virus binds for entry into the host cell, were investigated in an admixed Brazilian population. First, the six exons encoding the ST3GAL1 gene were sequenced in 68 patients infected with strain A(H1N1)pdm09. In a second phase of the study, the rs113350588 and rs1048479 polymorphisms identified in this sample were genotyped in a sample of 356 subjects from the northern and northeastern regions of Brazil with a diagnosis of pandemic influenza. Functional analysis of the polymorphisms was performed in silico and the influence of these variants on the severity of infection was evaluated. The results suggest that rs113350588 and rs1048479 may alter the function of ST3GAL1 either directly through splicing regulation alteration and/or indirectly through LD with SNP with regulatory function. In the study the rs113350588 and rs1048479 polymorphisms were in linkage disequilibrium in the population studied (D' = 0.65). The GC haplotype was associated with an increased risk of death in subjects with influenza (OR = 4.632, 95% CI = 2.10;1.21). The AT haplotype was associated with an increased risk of severe disease and death (OR = 1.993, 95% CI = 1.09;3.61 and OR 4.476, 95% CI = 2.37;8.44, respectively). This study demonstrated for the first time the association of ST3GAL1 gene haplotypes on the risk of more severe disease and death in patients infected with Influenza A(H1N1)pdm09 virus.
不同的宿主基因变异可能与甲型H1N1流感大流行病毒的毒力和传播性有关，影响诸如病毒与受感染个体细胞上的进入受体结合以及宿主免疫反应等事件。在本研究中，对编码甲型H1N1流感病毒进入宿主细胞所结合的Siaα2-3Galβ1-受体的ST3GAL1基因的两个基因变异，在一个巴西混合人群中进行了研究。首先，对68例感染甲型H1N1流感病毒毒株的患者的ST3GAL1基因的六个外显子进行了测序。在研究的第二阶段，在来自巴西北部和东北部地区的356名被诊断为甲型H1N1流感大流行的受试者样本中，对在该样本中鉴定出的rs113350588和rs1048479多态性进行了基因分型。对这些多态性进行了计算机模拟功能分析，并评估了这些变异对感染严重程度的影响。结果表明，rs113350588和rs1048479可能直接通过剪接调控改变和/或间接通过与具有调控功能的单核苷酸多态性的连锁不平衡来改变ST3GAL1的功能。在该研究中，rs113350588和rs1048479多态性在所研究的人群中处于连锁不平衡状态（D' = 0.65）。GC单倍型与流感患者死亡风险增加相关（比值比 = 4.632，95%置信区间 = 2.10；1.21）。AT单倍型与严重疾病和死亡风险增加相关（比值比分别为1.993，95%置信区间 = 1.09；3.61和比值比4.476，95%置信区间 = 2.37；8.44）。本研究首次证明了ST3GAL1基因单倍型与感染甲型H1N1流感病毒患者更严重疾病和死亡风险之间的关联。
