Dang Tran Ngoc, Naka Izumi, Sa-Ngasang Areerat, Anantapreecha Surapee, Wichukchinda Nuanjun, Sawanpanyalert Pathom, Patarapotikul Jintana, Tsuchiya Naoyuki, Ohashi Jun
Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Faculty of Public Health, University of Medicine and Pharmacy at Ho Chi Minh city, Ho Chi Minh City, Viet Nam.
BMC Med Genet. 2016 Jul 11;17(1):43. doi: 10.1186/s12881-016-0305-3.
Dengue hemorrhagic fever (DHF) is a severe life-threatening form of dengue infection. Low platelet count is one of the characteristic clinical manifestations in patients with severe dengue. However, little is known about genetic factors in the host that cause low platelet count in patients with dengue.
A previous genome-wide association study of hematological and biochemical traits identified single nucleotide polymorphisms (SNPs) associated with low platelet count in healthy subjects. To examine the possible association of these SNPs with DHF, 918 Thai patients with dengue [509 patients with DHF and 409 with dengue fever (DF)] were genotyped for five SNPs: rs5745568 in BAK1, rs6141 in THPO, rs6065 in GP1BA, rs739496 in SH2B3, and rs385893 in RCL1. In addition, rs4804803 in CD209, that has been reported to be associated with dengue infection, was also genotyped to examine if rs4804803 affects the association detected in this study.
The allele frequencies of each SNP were compared between the DHF and DF groups. Among the five SNPs, the G allele of rs5745568 in BAK1 was significantly associated with a risk for DHF [P = 0.006 and crude odd ratio (95 % confidence interval) = 1.32 (1.09-1.60)]. The association of this allele with DHF was also significant in a logistic regression analysis adjusted for age, sex, hospital (i.e., geographic region), immune status (i.e., primary or secondary infection), and virus serotype [P = 0.016 and adjusted odd ratio (95 % confidence interval) = 1.29 (1.05-1.58)]. The result was not influenced by rs4804803 [P = 0.0167 and adjusted OR (95 % CI) = 1.29 (1.05-1.58)]. No other SNPs including rs4804803 showed significant association.
The low-level constitutive production of platelets caused by the G allele of rs5745568 seems to increase the risk of bleeding in dengue infection. Our results suggest that BCL-2 homologous antagonist/killer (BAK) protein, encoded by BAK1, plays a crucial role in the pathogenesis of DHF.
登革出血热（DHF）是登革热感染的一种严重的、危及生命的形式。血小板计数低是重症登革热患者的特征性临床表现之一。然而，关于宿主中导致登革热患者血小板计数低的遗传因素知之甚少。
先前一项关于血液学和生化特征的全基因组关联研究确定了与健康受试者血小板计数低相关的单核苷酸多态性（SNP）。为了研究这些SNP与DHF的可能关联，对918名泰国登革热患者[509例DHF患者和409例登革热（DF）患者]进行了5个SNP的基因分型：BAK1中的rs5745568、THPO中的rs6141、GP1BA中的rs6065、SH2B3中的rs739496以及RCL1中的rs385893。此外，还对CD209中已报道与登革热感染相关的rs4804803进行了基因分型，以检查rs4804803是否影响本研究中检测到的关联。
比较了DHF组和DF组中每个SNP的等位基因频率。在这5个SNP中，BAK1中rs5745568的G等位基因与DHF风险显著相关[P = 0.006，粗比值比（95%置信区间）= 1.32（1.09 - 1.60）]。在对年龄、性别、医院（即地理区域）、免疫状态（即原发性或继发性感染）和病毒血清型进行校正的逻辑回归分析中，该等位基因与DHF的关联也很显著[P = 0.016，校正比值比（95%置信区间）= 1.29（1.05 - 1.58）]。结果不受rs4804803的影响[P = 0.0167，校正OR（95%CI）= 1.29（1.05 - 1.58）]。包括rs4804803在内的其他SNP均未显示出显著关联。
rs5745568的G等位基因导致的血小板低水平组成性产生似乎增加了登革热感染时出血的风险。我们的结果表明，由BAK1编码的BCL - 2同源拮抗剂/杀手（BAK）蛋白在DHF的发病机制中起关键作用。
