Kisia Lily E, Cheng Qiuying, Raballah Evans, Munde Elly O, McMahon Benjamin H, Hengartner Nick W, Ong'echa John M, Chelimo Kiprotich, Lambert Christophe G, Ouma Collins, Kempaiah Prakasha, Perkins Douglas J, Schneider Kristan A, Anyona Samuel B
Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno, Kenya.
University of New Mexico-Kenya Global Health Programs, Kisumu, Siaya, Kenya.
Trop Med Health. 2022 Jun 25;50(1):41. doi: 10.1186/s41182-022-00432-5.
Plasmodium falciparum infections remain among the leading causes of morbidity and mortality in holoendemic transmission areas. Located within region 5q31.1, the colony-stimulating factor 2 gene (CSF2) encodes granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor that mediates host immune responses. Since the effect of CSF2 variation on malaria pathogenesis remains unreported, we investigated the impact of two genetic variants in the 5q31.1 gene region flanking CSF2:g-7032 G > A (rs168681:G > A) and CSF2:g.64544T > C (rs246835:T > C) on the rate and timing of malaria and severe malarial anemia (SMA, Hb < 5.0 g/dL) episodes over 36 months of follow-up. Children (n = 1654, aged 2-70 months) were recruited from a holoendemic P. falciparum transmission area of western Kenya. Decreased incidence rate ratio (IRR) for malaria was conferred by inheritance of the CSF2:g.64544 TC genotype (P = 0.0277) and CSF2 AC/GC diplotype (P = 0.0015). Increased IRR for malaria was observed in carriers of the CSF2 AT/GC diplotype (P = 0.0237), while the inheritance of the CSF2 AT haplotype increased the IRR for SMA (P = 0.0166). A model estimating the longitudinal risk of malaria showed decreased hazard rates among CSF2 AC haplotype carriers (P = 0.0045). Investigation of all-cause mortality revealed that inheritance of the GA genotype at CSF2:g-7032 increased the risk of mortality (P = 0.0315). Higher risk of SMA and all-cause mortality were observed in younger children (P < 0.0001 and P = 0.0015), HIV-1(+) individuals (P < 0.0001 and P < 0.0001), and carriers of HbSS (P = 0.0342 and P = 0.0019). Results from this holoendemic P. falciparum area show that variation in gene region 5q31.1 influences susceptibility to malaria, SMA, and mortality, as does age, HIV-1 status, and inheritance of HbSS.
在疟疾高度流行传播地区，恶性疟原虫感染仍然是发病和死亡的主要原因之一。集落刺激因子2基因（CSF2）位于5q31.1区域，编码粒细胞-巨噬细胞集落刺激因子（GM-CSF），这是一种介导宿主免疫反应的造血生长因子。由于CSF2变异对疟疾发病机制的影响尚未见报道，我们调查了CSF2侧翼5q31.1基因区域的两个基因变异：g-7032 G＞A（rs168681：G＞A）和CSF2：g.64544T＞C（rs246835：T＞C）对36个月随访期间疟疾和严重疟疾贫血（SMA，血红蛋白＜5.0 g/dL）发作的发生率和发作时间的影响。儿童（n = 1654，年龄2至70个月）来自肯尼亚西部疟疾高度流行的恶性疟原虫传播地区。CSF2：g.64544 TC基因型（P = 0.0277）和CSF2 AC/GC双倍型（P = 0.0015）的遗传导致疟疾发病率比值（IRR）降低。CSF2 AT/GC双倍型携带者的疟疾IRR升高（P = 0.0237），而CSF2 AT单倍型的遗传增加了SMA的IRR（P = 0.0166）。一个估计疟疾纵向风险的模型显示，CSF2 AC单倍型携带者的危险率降低（P = 0.0045）。全因死亡率调查显示，CSF2：g-7032处GA基因型的遗传增加了死亡风险（P = 0.0315）。年龄较小的儿童（P＜0.0001和P = 0.0015）、HIV-1阳性个体（P＜0.0001和P＜0.0001）以及HbSS携带者（P = 0.0342和P = 0.0019）发生SMA和全因死亡的风险更高。来自这个恶性疟原虫高度流行地区的结果表明，5q31.1基因区域的变异会影响对疟疾、SMA和死亡率的易感性，年龄、HIV-1状态以及HbSS的遗传也是如此。
