Hobbs Maurine R, Udhayakumar Venkatachalam, Levesque Marc C, Booth Jennifer, Roberts Jacquelin M, Tkachuk Ariana N, Pole Ann, Coon Hilary, Kariuki Simon, Nahlen Bernard L, Mwaikambo Esther D, Lal Altaf L, Granger Donald L, Anstey Nicholas M, Weinberg J Brice
Department of Internal Medicine, University of Utah and VA Medical Centers, Salt Lake City, UT, USA.
Lancet. 2002 Nov 9;360(9344):1468-75. doi: 10.1016/S0140-6736(02)11474-7.
Nitric oxide (NO) is a mediator of immunity to malaria, and genetic polymorphisms in the promoter of the inducible NO synthase gene (NOS2) could modulate production of NO. We postulated that NOS2 promoter polymorphisms would affect resistance to severe malaria.
We assessed genomic DNA from healthy children and from those diagnosed with malaria from Tanzania (n=47 and n=138, respectively) and Kenya (n=1106) for polymorphisms by single-stranded conformational polymorphism (SSCP) analysis and sequencing. We also measured in-vivo NO production in Tanzanian children.
We identified a novel single nucleotide polymorphism, -1173 C-->T, in the NOS2 promoter that was significantly associated with protection from symptomatic malaria (odds ratio 0.12, 95% CI 0.03-0.48, p=0.0006) in 179 Tanzanian children, and significantly associated with protection from severe malarial anaemia (adjusted relative risk 0.25, 95% CI 0.09-0.66, p=0.0005) in 1106 Kenyan children studied over 5 years. The risk of parasitaemia was not significantly different in wild-type or -1173 C-->T individuals. -1173 C-->T protection in Tanzanians was independent of the previously recognised NOS2-954 G-->C polymorphism. The (CCTTT)(n) NOS2 polymorphism (Tanzania and Kenya) was not associated with severe malaria outcomes. -1173 C-->T was associated with increased fasting urine and plasma NO metabolite concentrations in Tanzanian children, suggesting that the polymorphism was functional in vivo. Interpretation The NOS2 promoter -1173 C-->T single nucleotide polymorphism is associated with protection against cerebral malaria and severe malarial anaemia. Increased NO production in individuals with the -1173 C-->T polymorphism lends support to a protective role for NO against these syndromes. Targeted interventions to increase NO delivery or production could provide novel preventive and therapeutic strategies against these major causes of mortality in African children.
一氧化氮（NO）是疟疾免疫的介质，诱导型一氧化氮合酶基因（NOS2）启动子的基因多态性可调节NO的产生。我们推测NOS2启动子多态性会影响对重症疟疾的抵抗力。
我们通过单链构象多态性（SSCP）分析和测序，评估了来自坦桑尼亚（分别为47名和138名）和肯尼亚（1106名）的健康儿童以及被诊断为疟疾的儿童的基因组DNA中的多态性。我们还测量了坦桑尼亚儿童体内的NO产生情况。
我们在NOS2启动子中鉴定出一种新的单核苷酸多态性，即-1173 C→T，在179名坦桑尼亚儿童中，该多态性与预防有症状疟疾显著相关（优势比0.12，95%可信区间0.03 - 0.48，p = 0.0006），在对1106名肯尼亚儿童进行的为期5年的研究中，该多态性与预防重症疟疾贫血显著相关（校正相对风险0.25，95%可信区间0.09 - 0.66，p = 0.0005）。野生型或-1173 C→T个体的寄生虫血症风险无显著差异。坦桑尼亚人中-1173 C→T的保护作用独立于先前确认的NOS2 - 954 G→C多态性。（CCTTT）（n）NOS2多态性（坦桑尼亚和肯尼亚）与重症疟疾结局无关。-1173 C→T与坦桑尼亚儿童空腹尿和血浆中NO代谢物浓度升高相关，表明该多态性在体内具有功能。解读：NOS2启动子-1173 C→T单核苷酸多态性与预防脑型疟疾和重症疟疾贫血相关。-1173 C→T多态性个体中NO产生增加支持了NO对这些综合征的保护作用。针对性地增加NO递送或产生的干预措施可为预防和治疗非洲儿童这些主要死亡原因提供新的策略。
