Manjurano Alphaxard, Sepúlveda Nuno, Nadjm Behzad, Mtove George, Wangai Hannah, Maxwell Caroline, Olomi Raimos, Reyburn Hugh, Drakeley Christopher J, Riley Eleanor M, Clark Taane G
Joint Malaria Programme, Kilimanjaro Christian Medical College, Moshi National Institute for Medical Research, Dar es Salaam, Tanzania.
Departments of Immunology and Infection Centre of Statistics and Applications, University of Lisbon, Portugal.
J Infect Dis. 2015 Oct 1;212(7):1129-39. doi: 10.1093/infdis/jiv192. Epub 2015 Mar 24.
Populations exposed to Plasmodium falciparum infection develop genetic mechanisms of protection against severe malarial disease. Despite decades of genetic epidemiological research, the sickle cell trait (HbAS) sickle cell polymorphism, ABO blood group, and other hemoglobinopathies remain the few major determinants in severe malaria to be replicated across different African populations and study designs. Within a case-control study in a region of high transmission in Tanzania (n = 983), we investigated the role of 40 new loci identified in recent genome-wide studies. In 32 loci passing quality control procedures, we found polymorphisms in USP38, FREM3, SDC1, DDC, and LOC727982 genes to be putatively associated with differential susceptibility to severe malaria. Established candidates explained 7.4% of variation in severe malaria risk (HbAS polymorphism, 6.3%; α-thalassemia, 0.3%; ABO group, 0.3%; and glucose-6-phosphate dehydrogenase deficiency, 0.5%) and the new polymorphisms, another 4.3%. The regions encompassing the loci identified are promising targets for the design of future treatment and control interventions.
暴露于恶性疟原虫感染的人群会形成抵御严重疟疾疾病的遗传保护机制。尽管经过了数十年的遗传流行病学研究，但镰状细胞性状（HbAS）、镰状细胞多态性、ABO血型以及其他血红蛋白病仍然是少数几个在不同非洲人群和研究设计中有待重复验证的严重疟疾主要决定因素。在坦桑尼亚高传播地区开展的一项病例对照研究（n = 983）中，我们调查了近期全基因组研究中确定的40个新基因座的作用。在通过质量控制程序的32个基因座中，我们发现USP38、FREM3、SDC1、DDC和LOC727982基因中的多态性可能与严重疟疾的易感性差异有关。已确定的候选因素解释了严重疟疾风险变异的7.4%（镰状细胞性状多态性为6.3%；α地中海贫血为0.3%；ABO血型为0.3%；葡萄糖-6-磷酸脱氢酶缺乏症为0.5%），新的多态性又解释了4.3%。包含所确定基因座的区域是未来治疗和控制干预措施设计的有前景的靶点。
