Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.
Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.
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肯尼亚基利比儿童的人类候选基因多态性和严重疟疾的风险：一项病例对照协会的研究。
DOI：
10.1016/s2352-3026(18)30107-8
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发表时间：
2018-08
期刊：
影响因子：
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通讯作者：
MalariaGEN Consortium
中科院分区：
文献类型：
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作者：
Ndila CM;Uyoga S;Macharia AW;Nyutu G;Peshu N;Ojal J;Shebe M;Awuondo KO;Mturi N;Tsofa B;Sepúlveda N;Clark TG;Band G;Clarke G;Rowlands K;Hubbart C;Jeffreys A;Kariuki S;Marsh K;Mackinnon M;Maitland K;Kwiatkowski DP;Rockett KA;Williams TN;MalariaGEN Consortium
人类遗传因素是疟疾风险的重要决定因素。我们研究了多个候选多态性（许多与红细胞的结构或功能有关）与严重恶性疟原虫疟疾及其特定表型（包括脑型疟疾、严重疟疾贫血和呼吸窘迫）风险之间的关联。我们在肯尼亚基利菲县进行了一项病例对照研究。我们招募了患有严重疟疾的儿童作为病例，送往基利菲县医院的高度依赖病房。我们纳入了 2006 年 8 月 1 日至 2010 年 9 月 30 日期间在当地社区出生的婴儿作为对照，他们是遗传学研究的一部分。我们测试了一系列候选疟疾保护基因与严重疟疾及其特定表型风险之间的关联。我们使用排列方法来解释多态性和严重疟疾之间的多重比较。我们判断 p 值小于 0·005 对于候选基因与严重疟疾之间关联的初步分析是显着的。 1995年6月11日至2008年6月12日期间，2244名患有严重疟疾的儿童被纳入该研究，其中3949名婴儿被纳入研究。总体而言，2244 名重症疟疾儿童中有 263 名（12%）在医院死亡，其中 1233 名脑型疟疾儿童中有 196 名（16%）在医院死亡。我们研究了 70 个候选严重疟疾相关基因的 121 个多态性。我们发现严重疟疾的总体风险与 15 个基因或位置的多态性之间存在显着关联，其中大多数与红细胞有关：ABO、ATP2B4、ARL14、CD40LG、FREM3、INPP4B、G6PD、HBA（HBA1 和 HBA2）、HBB、IL10、LPHN2（也称为 ADGRL2）、LOC727982、RPS6KL1、 CAND1 和 GNAS。综合起来，这些遗传关联占普通人群中个体患严重疟疾风险差异的 5·2%。我们证实了严重疟疾与镰状细胞性状之间已建立的关联（比值比 [OR] 0·15，95% CI 0·11–0·20；p=2·61 × 10−58）、O 型血型（0·74、0·66–0·82；p=6·26 × 10−8）和 –α3·7-地中海贫血之间存在关联（0·83，0·76–0·90；p=2·06 × 10−6）。我们还发现严重疟疾的总体风险与 ATP2B4（OR 0·76，95% CI 0·63–0·92；p=0·001）和 FREM3（0·64，0·53–0·79；p=3·18 × 10−14）的多态性之间存在很强的相关性。与 FREM3 的关联可以通过与编码罕见 Dantu 血型抗原的糖蛋白基因区域（包括 GYPA、GYPB 和 GYPE）内复杂结构突变的连锁不平衡来解释。 Dantu 杂合性与严重疟疾风险相关（OR 0·57，95% CI 0·49–0·68；p=3·22 × 10−11），纯合性（0·26，0·11–0·62；p=0·002）也是如此。 ATP2B4和丹徒血型抗原均与红细胞的结构和功能相关。 ATP2B4 编码质膜钙转运 ATP 酶 4（红细胞上的主要钙泵），糖蛋白是寄生虫侵入红细胞的配体。未来的工作应旨在揭示这些多态性可导致严重疟疾保护的机制，并研究这些关联对更广泛健康的影响。威康信托基金会、英国医学研究委员会、欧盟和美国国立卫生研究院基金会是比尔和梅琳达·盖茨全球健康重大挑战计划的一部分。
Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative.