Common TLR1 genetic variation is not associated with death from melioidosis, a common cause of sepsis in rural Thailand.
Common TLR1 genetic variation is not associated with death from melioidosis, a common cause of sepsis in rural Thailand.
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DOI：
10.1371/journal.pone.0083285
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
West TE
中科院分区：
文献类型：
--
作者：
Chantratita N;Tandhavanant S;Myers ND;Chierakul W;Wuthiekanun V;Mahavanakul W;Limmathurotsakul D;Peacock SJ;West TE
类鼻疽，由革兰氏阴性细菌类鼻疽伯克霍尔德氏菌引起的感染，是泰国东北部败血症的常见原因。在白色北美人中，TLR 1的常见功能性遗传变异与器官衰竭和败血症死亡相关。我们假设TLR 1变异与类鼻疽泰国患者的预后相关。我们整理了北美白色人群中常见的三种TLR 1变体的全球频率：rs 5743551（-7202 A/G），rs 4833095（742 A/G）和rs 5743618（1804 G/T）。我们注意到次要等位基因从北美白色受试者到亚洲人群的逆转，这在rs 5743618中特别明显。在欧洲血统的犹他州居民中，rs 5743618 T等位基因的频率为17%，而在越南受试者中，频率> 99%。我们对427例类鼻疽患者进行了一项遗传关联研究，以确定TLR 1变异与器官衰竭或死亡的关联。我们对rs 5743551和rs 4833095进行了基因分型。这些变异都处于高度连锁不平衡状态，但这两种变异都与器官衰竭或住院死亡无关。在300名健康的泰国人中，我们进一步测试了TLR 1变异与对TLR 1激动剂Pam 3CSK 4的离体血液反应的关联。这两种变体都与Pam 3CSK 4诱导的血液细胞因子反应密切相关。我们通过检索公共数据库和已发表的文献，确定了TLR 1的其他常见变异，并筛选了另外三种TLR 1变异与Pam 3CSK 4诱导的反应的关联，但没有发现。我们的结论是TLR 1变异的遗传结构在东南亚人与其他人群相比有很大不同，在泰国人中TLR 1的常见变异与类鼻疽的结果或对Pam 3CSK 4的血液反应改变无关。我们的研究结果强调了需要进一步研究TLR 1和其他先天免疫遗传调节剂的炎症宿主反应和决定因素的败血症在东南亚人口。
Melioidosis, infection caused by the Gram-negative bacterium Burkholderia pseudomallei, is a common cause of sepsis in northeast Thailand. In white North Americans, common functional genetic variation in TLR1 is associated with organ failure and death from sepsis. We hypothesized that TLR1 variants would be associated with outcomes in Thais with melioidosis. We collated the global frequencies of three TLR1 variants that are common in white North American populations: rs5743551 (-7202A/G), rs4833095 (742A/G), and rs5743618 (1804G/T). We noted a reversal of the minor allele from white North American subjects to Asian populations that was particularly pronounced for rs5743618. In the Utah residents of European ancestry, the frequency of the rs5743618 T allele was 17% whereas in Vietnamese subjects the frequency was >99%. We conducted a genetic association study in 427 patients with melioidosis to determine the association of TLR1 variation with organ failure or death. We genotyped rs5743551 and rs4833095. The variants were in high linkage disequilibrium but neither variant was associated with organ failure or in-hospital death. In 300 healthy Thai individuals we further tested the association of TLR1 variation with ex vivo blood responses to Pam3CSK4, a TLR1 agonist. Neither variant was robustly associated with blood cytokine responses induced by Pam3CSK4. We identified additional common variation in TLR1 by searching public databases and the published literature and screened three additional TLR1 variants for associations with Pam3CSK4-induced responses but found none. We conclude that the genetic architecture of TLR1 variation differs substantially in southeast Asians compared to other populations and common variation in TLR1 in Thais is not associated with outcome from melioidosis or with altered blood responses to Pam3CSK4. Our findings highlight the need for additional studies of TLR1 and other innate immune genetic modulators of the inflammatory host response and determinants of sepsis in southeast Asian populations.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
Pino-Yanes M;Corrales A;Casula M;Blanco J;Muriel A;Espinosa E;García-Bello M;Torres A;Ferrer M;Zavala E;Villar J;Flores C;GRECIA and GEN-SEP Groups
通讯作者：
GRECIA and GEN-SEP Groups
影响因子：
4.5
作者：
Patin E;Laval G;Barreiro LB;Salas A;Semino O;Santachiara-Benerecetti S;Kidd KK;Kidd JR;Van der Veen L;Hombert JM;Gessain A;Froment A;Bahuchet S;Heyer E;Quintana-Murci L
通讯作者：
Quintana-Murci L
影响因子：
15.8
作者：
Cheng, Allen C.;West, T. Eoin;Peacock, Sharon J.
通讯作者：
Peacock, Sharon J.
影响因子：
4.4
作者：
Johnson, Christopher M.;Lyle, Elizabeth A.;Tapping, Richard I.
通讯作者：
Tapping, Richard I.