Genetic Association and Expression Studies Indicate a Role of Toll-Like Receptor 8 in Pulmonary Tuberculosis

被引：213

作者：

Davila, Sonia ^{[1
]}

Hibberd, Martin L. ^{[1
]}

Dass, Ranjeeta Hari ^{[1
]}

Wong, Hazel E. E. ^{[1
]}

Sahiratmadja, Edhyana ^{[2
,3
]}

Bonnard, Carine ^{[1
]}

Alisjahbana, Bachti ^{[4
]}

Szeszko, Jeffrey S. ^{[5
]}

Balabanova, Yanina ^{[6
,7
,8
]}

Drobniewski, Francis ^{[6
,7
]}

van Crevel, Reinout ^{[9
]}

van de Vosse, Esther ^{[10
]}

Nejentsev, Sergey ^{[5
,11
]}

Ottenhoff, Tom H. M. ^{[2
]}

Seielstad, Mark

机构：

[1] Genome Inst Singapore, Singapore, Singapore

[2] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, Leiden, Netherlands

[3] Eijkman Inst Mol Biol, Jakarta, Indonesia

[4] Padjadjaran State Univ, Dept Internal Med, Hasan Sadikin Hosp, Bandung, Indonesia

[5] Univ Cambridge, Dept Med Genet, Cambridge Inst Med Res,Juvenile Diabet Res Fdn, Wellcome Trust Diabet & Inflammat Lab, Cambridge, England

[6] Barts & London Med Sch, Inst Cell & Mol Sci, Ctr Infect Dis, Clin TB & HIV Grp, London, England

[7] Barts & London Med Sch, Hlth Protect Agcy, Mycobacterium Reference Unit, London, England

[8] Samara Reg TB Serv, Samara, Russia

[9] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 ED Nijmegen, Netherlands

[10] Leiden Univ, Med Ctr, Dept Infect Dis, Leiden, Netherlands

[11] Univ Cambridge, Dept Med, Cambridge CB2 2QQ, England

来源：

PLOS GENETICS | 2008年 / 4卷 / 10期

基金：

英国惠康基金;

关键词：

D O I：

10.1371/journal.pgen.1000218

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Despite high rates of exposure, only 5-10% of people infected with Mycobacterium tuberculosis will develop active tuberculosis (TB) disease, suggesting a significant role for genetic variation in the human immune response to this infection. Here, we studied TB association and expression of 18 genes involved in the Toll-like receptor (TLR) pathways. Initially, we genotyped 149 sequence polymorphisms in 375 pulmonary TB patients and 387 controls from Indonesia. We found that four polymorphisms in the TLR8 gene on chromosome X showed evidence of association with TB susceptibility in males, including a non-synonymous polymorphism rs3764880 (Met1Val; P = 0.007, odds ratio (OR) = 1.8, 95% c.i. = 1.2-2.7). We genotyped these four TLR8 polymorphisms in an independent collection of 1,837 pulmonary TB patients and 1,779 controls from Russia and again found evidence of association in males (for rs3764880 P = 0.03, OR = 1.2, 95% c.i. = 1.02-1.48). Combined evidence for association is P = 1.2 x 10(-3)-6 x 10(-4). In addition, a quantitative PCR analysis indicated that TLR8 transcript levels are significantly up-regulated in patients during the acute phase of disease (P = 9.36 x 10(-5)), relative to baseline levels following successful chemotherapy. A marked increase in TLR8 protein expression was also observed directly in differentiated macrophages upon infection with M. bovis bacille Calmette-Guerin (BCG). Taken together, our results provide evidence, for the first time, of a role for the TLR8 gene in susceptibility to pulmonary TB across different populations.

引用

页数：8

共 40 条

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