SLC11A1 (NRAMP1) Polymorphisms and Tuberculosis Susceptibility: Updated Systematic Review and Meta-Analysis XiangWei Li1, Yu Yang1, Feng Zhou 1 , Yunzhi Zhang 2 , Hongzhou Lu2, Qi Jin1*, Lei Gao1* 1 State Key Laboratory for Molecular Virology and Genetic Engineering, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, 2 Department of Infectious Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China Abstract Background: Natural resistance associated macrophage protein 1 (NRAMP1), encoded by the SLC11A1 gene, has been described to regulate macrophage activation and be associated with infectious and autoimmune diseases. The relation between SLC11A1 polymorphisms and tuberculosis susceptibility has been studied in different populations. Methods: We systematically reviewed published studies on SLC11A1 polymorphisms and tuberculosis susceptibility until September 15, 2010 and quantitatively summarized associations of the most widely studied polymorphisms using meta- analysis. Results: In total, 36 eligible articles were included in this review. In Meta-analysis, significant associations were observed between tuberculosis risk and widely studied SLC11A1 polymorphisms with summarized odds ratio of 1.35 (95%CI, 1.17– 1.54), 1.25 (95% CI, 1.04–1.50), 1.23 (95% CI, 1.04–1.44), 1.31 (95%CI, 1.08–1.59) for 39 UTR, D543N, INT4, and 59 (GT)n, respectively. Heterogeneity between studies was not pronounced, and the associations did not remarkably vary in the stratified analysis with respect to study population and study base. Conclusions: The association between SLC11A1 polymorphisms and tuberculosis susceptibility observed in our analyses supports the hypothesis that NRAMP1 might play an important role in the host defense to the development of tuberculosis. Citation: Li X, Yang Y, Zhou F, Zhang Y, Lu H, et al. (2011) SLC11A1 (NRAMP1) Polymorphisms and Tuberculosis Susceptibility: Updated Systematic Review and Meta-Analysis. PLoS ONE 6(1): e15831. doi:10.1371/journal.pone.0015831 Editor: Jean Louis Herrmann, Hopital Raymond Poincare - Universite Versailles St. Quentin, France Received October 3, 2010; Accepted November 25, 2010; Published January 25, 2011 Copyright: 2011 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The work was supported by Eleven Fifth Key Research grant from the Ministry of Science and Technology, the People’s Republic of China (NO: 2008ZX10003-005,2008ZX10001-006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: gaolei@ipbcams.ac.cn (LG); jinqi@ipbcams.ac.cn (QJ) Introduction Host genetic susceptibility to infectious disease has been widely studied in recent years, which is helpful for high-risk population identification and therefore promotes diseases prevention and early diagnosis [1,2]. Moreover, such study also contributes to clarify potential mechanisms underlying host defense to the disease development. Natural resistance associated macrophage protein 1 (NRAMP1), encoded by the SLC11A1 gene, has multiple effects on macrophage activation and has been reported to play an important role in host innate immune response against infections [3]. Tuberculosis (TB), caused by infection of Mycobacterium tuberculosis, remains a major challenge to global public health. As estimated, that one-third of the world’s population is infected, but that only a minority of those infected ever develop TB [4]. Host genetic susceptibility, together with some environmental and lifestyle factors, has been suggested to contribute to such clinical diversity [5,6]. In 1998, for the first time, relation between SLC11A1 polymorphisms and TB susceptibility was reported in a population from West Africa [7]. Later, the association of several SLC11A1 loci have been extensively investigated, including 39 UTR (1729+55del4), D543N (Asp543Asn), INT4 (469+14G/C), and 59 promoter (GT)n. However, the results were not consistent between the studies. A meta-analysis, which based on literature review until December 2004, suggested an ethnicity specific effect of SLC11A1 polymorphisms on TB risk [8]. In the past five years, the number of original studies addressing this topic has doubled. Therefore, it is necessary to update the meta-analysis which might provide more solid evidence and minimize potential bias caused by limited publications in the past. In this article, we performed a systematic review and meta- analysis, based on literature identification until 15 September 2010, to summarize associations between the most widely studied SLC11A1 polymorphisms and TB susceptibility. Results A total of 336 articles were achieved by literature search, from the PubMed, EMBASE and CBM databases, using different combination of key terms. As shown in Figure 1, after excluding those overlapped between the databases, 217 abstracts were retrieved for detailed evaluation. Forty seven studies addressing the association of SLC11A1 polymorphisms and TB were PLoS ONE | www.plosone.org 1 January 2011 | Volume 6 | Issue 1 | e15831