The Influence of Single Nucleotide Polymorphisms of NOD2 or CD14 on Susceptibility to Tuberculosis: A Systematic Review

doi:10.21203/rs.3.rs-91021/v1

Download PDF

Research

The Influence of Single Nucleotide Polymorphisms of NOD2 or CD14 on Susceptibility to Tuberculosis: A Systematic Review

https://doi.org/10.21203/rs.3.rs-91021/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background: Tuberculosis (TB) is still one of the leading causes of death worldwide. Genetic studies have pointed to the relevance of the NOD2 and CD14 polymorphic alleles in association with susceptibility or resistance to TB.

Methods: A systematic review was performed on search platforms to examine the association between single nucleotide polymorphisms (SNP) and TB risk. Study quality was evaluated using the Newcastle-Ottawa Quality Scale (NOQS)

Results: Thirteen studies matched the selection criteria. Of those, 9 investigated CD14 SNPs, and 6 reported a significant association between the T allele and TT genotypes of the rs2569190 SNP and increased TB risk. In contrast, the genotype CC was found to be protective against the disease. Furthermore, in two studies, rs2569191 SNP of the CD14, G allele was described to be significantly associated with increased TB risk. Four studies reported data uncovering the relationship between NOD2 SNPs and TB risk, with two of them reporting significant associations of rs1861759 and rs7194886 and higher TB risk in a Chinese Han population. Paradoxically, minor allele carriers (CG or GG) of rs2066842 and rs2066844 NOD2 SNPs were associated with lower TB risk in African Americans.

Conclusions: The CD14 rs2569190 and rs2569191 polymorphisms influence TB risk depending on the allele. Furthermore, there is significant association between NOD2 SNPs rs1861759 and rs7194886 and augmented risk of TB, especially in persons with Chinese ethnicity. The referred polymorphisms of CD14 and NOD2 genes likely play an important role in TB susceptibility and physiopathology; such effect may be affected by ethnicity.

Systematic review registration: CRD42020186523

Infectious Diseases

NOD2

CD14

Single-nucleotide polymorphism

tuberculosis

Tuberculosis (TB) is one of the 10 leading causes of death around the world [1]. Approximately 1.7 billion people are infected by Mycobacterium tuberculosis (Mtb) worldwide [1]. The occurrence of this infection at different rates across countries and ethnicities indicates that genetic determinants may underly susceptibility to TB [2]. In this perspective, there are still notable gaps in the mechanism behind host susceptibility or resistance to TB.

The immune system has a fundamental participation in the response to Mtb [3]. Thus, it is expected that polymorphisms in immune-related genes may directly affect the capacity of a host exposed to Mtb to control infection. Indeed, many studies have reported relationships between SNPs of immune-related genes and susceptibility to TB, for example, results from genetic studies have suggested an association between SNPs in TLR4 [4], TNFA [5] and increased risk of active TB among highly exposed individuals. In addition to these genes, the nucleotide-binding oligomerization Domain Containing protein 2 (NOD2) and Cluster Differentiation antigen 14 (CD14) genes are frequently studied in this setting, since they account for proteins that act in the recognition of mycobacterial molecular patterns and lead to immune activation against Mtb [6]. Despite the existence of several studies in NOD2 and CD14, many of them are in disagreement with each other, and present results restricted to certain populations [6].

The CD14 gene codifies a glycosylphosphatidylinositol anchored surface molecule present on the surface of monocytes, macrophages and polymorphonuclear leucocytes, which functions as a key pattern recognition receptor (PRR) protein in innate immunity. CD14 plays a role in mediating signals from Toll-like receptors (TLRs) that recognize Mtb [7]. Additionally, CD14 knock-out mice exhibit increased susceptibility to Mtb infection compared to wild-type controls [8]. Several studies have investigated whether the susceptibility to TB is influenced by polymorphisms of this gene and, however, the results have been inconsistent and inconclusive [3, 9]. For that reason, it is still not possible to define the real impact of CD14 on TB susceptibility in different populations, as studies with distinct ethnicities show conflicting results.

NOD2 is expressed in numerous cell types of the immune system, including macrophages, neutrophils and eosinophils [10, 11]. It encodes a protein specialized and functions as an intracellular PRR of peptidoglycan through the recognition of muramyl dipeptide (MDP), a motif common to all bacteria [12], with stimulating signal towards activation of immune responses [13]. When NOD2 is activated by specific substances produced by bacteria, it turns on a protein complex named nuclear-factor-kappa-B (NFkB), resulting in NFκB-mediated transcription of pro- inflammatory mediators [14]. As such, there is mounting evidence that deregulation of NOD2 signaling causes or contributes to a variety of human diseases, including asthma [15], cancer [16], inflammatory bowel disease [17] and TB [18]. Of note, studies have reported conflicting results on the relationship between NOD2 SNPs and susceptibility to TB, with findings arguing that mutations in the NOD2 gene could lead to both the increased and decreased risk of TB [19]. Notwithstanding, like most of the studies on CD14 SNPs, the majority of the results diverge depending on the investigated population, leaving several gaps for a complete understanding of these relationships.

The present study aimed at summarizing the compelling body of evidence testing the influence of polymorphisms of abovementioned PRRs on TB susceptibility. We performed a systematic review to evaluate the association between the all reported polymorphisms of CD14 and NOD2 and TB susceptibility, and how such association may be affected by different populations.

Study aim

We performed a systematic review on the influence of CD14 and NOD2 SNPs in TB susceptibility following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations.

Literature search

A systematic search was conducted between XX 2019 and June 25 2020 by two independent researchers (the authors JMC-A and DNA) in the following databases: PubMed (MEDLINE and EMBASE), Europe PubMed Central (PMC), Cochrane, Scientific Electronic Library Online (SciELO), and Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs). The keywords used in the search were ‘Mycobacterium tuberculosis’, ‘tuberculosis’; ‘CD14’ or ‘NOD2’; and ‘polymophism’, ‘SNPs’ or ‘genetic polymorphism’ with various combinations. Every original research article found in the search that was in English, Spanish, or Portuguese was considered, with no restriction on the publication date. Reviews, letters to the editor, and comments were not included but were sources of additional references that did not appear in the first search.

Selection of studies

Initially, titles and abstracts were reviewed and analyzed for eligibility (Fig. 1). Thereafter, all the eligible articles were fully read. These two steps were performed by two independent reviewers (JMC-A and DNA). The inclusion criteria were: (1) the main subject of the article must have been the genetic influence on TB susceptibility; (2) the study must have been related to a SNP in CD14 and/or NOD2 genes. Articles that did not mention TB susceptibility, polymorphism in the genes indicated above, had non-sufficient data, reviews, meta-analyses, animal model studies, letters to the editor, or which were clearly not related to the theme were excluded.

Table 1

Characteristics of Included Studies
Author/Year	Country	Study Design	Ethnicity	Gene / studied SNP	TB diagnosis	Sample Size	Inclusion and Exclusion Criteria Cases	Inclusion and Exclusion Criteria Controls	Outcomes
Zheng, M. et al, 2018	China	Case Control	Chinese han	CD14 (-159) rs2569190 C > T	Spinal	240 TB and 150 controls; N = 390.	Patients diagnoses with extra-pulmonary TB, who tested negative for PTB. Every included patients are free of comorbidities.	Age- and sex-matched healthy subjected were enrolled as controls.	The frequency of the rs2569190 T allele was significantly higher in spinal TB patients than in controls (OR = 1.97, 95% CI = 1.24–3.42 ) (p < 0.01), and the frequency of the CT + TT genotypes (OR = 2.10, 95% CI = 1.09–3.85) were also significantly higher in spinal TB patients than in controls (p < 0.05).
Xue, Y. et al, 2012	China	Case Control	Chinese Han	CD14 (-1619) rs2915863 G > A; (-1359) rs3138078 T > G ; (-159) rs2569190 C > T; (-1145) rs2569191 A > G; rs3138076 T > C; rs5744454 T > G, rs5744455 G > T	Pulmonary	318 TB and 380 controls; N = 698.	Patients with PTB confirmed by clinical, radiological and bacteriological investigation. Patients were excluded if they tested positive for HIV or if they were undergoing immunosuppressive agentes.	Healthy individuals, with no history of TB or immune diseases.	The G allele of rs2915863 (OR = 1.41, 95% CI = 1.12–1.76), G allele of rs3138078 (OR = 1.77, 95% CI = 1.39–2.24), G allele of rs2569191(OR = 1.78, 95% CI = 1.43–2.22), and T allele of rs2569190 (OR = 1.73, 95% CI = 1.40–2.15, respectively) were significantly associated with TB. rs3138076, rs5744454 and rs5744455 there were no statistic relevant associations
Zhao, M. et al, 2012	China	Case Control	Chinese Han	CD14 (-159) rs2569190 C > T ; (-1145) rs2569191 G > A	Pulmonary and extrapulmonary TB	432 TB and 404 controls. N = 836.	Patients were undergoing standard TB treatment at the TB clinic of the Sixth Hospital of Shaoxing and Hangzhou Red Cross Hospital between October 2005 and October 2009. They were excluded if: HIV + or were taking immunosuppressive agents.	Healthy, unrelated blood donors with no history of TB or other immune diseases. All control subjects were from the same ethnic population and geographical origin, and were living in the same region as the patients with TB.	Both the frequency of allele T in the rs2569190 (OR = 1.4, 95% CI = 1.148–1.708) and allele G in the rs2569191 (OR = 1.512, 95% CI = 1.236–1.849) were significantly more frequent in cases than in controls and were also significantly associated with TB. The frequencies of genotypes CT and CC in the rs2569190 (OR = 0.46 and 0.63, respectively; 95% CI = 0.34–0.63 and 0.42–0.93), as well as the frequencies of genotypes AG and AA in the rs2569191 (OR = 0.60 and 0.44, respectively; 95%CI = 0.44–0.83 and 0.29–0.65), were lower in cases than in controls and were also protective against the disease.
Alavi-Naini, R. et al, 2012	Iran	Case-control	Persian, Balouch and Afghan Iranians	CD14 (-159) rs2569190 C > T	Pulmonary	120 TB patients and 131 controls; N = 251.	Culture positive PTB patients were included. They had no other comorbities such as Myocardial infarction, septic shock, liver cirrhosis or pancreatitis.	Healthy subjects matched for age, sex and ethnicity. The inclusion criteria were abscece of clinical symptoms or signs for active TB and normal chest X-ray, no medical history of TB or other infectious or autoimmune diseases.	The frequency of the rs2569190 T allele was 57% in TB patients and 44% in controls and was significantly different (p < 0.002). The risk of TB was 2.3- fold greater in individuals with the T-allele (CT + TT) than in those without (OR = 2.3, 95% CI = 1.2–4.3, p = 0.006).
Rosas-Taraco, A. et al, 2007	Mexico	Case-control	White and Mestizo Mexican	CD14 (-159) rs2569190 C > T	Pulmonary	104 TB, 67 household contacts and 114 Controls, N = 285.	All patients had active pulmonary TB diagnosed on the basis of clinical findings and smear or culture positive for PTB. All participants were negative for HIV and diabetes, not treated with steroids or immunossuppressive agents	67 of the controls were household contacts not rellated by the cases genetically. Also included 114 healthy individuals. All of them were Mexican older than 18 yeas.	The frequency of the rs2569190 homozygous TT genotype was highest in patients with pulmonary TB (OR = 3.37, 95% CI = 1.58–7.19 p = < 0.002). The frequency of the rs2569190 allele T had a significantly higher risk for the development of pulmonary TB (OR = 2.267; 95% CI = 1.5–3.3).
Ayaslioglu, E. et al, 2012	Turkey	Case-control	Turkish	CD14 (-159) rs2569190 C > T	Pulmonary and extrapulmonary TB	88 TB and 116 control. N = 204.	Subjects who had a diagnosis of tuberculosis; age ≥ 16 years; and consented to be included into the study. Patients who had had infectious diseases in the last 6 weeks; had significant chronic immunosuppressive systemic diseases ; was pregnant or HIV + were excluded.	Subjects with no known diseases. Patients who had had infectious diseases in the last 6 weeks; had significant chronic immunosuppressive systemic diseases ; was pregnant or HIV + were excluded.	There was no significant difference in terms of genotype distribution between patients with tuberculosis and controls .
Kang, Y. et al, 2009	South Korea	Case-control	Korean	CD14 (-159) rs2569190 C > T	Pulmonary and extrapulmonary TB	274 TB and 422 healthy controls; N = 696.	Patients with confirmed tuberculosis were enrolled from Seoul National University Hospital in Korea. Patients with a positive HIV test were excluded.	A group of healthy blood donors with normal chest X-ray and without respiratory symptoms and signs were recruited from medical students and employees of Seoul National University College of Medicine/Seoul National University Hospital.	The frequency of the rs2569190 T allele was higher in tuberculosis patients than in healthy controls (64% vs. 57%; p = 0.01), and rs2569190 TT genotypes (OR = 1.60; 95% CI, 1.01–2.54) were over-represented among tuberculosis patients (43% vs. 32%; p = 0.016).
Druszczyñska, M. et al, 2006	Poland	Case-control	Caucasian Polish	CD14 (-159) rs2569190 C > T	Pulmonary TB	126 TB And 122 Controls. N = 248.	Not reported	Not reported	No association was found between the rs2569190 and the presence of TB.
Pacheco, E. et al, 2004	Colombia	Case-control	Caucasian and Mestizo Colombian	CD14 (-159) rs2569190 C > T	Pulmonary and extrapulmonary TB	267 TB patients and 112 controls. N = 379	Patients were recruited from different health units in the metropolitan area of Medellin, Colombia. Individuals, who were HIV+, or with a history of cancer, autoimmune, metabolic or endocrine diseases, as well as pregnant women, were excluded from the study.	Tuberculin-positive healthy control individuals were recruited from the Facultad de Medicina at the Universidad de Antioquia, and the institutions from where the patients were recruited.	No association was found between the allele and genotype frequencies and the presence of TB or between the different forms of the disease.
Hall, N. et al, 2015	Uganda	Case Control	USA	NOD2 rs6500328 A > G, rs2111234 G > A and rs17313265 C > T	TB¹	240 cases and 595 controls (household contact). N = 835.	Analysis was gathered from two phases of a household contact study conducted in Kampala, Uganda. Subjects from the Household Contact Study were enrolled from 1995–1999. Individuals who presented at the study clinic with active culture positive pulmonary TB were enrolled as index cases.	Analysis was gathered from two phases of a household contact study conducted in Kampala, Uganda. Subjects from the Household Contact Study were enrolled from 1995–1999. Healthy household contacts underwent a follow-up evaluation every three months for the first six months and were enrolled as control	rs17313265 association with TB in Adults (Examination of age-specific effects with TB) (OR = 2.82, 95% CI = 1.05–7.53). rs6500328 (OR = 2.44, 95% CI = 1.01–5.88) and rs2111234 (OR = 1.56 95% CI = 1.07–2.28) showed a nominal association with resistance to Mycobacterium tuberculosis (Mtb) infection.
Zhao, M. et al, 2012	China	Case Control	Chinese Han, Uygur and Kazak	NOD2 (Arg587Arg) rs1861759 T > G	Pulmonary	425 TB and 380 controls; N = 805	Han population: 219 PTB and 215 healthy controls; For the uygur population 86 PTB patients and 72 controls; For the Kazak 120 PTB patients and 93 healthy controls. The patients were diagnosed based on the TST test, chest X-ray or sputum smear culture results.	They were HIV negative patients and controls without any auto immune, chronic inflammatory or any other disease condition. All selected patients had no mixed descendants whithin 3 generations.	By comparing the TG genotype frequencies of rs1861759 in the Han population, a significant difference was observed between the patients with TB and the healthy controls (OR = 2.16; 95% CI = 1.31–3.58; p = 0.0023; ).
Pan, H. et al, 2012	China	Case Control	Chinese Han	NOD2 rs7194886 C > T and rs9302752 T > C	Pulmonary	1043 TB and 808 controls; N = 1851	Patients older than 15 years,, Han chinese. They were divided in 3 groups Clinical simptoms of TB; Sputum smear positive and Bacteriological confirmed TB. 234 of 1043 TB patients were sputum smear negative.	Every control wasolder than 15 years, without history of TB and/or a malignancy.	The individuals carrying the CT⁄TT genotype of rs7194886 had an increased risk of pulmonary tuberculosis (OR= 1.35, 95% CI = 1.05–1.72). Allele frequency analysis found that variant allele T of rs7194886 (OR = 1.25, 95% CI = 1.00–1.57) was associated with an increased risk of tuberculosis. Haplotype rs9302752 C– rs7194886 T was associated with an increased risk of being sputum culture-positive tuberculosis (p = 0.039).
Austin, C. et al, 2008	USA	Case Control	African americans	NOD2 (Pro268Ser) rs2066842 C > T (Arg702Trp) rs2066844 C > T, and (Ala725Gly) rs5743278 C > G	Pulmonary and extrapulmonary TB	377 TB and 187 Controls; N = 564.	All cases patients were HIV negative, and had their ethnicities determinated by self indication. TB diagnosis were given based on bacille culture (286/312 PTB cases and 33/43 of EPTB), in thoses negative patients diagnosis was based on clinical manifestations, chest X-ray an clinical improvement to antimycobacterium treatmant.	African americans without history of TB, autoimmune disease or other diseases.	Minor allele carriers (heterozygous and homozygous) of rs2066842 (OR = 0.55, 95% CI = 0.32– 0.94, p = 0.02 ) and rs2066844 (OR = 0.27, 95% CI = 0.08–0.88; p = 0.01) presented decreased risks for TB disease. Conversely, the minor allele carrier (heterozygous) of rs2066844 (OR = 2.16, 95% CI = 1.10–4.72; p = 0.03 ) showed an increased risk for TB disease.
Abbreviations: NOD2: nucleotide-binding oligomerization domain-containing protein 2; CD14: Cluster Differentiation antigen 14,TB: tuberculosis; PTB: pulmonary tuberculosis; EPTB: extrapulmonary tuberculosis OR: odds ratio; CI: confidence intervals; USA: United States of America,
¹ Did not specify the TB type

Data extraction

Data extraction was performed individually by two researchers (DNA and CDF), and discrepancies between them were resolved by a third reviewer (JMC-A). All the information on important variables, publication date, methods, results, and conclusions of the included articles were registered in tables built-in Microsoft Excel, made by two different researchers. Lastly, the content of those Excel tables was checked by a third reviewer (JMC-A), attesting the registry compliance.

Quality assessment

The quality assessment of each individual study was further performed according to the Newcastle-Ottawa Quality Scale (NOQS) [20] (Table 2), which measures the quality of a study based on three aspects: selection (maximum, 4 stars), comparability (maximum, 2 stars) and exposure (maximum, 3 stars). Thus, in the processing of the article quality analysis, a maximum of 9 stars could be obtained. Publication with a total score of 0–3 was classified as low quality, 4–6 as moderate-quality, and ≥ 7 as high quality.

Table 2

Quality Assessment of Studies Included in the Systematic Review by Newcastle Ottawa Scale
N°	Source	Selection				Comparability		Exposure			Overall score^a
N°	Source	1	2	3	4	5A	5B	6	7	8
1	Zhao, M. et al, (2012)^b	*	*	0	*	*	NA	*	*	NA	6
2	Kang, Y. et al, (2009)	*	*	*	*	*	NA	*	*	NA	7
3	Alavi-Naini, R. et al, (2012)	*	*	0	*	*	NA	*	*	NA	6
4	Zhao, M. et al, (2012)^c	*	*	*	*	*	NA	*	*	NA	7
5	Rosas-Taraco, A. et al, (2007)	*	*	*	*	*	NA	*	*	NA	7
6	Pacheco, E. et al, (2004)	*	*	*	0	*	NA	*	*	NA	6
7	Austin, C. et al, (2008)	*	*	0	*	*	NA	*	*	NA	6
8	Zheng, M. et al, (2018)	*	*	0	0	*	NA	*	*	NA	5
9	Xue, Y. et al, (2012)	*	*	*	*	*	NA	*	*	NA	7
10	Hall, N. et al, (2015)	*	*	*	*	*	NA	*	0	NA	6
11	Pan, H. et al, (2012)	*	0	*	*	*	NA	*	*	NA	6
12	Ayaslioglu, E. et al, (2012)	*	*	*	*	*	NA	*	*	NA	7
13	Druszczyñska, M. et al, (2006)	*	0	0	*	*	NA	*	*	NA	5
Star (*) indicates the score given to the study according to the NOS quality assessment scale.
^a Determined by the total number of stars assigned to study: 0–3 Stars = Poor; 4–6 Stars = Moderate; ≥7 Stars = Good quality.
^b [29] ^{c [23]}
Abbreviations: NA: not applicable.

Selection of articles

Our primary search identified a total of 326 articles (Fig. 1). Through the study selection process, 13 articles met the inclusion criteria and were included in the systematic review [3, 9, 21–31]. The majority of the studies evaluated CD14 gene polymorphisms (n = 9), whereas four studies analyzed NOD2 polymorphisms. All of the selected studies adopted the case-control design, in which the case was defined as patients with tuberculosis, whether pulmonary, extrapulmonary, or both and controls were defined as individuals not infected with Mtb. The majority of articles investigated the relationship between presence of polymorphisms and the risk of developing only pulmonary TB (n = 7), whereas five studies tested association of SNPs with pulmonary and other forms of TB, and one assessed the relationship with susceptibility to spinal TB (Table 1).

In this systematic review, data on 4,054 TB patients were examined, whereas 3,993 individuals were identified as controls. The median sample size (IQR) per study was 267 (123–401) and 187 (127–413) for TB patients and healthy controls, respectively. The detailed characteristics of each study are shown in Table 1.

As observed in Fig. 2, most studies originated from Asia (n = 8) [21–26, 29, 30], with China leading as the most frequent study site (n = 5) [21–23, 29, 30], followed by Turkey (n = 1) [25], Iran (n = 1) [24] and South Korea (n = 1) [26]. The American continent also contributed to some studies (n = 3): 1 in the USA [31], 1 in Mexico [3] and 1 in Colombia [9]. Only one study was set in Africa, specifically in Uganda [28], and Europe was represented by one study from Poland [27]. It is also possible to visualize in the Fig. 2 that the CD14 polymorphisms were studied in diverse populations from various ethnicities, including Mexican, Colombian, Polish, Turkish, Iranian, South Korean and Chinese. In contrast, the NOD2 polymorphisms were studied in 3 restricted populations: North Americans, Chinese and Ugandan.

Quality Assessment

The quality scores of the studies, assessing the risk of bias, are displayed in Table 2. Five studies were of good quality and eight were of moderate quality (Table 2).

CD14 polymorphisms and risk of tuberculosis

In the present review, CD14 polymorphisms were the most frequently studied in the context of TB susceptibility. In total, 9 studies reported potential associations, presenting data for different populations. The sample sizes varied between 3987–1969 TB cases and 2018 controls. The studies reported data on 7 CD14 SNPs: rs2569190 [3, 9, 21–27], rs2569191 [22, 23], rs3138078 [22], rs2915863 [22], rs3138076 [22], rs5744455 [22] and rs5744454 [22]. Of the 9 publications which investigated this gene locus, six studies reported a significant association between the T allele of SNP rs2569190 and higher odds of TB [3, 21–24, 26]. The T allele was significantly more frequent in TB patients compared with healthy controls in subpopulations from China [21–23], Mexico [3], Iran [24] and South Korea [26]. Also, analyzes of odds ratio (OR) revealed an increased risk of TB when this allele was present, in case of both pulmonary and extrapulmonary disease. Of note, three of such studies [21–23] reported this aforementioned association in Chinese participants, reinforcing the idea that this CD14 allele may indeed increase the risk of developing TB in this particular population.

With regards to genotypes, the CD14 TT genotype was significantly more common in TB patients than in healthy controls and increased the risk of TB in five [3, 21, 23, 24, 26] of the six studies which analyzed the rs2569190 SNP. Only in one Chinese study, Zhao et al [23], the occurrence of the T allele in homozygosis was reported not to be related with a significant risk of TB in the OR analyzes (OR = 1). Nevertheless, in the same study, the presence of T allele alone was shown to be not only more frequent in TB cases, but also was described as a risk factor for TB development in the same population (OR = 1.4; 95% CI = 1.148–1.708; p = 0.001). In addition, Zheng et al [23] described that the association of TT with the CT genotype (TT + CT) was found significantly more frequent in spinal TB patients than in controls (85.00% vs 44.17%; P < 0.05), with an OR of 2.10 (CI 95%= 1.09–3.85). Therefore, it is possible to conclude that the CD14 T allele may directly impact the risk of TB development. When such allele is present in the genetic loci, either in heterozygosis or homozygosis, the odds to progress with active TB is shown to be high.

In contrast, Zhao et al [23] reported that frequencies of the CD14 genotypes CT and CC in the rs2569190 polymorphism were lower in TB cases than in controls. Logistic regression analysis of such results demonstrated that presence of CT and CC genotypes are likely protective against TB (OR = 0.46 and 0.63, respectively; 95% CI = 0.34–0.63 and 0.42–0.93). In agreement with these latter findings, Alavi-Naini et al. [24] described that the C allele in homozygosis was a protection factor in a sub-analysis of Iranian subjects, with an OR of 0.44 (95% CI 0.23–0.83; p = 0.006), whereas the CT genotype was not significantly associated with a lower risk for TB (OR = 1.03, 95% CI = 0.6–1.7; p = 0.5). Thus, the CC genotype might be a protective factor in the TB pathophysiology.

Noteworthy, three articles did not find any evidence for a significant association between SNP rs2569190 and TB development – Ayaslioglu et al [25], Druszczyñska et al [27] and Pacheco et al [9]. There was no significant difference in terms of genotype frequency and allele distribution between TB patients and controls, or between distinct TB clinical forms. Moreover, no association was found between the CD14-159C/T polymorphism and TB clinical severity in studies that evaluated Turkish, Caucasian Polish or White and Mestizo Colombian patients. In the Turkish study, one hypothesis described for the lack of association was the small sample size (88 TB cases and 116 controls) [25]. Moreover, Druszczyñska et al [27] have not specified whether TB patients and controls enrolled were from the same region, which could possibly have influenced the findings. Discrepancies related to ethnicity or other epidemiologic or environmental characteristics among the diverse populations investigated may have contributed to these conflicting results.

Additional investigations evaluating the CD14 SNP rs2569191 revealed significant associations with odds of TB in 2 distinct publications from China [22, 23]. Both studies reported that the G allele of A-1145G was more prevalent in TB cases than in controls, indicating an increased TB risk. In one of these studies [22], individuals with the GG genotype of A-1145G were more likely to present with TB (OR = 2.78, 95% CI = 1.79–4.32; p = 0.016). Paradoxically, the second investigation [23] suggested that the frequencies of genotypes AG and AA were lower in TB cases than in controls, arguing for a protective role against TB (OR = 0.60 and 0.44, respectively; 95% CI = 0.44–0.83 and 0.29–0.65). Therefore, CD14 SNP rs2569191 may play an important role in TB vulnerability in persons from China through either being associated with increased or decreased susceptibility, depending on the genotype.

The others CD14 SNPs (rs3138078, rs2915863, rs2569192, rs3138076, rs5744455 and rs5744454) were evaluated by only one study [22]. In such investigation, the alleles significantly associated with TB were only the G allele of rs2915863 and the G allele of rs3138078. For the SNPs rs2569192; rs3138076; rs5744455 and rs5744454 there were no statistically relevant associations. Since no other study has analyzed these SNPs, it is not possible to conclude whether they have a potential influence on susceptibility to TB.

NOD2 polymorphisms and TB

In regard to the NOD2 gene, the results from the studies were very diverse, with the SNPs being associated with either increased or decreased susceptibility to TB in each one of the study populations based on ethnicity, age group or biological sex. In such studies, a total of 2085 TB cases and 2347 controls were investigated. These studies were performed in different countries including China, Uganda and North America, with the latter being focused on African Americans.

Two publications reported data on NOD2 SNPs in China [29, 30], with a total of 2651 individuals. Zhao et al [29], demonstrated that the frequency of the TG genotype in rs1861759 SNP was substantially associated with TB (OR = 2.16; 95% CI = 1.31–3.58; p = 0.0023) in the Han population. Interestingly, the same study did not identify this relationship between the TG genotype and TB in Chinese participants from Kazak or Uygur ancestry. A different study investigating Han Chinese individuals [30] identified the NOD2 SNP rs7194886 as a risk factor for TB. Patients with the SNP rs7194886 who presented the CT or TT genotypes were more likely to present with the disease when compared to individuals with the CC genotype, with an OR of 1.35 (95% CI = 1.05–1.72). In addition, this same study found that the frequency of the rs7194886 T allele was associated with TB risk (OR = 1.25, 95% CI = 1.00–1.57). Furthermore, the study evaluated that the effects of the rs7194886 polymorphism seems to be greater in either smokers or men [30], with an OR of 1.53 (95% CI = 1.07–2.18) and 1.44 (95% CI = 1.08–1.92) respectively. In addition, the Haplotype rs9302752 C– rs7194886 T was linked with a higher risk of presenting with sputum culture-positive TB (p = 0.039).

The study involving African American patients [31] reported an association between rs2066842, rs2066844, and rs5743278 NOD2 SNPs and odds of TB. The study participants who were carriers of the CC genotype in rs2066842 and rs2066844 SNPs were less likely to have TB, with an OR of 0.55 (95% CI = 0.32–0.94) and 0.27 (95% CI = 0.08–0.88), respectively. In converse, individuals who were heterozygous (CG) in rs5743278 exhibited an increased chance of having TB (OR = 2.16, 95% CI = 1.01–4.72).

Furthermore, in the adult African population from Uganda [28], presence of the SNP rs17313265 seemed to increase the susceptibility to TB (OR = 1.98, 95% CI = 1.23, 3.19). Notably, increased frequency of the rs6500328 and rs2111234 SNPs was found in persons who did not TB, suggesting that such SNPs may be linked to resistance against Mtb infection, with OR of 2.44 (95% CI = 1.01. 5.88) and 1.56 (95% CI = 1.07, 2.28), respectively.

The molecular basis of infectious diseases is an indispensable approach to understand how the gene regulation ultimately determines clinical outcomes. In recent decades, a great deal of research has been done on the associations between genetic polymorphisms and susceptibility to TB [32, 33]. Most of the target loci are PRRs contributing to mycobacterial diseases, especially TB [34]. CD14 and NOD2 are considered to be key PRRs in the innate immune system [35]. In this systematic review, a variety of studies were identified evaluating seven CD14 SNPs and four evaluating nine NOD2 SNPs, and those genetic variants were associated with Mtb infection.

We identified a significant association between the T allele of CD14 SNP rs2569190 and TB, in which this allele increased the risk of having pulmonary and extrapulmonary TB in different ethnic groups. This polymorphism is located in the promoter region of the CD14 gene [35] and the T allele was attributed to a negative regulator of in vitro T-cell proliferation and decreased production of cytokines, including interferon-y (IFN-γ) [26]. IFN- γ is an essential cytokine for the control of mycobacterial infection [36], and for that reason it is possible to hypothesize that rs2569190 may result in an environment that favors development of TB. Interestingly, other studies also related this SNP with occurrence of ischemic stroke [37], cardiovascular disease [38] and asthma [39], indicating that these polymorphisms could actually lead to a more profound alteration in immune responses that may affect a large number of clinical conditions.

Another important association of CD14 polymorphism with TB was described in this review, involving the SNP rs2569191. In this setting, the G allele of A-1145G was more prevalent in TB cases than in controls and thus related to increased TB risk in two Chinese studies. An interesting link between such SNP and circulating concentrations of IgE has been proposed. In a study performed in patients with asthma, the authors identified a heightened IgE concentrations in those who had the G allele of A-1145G [40]. Moreover, other studies identified the IgE as a marker of the Mtb infection, in which pre-treatment levels of serum total IgE concentrations in TB patients were significantly higher than in healthy individuals; such levels decreased after successful antitubercular treatment [41, 42]. It is possible that the polymorphism rs2569191 plays an important role in TB susceptibility which may be related to IgE concentrations. Future studies in other ethnic groups are warranted to directly test this hypothesis.

NOD2 is one of the most well-studied genes in the context of the innate immune response against microbial pathogens [43]. This gene accounts for a cytoplasmic receptor belonging to the NOD-like receptor family [44] and it is known to participate in the induction of inflammation during Mtb infection [45]. In experimental conditions, Mtb recognition is NOD2-dependent [46]. Mice genetically deficient in NOD2 are shown to be more susceptible to TB [47]. Here, we found two studies [29, 30] in the Chinese population that reported three different polymorphisms (rs1861759, rs7194886 and rs9302752) associated with increased TB risk. The rs1861759 (synonymous variant) TG genotype has been described to be related to higher risk of TB [29]. Individuals with the rs7194886 CT or TT genotype are more likely to develop TB [30]. The rs9302752 C allele has been linked to a higher risk of being sputum culture-positive TB. To our knowledge, these three polymorphisms do not appear in other TB studies. Curiously, such SNPs have been also related to increased risk of leprosy [48].

In an African-American study [31], it was observed that the three NOD2 polymorphisms exhibit impact on TB risk. The polymorphism rs2066844 represents missense mutations which variants are located in the C-terminal region and cause defective production of proinflammatory mediators [49]. The rs2066842 is a missense variant but, when presented alone, is not related with altered gene function [50]. Importantly, the two polymorphisms in our systematic review related to protection against TB in the context of the presence of allele C [31]. Nevertheless, the presence of the T allele in such mutations was contrastingly associated with increased TB risk. The association between the presence of the T allele and augmented pathology has been described for other diseases such as Crohn's disease [51] and gastric cancer [52]. The genotyping heterozygous (CG) of rs5743278 has been linked to higher risk of TB [51]. It is possible that the rs5743278 SNP causes an amino acid change from a low hydrophobic arginine to a highly hydrophobic tryptophan, modifying the stability of the NOD2 structure or its ability to properly interact with Mtb ligands [51]. Finally in our review one study in a population from Uganda described the NOD2 rs17313265 polymorphism as being related with increased susceptibility to TB in adults whereas the SNPs rs6500328 and rs2111234 exhibited an association with resistance to Mtb infection [28]. Furthermore, these three polymorphisms have not been reported in other studies with TB patients. The results presented so far indicate that NOD2 polymorphisms may be dramatically affected by ethnicity and/or ancestry. This scenario reinforces the need of additional investigations performed in a variety of ethnic populations and especially with study design using family-based control subjects to eliminate the bias in stratification of the populations.

To our knowledge, the present study is the first systematic review to explore the relation of all CD14 and NOD2 SNP polymorphisms with the susceptibility to pulmonary and/or extrapulmonary TB in different ethnicities. A strength of our study was the comprehensive search strategy, which used detailed inclusion and exclusion criteria. Moreover, methodological quality was assessed in duplicate using the Newcastle-Ottawa scale [20], which reduced the subjectivity of the selection of studies and allowed for precise evaluation of the risk of bias in several domains. There was no report categorized as low quality, resulting in a review with reduced risk of bias. Another important strength is that the inclusion of the SNPs was not limited to one specific locus or ethnicity, allowing the study to observe different loci associated with TB risk or not in various populations.

Our study has some limitations. It was not possible to perform a meta-analysis mainly because a considerable part of the SNP polymorphisms appeared in only one study at a time and only a few were reported in more than one publication. Additionally, some studies lacked the Odds Ratio analyses, and for this reason we were able to perform only a detailed systematic investigation. However, the need for a study to compile and critically revise these results in different ethnicities reinforces the importance of our work, regardless of quantitative analyzes.

This review revealed that there is strong evidence that the T allele of rs2569190 CD14 polymorphism increases the risk of pulmonary and/or extrapulmonary TB in perons from different ethnicities. In addition, the CD14 SNP rs2569191 and the NOD2 SNPs rs1861759 and rs7194886 are shown here to be associated with a high TB risk in the Chinese population. In contrast, Minor allele carriers (CG or GG) of rs2066842 and rs2066844 were at low risk of TB in African Americans. Since such genes account for key molecules of the immune system, the referred polymorphisms of CD14 and NOD2 genes likely play an important role in TB physiopathology. These results add knowledge to the field by reinforcing the genetic influence on susceptibility to active TB. Such knowledge, if validated by larger studies, may help development of tools for assessment of TB risk and hopefully predict clinical outcomes in precision medicine approaches.

Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER)
Universidade Salvador (UNIFACS)
Faculdade de Tecnologia e Ciências (FTC)
Tuberculosis (TB)
Single nucleotide polymorphisms (SNP)
Newcastle-Ottawa Quality Scale (NOQS)
Mycobacterium tuberculosis (Mtb)
Domain containing protein 2 (NOD2)
Cluster Differentiation antigen 14 (CD14)
Pattern recognition receptor (PRR)
Toll-like receptors (TLRs)
Muramyl dipeptide (MDP)
nuclear-factor-kappa-B (NFkB)
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
Scientific Electronic Library Online (SciELO)
Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs)
Median sample size (IQR)
Odds ratio (OR)
Interferon-y (IFN-γ)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Organization of American States - Partnerships Program for Education and Training (OAS-PAEC)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES)
Fundação de Amparo à Pesquisa da Bahia (FAPESB)
Pulmonary tuberculosis (PTB)
Extrapulmonary tuberculosis (EPTB)
Confidence interval (CI)
United States of America (USA)
Not applicable (NA)

Potential conflicts of interest: All authors: No reported conflicts of interest.

Funding: This study was supported by the Intramural Research Program of the Fundação Oswaldo Cruz, Brazil. BBA is a senior investigator of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). JMC-A was supported by the Organization of American States - Partnerships Program for Education and Training (OAS-PAEC) and his study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance Code 001. MBA and CDF received research fellowships from the Fundação de Amparo à Pesquisa da Bahia (FAPESB). DNA and CAC received research fellowships from CNPq.

Acknowledgments: The authors acknowledge the colleagues from the Laboratório de Inflamação e Biomarcadores, Fundação Oswaldo Cruz, for making important considerations to our work.

Ethics approval and consent to participate: There were no patients directly involved in the research. The present study used publicly data from previously published studies to perform a systematic review. All information given to the research team was de-identified. Thus, the study was exempted from revision by the Institutional Review Board of the Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil, and did not require signed consent forms.

Consent for publication: not applicable.

Availability of data and material: All data used in the present study were retrieved from the publications used in the systematic review and are publicly available.

Authors' contributions: JMC-A, CDF and DNA conceived the study. JMC-A, CDF, DNA and MBA were responsible for the data collection. JMC-A, CDF, DNA, MBA and BBA analyzed the data and built the figures and tables. JMC-A, CDF and DNA performed the scientific literature search. JMC-A, CDF and DNA participated in the writing of the first draft of the manuscript. BBA critically revised the article. All authors approved the final version of the manuscript.

WHO WHO: Global tuberculosis report 2019. . WHO 2019.
Zhai W, Wu F, Zhang Y, Fu Y, Liu Z: The Immune Escape Mechanisms of Mycobacterium Tuberculosis. Int J Mol Sci 2019, 20(2).
Rosas-Taraco AG, Revol A, Salinas-Carmona MC, Rendon A, Caballero-Olin G, Arce-Mendoza AY: CD14 C(-159)T polymorphism is a risk factor for development of pulmonary tuberculosis. J Infect Dis 2007, 196(11):1698-1706.
Fouad NA, Saeed AM, Mahedy AW: Toll Like Receptor-4 Gene Polymorphism and Susceptibility to Pulmonary Tuberculosis. Egypt J Immunol 2019, 26(2):1-10.
Yi YX, Han JB, Zhao L, Fang Y, Zhang YF, Zhou GY: Tumor necrosis factor alpha gene polymorphism contributes to pulmonary tuberculosis susceptibility: evidence from a meta-analysis. Int J Clin Exp Med 2015, 8(11):20690-20700.
Zhang Z, Zhu H, Pu X, Meng S, Zhang F, Xun L, Liu Q, Wang Y: Association between tumor necrosis factor alpha-238G/a polymorphism and tuberculosis susceptibility: a meta-analysis study. BMC Infect Dis 2012, 12:328.
Bernardo J, Billingslea AM, Blumenthal RL, Seetoo KF, Simons ER, Fenton MJ: Differential responses of human mononuclear phagocytes to mycobacterial lipoarabinomannans: role of CD14 and the mannose receptor. Infect Immun 1998, 66(1):28-35.
Reiling N, Holscher C, Fehrenbach A, Kroger S, Kirschning CJ, Goyert S, Ehlers S: Cutting edge: Toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol 2002, 169(7):3480-3484.
Pacheco E, Fonseca C, Montes C, Zabaleta J, Garcia LF, Arias MA: CD14 gene promoter polymorphism in different clinical forms of tuberculosis. FEMS Immunol Med Microbiol 2004, 40(3):207-213.
Jiao D, Wong CK, Qiu HN, Dong J, Cai Z, Chu M, Hon KL, Tsang MS, Lam CW: NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation. Cell Mol Immunol 2016, 13(4):535-550.
Landes MB, Rajaram MV, Nguyen H, Schlesinger LS: Role for NOD2 in Mycobacterium tuberculosis-induced iNOS expression and NO production in human macrophages. J Leukoc Biol 2015, 97(6):1111-1119.
Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ: Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003, 278(11):8869-8872.
Genetics Home Reference [https://ghr.nlm.nih.gov/.]
Bai X, Feldman NE, Chmura K, Ovrutsky AR, Su WL, Griffin L, Pyeon D, McGibney MT, Strand MJ, Numata M et al: Inhibition of nuclear factor-kappa B activation decreases survival of Mycobacterium tuberculosis in human macrophages. PLoS One 2013, 8(4):e61925.
Cai X, Xu Q, Zhou C, Zhou L, Dai W, Ji G: The association of nucleotide-binding oligomerization domain 2 gene polymorphisms with the risk of asthma in the Chinese Han population. Mol Genet Genomic Med 2019, 7(6):e00675.
Branquinho D, Freire P, Sofia C: NOD2 mutations and colorectal cancer - Where do we stand?World J Gastrointest Surg 2016, 8(4):284-293.
Sidiq T, Yoshihama S, Downs I, Kobayashi KS: Nod2: A Critical Regulator of Ileal Microbiota and Crohn's Disease. Front Immunol 2016, 7:367.
Ferwerda G, Girardin SE, Kullberg BJ, Le Bourhis L, de Jong DJ, Langenberg DM, van Crevel R, Adema GJ, Ottenhoff TH, Van der Meer JW et al: NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog 2005, 1(3):279-285.
Aravindan PP: Host genetics and tuberculosis: Theory of genetic polymorphism and tuberculosis. Lung India 2019, 36(3):244-252.
Deeks JJ, Dinnes J, D'Amico R, Sowden AJ, Sakarovitch C, Song F, Petticrew M, Altman DG, International Stroke Trial Collaborative G, European Carotid Surgery Trial Collaborative G: Evaluating non-randomised intervention studies. Health Technol Assess 2003, 7(27):iii-x, 1-173.
Zheng M, Shi S, Wei W, Zheng Q, Wang Y, Ying X, Lu D: Correlation between MBL2/CD14/TNF-alpha gene polymorphisms and susceptibility to spinal tuberculosis in Chinese population. Biosci Rep 2018, 38(1).
Xue Y, Zhao ZQ, Chen F, Zhang L, Li GD, Ma KW, Bai XF, Zuo YJ: Polymorphisms in the promoter of the CD14 gene and their associations with susceptibility to pulmonary tuberculosis. Tissue Antigens 2012, 80(5):437-443.
Zhao MY, Xue Y, Zhao ZQ, Li FJ, Fan DP, Wei LL, Sun XJ, Zhang X, Wang XC, Zhang YX et al: Association of CD14 G(-1145)A and C(-159)T polymorphisms with reduced risk for tuberculosis in a Chinese Han population. Genet Mol Res 2012, 11(3):3425-3431.
Alavi-Naini R, Salimi S, Sharifi-Mood B, Davoodikia AA, Moody B, Naghavi A: Association between the CD14 gene C-159T polymorphism and serum soluble CD14 with pulmonary tuberculosis. Int J Tuberc Lung Dis 2012, 16(10):1383-1387.
Ayaslioglu E, Kalpaklioglu F, Kavut AB, Erturk A, Capan N, Birben E: The role of CD14 gene promoter polymorphism in tuberculosis susceptibility. J Microbiol Immunol Infect 2013, 46(3):158-163.
Kang YA, Lee HW, Kim YW, Han SK, Shim YS, Yim JJ: Association between the -159C/T CD14 gene polymorphism and tuberculosis in a Korean population. FEMS Immunol Med Microbiol 2009, 57(3):229-235.
Druszczynska M, Strapagiel D, Kwiatkowska S, Kowalewicz-Kulbat M, Rozalska B, Chmiela M, Rudnicka W: Tuberculosis bacilli still posing a threat. Polymorphism of genes regulating anti-mycobacterial properties of macrophages. Pol J Microbiol 2006, 55(1):7-12.
Hall NB, Igo RP, Jr., Malone LL, Truitt B, Schnell A, Tao L, Okware B, Nsereko M, Chervenak K, Lancioni C et al: Polymorphisms in TICAM2 and IL1B are associated with TB. Genes Immun 2015, 16(2):127-133.
Zhao M, Jiang F, Zhang W, Li F, Wei L, Liu J, Xue Y, Deng X, Wu F, Zhang L et al: A novel single nucleotide polymorphism within the NOD2 gene is associated with pulmonary tuberculosis in the Chinese Han, Uygur and Kazak populations. BMC Infect Dis 2012, 12:91.
Pan H, Dai Y, Tang S, Wang J: Polymorphisms of NOD2 and the risk of tuberculosis: a validation study in the Chinese population. Int J Immunogenet 2012, 39(3):233-240.
Austin CM, Ma X, Graviss EA: Common nonsynonymous polymorphisms in the NOD2 gene are associated with resistance or susceptibility to tuberculosis disease in African Americans. J Infect Dis 2008, 197(12):1713-1716.
Shen W, Xiao L, Li Y, Zhou D, Zhang W: Association between polymorphisms in mannose-binding lectin 2 gene with pulmonary tuberculosis susceptibility. Hereditas 2020, 157(1):33.
Wu S, Liu X, Chen L, Wang Y, Zhang M, Wang M, He JQ: Polymorphisms of TLR2, TLR4 and TOLLIP and tuberculosis in two independent studies. Biosci Rep 2020, 40(8).
Yim JJ, Selvaraj P: Genetic susceptibility in tuberculosis. Respirology 2010, 15(2):241-256.
Azad AK, Sadee W, Schlesinger LS: Innate immune gene polymorphisms in tuberculosis. Infect Immun 2012, 80(10):3343-3359.
Jurcev-Savicevic A, Katalinic-Jankovic V, Mise K, Gudelj I: The role of interferon-gamma release assay in tuberculosis control. Arh Hig Rada Toksikol 2012, 63(1):49-59.
Wu YQ, Cheng SY, Xu XC, Li WC: Association between CD14 rs2569190 C>T polymorphism and ischemic stroke susceptibility: a meta-analysis based on 5,277 subjects. Neuropsychiatr Dis Treat 2019, 15:47-55.
Xu JJ, Liu KQ, Ying ZM, Zhu XW, Xu XJ, Zhao PP, Bai WY, Qiu MC, Zhang XW, Zheng HF: Effect of CD14 polymorphisms on the risk of cardiovascular disease: evidence from a meta-analysis. Lipids Health Dis 2019, 18(1):74.
Nieto-Fontarigo JJ, Salgado FJ, San-Jose ME, Cruz MJ, Casas-Fernandez A, Gomez-Conde MJ, Valdes-Cuadrado L, Garcia-Gonzalez MA, Arias P, Nogueira M et al: The CD14 (-159 C/T) SNP is associated with sCD14 levels and allergic asthma, but not with CD14 expression on monocytes. Sci Rep 2018, 8(1):4147.
Vercelli D: Gene-environment interactions in asthma and allergy: the end of the beginning?Curr Opin Allergy Clin Immunol 2010, 10(2):145-148.
Adams JF, Scholvinck EH, Gie RP, Potter PC, Beyers N, Beyers AD: Decline in total serum IgE after treatment for tuberculosis. Lancet 1999, 353(9169):2030-2033.
Ohrui T, Zayasu K, Sato E, Matsui T, Sekizawa K, Sasaki H: Pulmonary tuberculosis and serum IgE. Clin Exp Immunol 2000, 122(1):13-15.
Schenk M, Mahapatra S, Le P, Kim HJ, Choi AW, Brennan PJ, Belisle JT, Modlin RL: Human NOD2 Recognizes Structurally Unique Muramyl Dipeptides from Mycobacterium leprae. Infect Immun 2016, 84(9):2429-2438.
Toledo Pinto TG, Batista-Silva LR, Medeiros RCA, Lara FA, Moraes MO: Type I Interferons, Autophagy and Host Metabolism in Leprosy. Front Immunol 2018, 9:806.
Franchi L, Park JH, Shaw MH, Marina-Garcia N, Chen G, Kim YG, Nunez G: Intracellular NOD-like receptors in innate immunity, infection and disease. Cell Microbiol 2008, 10(1):1-8.
Behr MA, Divangahi M: Freund's adjuvant, NOD2 and mycobacteria. Curr Opin Microbiol 2015, 23:126-132.
Divangahi M, Mostowy S, Coulombe F, Kozak R, Guillot L, Veyrier F, Kobayashi KS, Flavell RA, Gros P, Behr MA: NOD2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity. J Immunol 2008, 181(10):7157-7165.
Zhang X, Yuan Z, Ji J, Li H, Xue F: Network or regression-based methods for disease discrimination: a comparison study. BMC Med Res Methodol 2016, 16:100.
Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Binder V et al: CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 2002, 70(4):845-857.
Bonen DK, Ogura Y, Nicolae DL, Inohara N, Saab L, Tanabe T, Chen FF, Foster SJ, Duerr RH, Brant SR et al: Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. Gastroenterology 2003, 124(1):140-146.
Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M et al: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001, 411(6837):599-603.
Rosenstiel P, Hellmig S, Hampe J, Ott S, Till A, Fischbach W, Sahly H, Lucius R, Folsch UR, Philpott D et al: Influence of polymorphisms in the NOD1/CARD4 and NOD2/CARD15 genes on the clinical outcome of Helicobacter pylori infection. Cell Microbiol 2006, 8(7):1188-1198.

Download PDF

Editorial decision: Major revision
06 Dec, 2020
Review #2 received at journal
05 Dec, 2020
Reviewer #2 agreed at journal
23 Nov, 2020
Review #1 received at journal
04 Nov, 2020
Editor assigned by journal
21 Oct, 2020
Reviewers invited by journal
21 Oct, 2020
Reviewer #1 agreed at journal
21 Oct, 2020
Editor invited by journal
20 Oct, 2020
Submission checks completed at journal
11 Oct, 2020
First submitted to journal
08 Oct, 2020

You are reading this latest preprint version

The Influence of Single Nucleotide Polymorphisms of NOD2 or CD14 on Susceptibility to Tuberculosis: A Systematic Review

Status:

Version 1

Abstract

Figures

Backgorund

Methods

Study aim

Literature search

Selection of studies

Data extraction

Quality assessment

Results

Selection of articles

Quality Assessment

Discussion

List of Abbreviations

Declarations

References

Status:

Version 1