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Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis

BMC Infectious Diseases volume 18, Article number: 282 (2018) Cite this article

Abstract

Background

Dengue and West Nile viruses are highly cross-reactive and have numerous parallels in geography, potential vector host (Aedes family of mosquitoes), and initial symptoms of infection. While the vast majority (> 80%) of both dengue and West Nile virus infections result in asymptomatic infections, a minority of individuals experience symptomatic infection and an even smaller proportion develop severe disease. The mechanisms by which these infections lead to severe disease in a subset of infected individuals is incompletely understood, but individual host differences including genetic factors and immune responses have been proposed. We sought to identify genetic risk factors that are associated with more severe disease outcomes for both viruses in order to shed light on possible shared mechanisms of resistance and potential therapeutic interventions.

Methods

We applied a search strategy using four major databases (Medline, PubMed, Embase, and Global Health) to find all known genetic associations identified to date with dengue or West Nile virus disease. Here we present a review of our findings and a meta-analysis of genetic variants identified.

Results

We found genetic variations that are significantly associated with infections of these viruses. In particular we found variation within the OAS1 (meta-OR = 0.83, 95% CI: 0.69–1.00) and CCR5 (meta-OR = 1.29, 95% CI: 1.08–1.53) genes is significantly associated with West Nile virus disease, while variation within MICB (meta-OR = 2.35, 95% CI: 1.68–3.29), PLCE1 (meta-OR = 0.55, 95% CI: 0.42–0.71), MBL2 (meta-OR = 1.54, 95% CI: 1.02–2.31), and IFN-γ (meta-OR = 2.48, 95% CI: 1.30–4.71), is associated with dengue disease.

Conclusions

Despite substantial heterogeneity in populations studied, genes examined, and methodology, significant associations with genetic variants were found across studies within both diseases. These gene associations suggest a key role for immune mechanisms in susceptibility to severe disease. Further research is needed to elucidate the role of these genes in disease pathogenesis and may reveal additional genetic factors associated with disease severity.

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Background

Dengue (DENV) and West Nile (WNV) viruses are mosquito-borne viruses in the Flaviviridae family, which also includes other viruses such as Zika and yellow fever. These viruses can cause disease with substantial public health impact. DENV and WNV are found in similar areas of the world, can be carried by the Aedes family of mosquitoes, have similar initial stages of infections and similar symptoms of mild febrile illness, and are highly cross-reactive; however, severe disease manifests differently for these two viruses [1,2,3]. West Nile Virus was first identified in Uganda in 1937, has been endemic in the United States since 1999 [4], and is estimated to have infected 3 million people [5]. While the majority of infections are asymptomatic, ~ 20% of infections lead to mild febrile disease in infected individuals and 1% of infected individual experience severe, neurological disease such as meningitis and encephalitis [6]. DENV has a vastly higher disease burden, with an estimated 50 million cases and 25,000 fatalities worldwide annually [7, 8]. The majority of DENV infections can be classified as asymptomatic or mild febrile illness, with approximately < 1% progressing to Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS). DHF is delineated from mild DENV febrile illness by the increase in vascular permeability, while DSS has the additional development of circulatory shock [7, 8].

For both WNV and DENV, known risk factors such as immune-compromised states or advanced age are associated with susceptibility to mild and severe disease [9, 10]. The mechanisms by which an infection leads to severe disease in a subset of all infected individuals is incompletely explained. Differing immune responses to infections, including elevated cytokine responses, have been proposed [11,12,13] and we have recently shown that geographic location is not a driver of severity of WNV infection in a localized region [14]. In addition to similarities in the early stages of infection [15,16,17], both viruses induce strong immune responses including chemokines (such as IL-8) and cytokines which up-regulate inflammatory reaction (such as TNF-α, IL-1, Il-6, and IFN-β) [18,19,20,21]. Renewed interest in understanding flaviviral infection and disease susceptibility comes as climate change expands the number of individuals at risk of exposure to WNV and DENV [3, 22], and with outbreaks of related flaviviruses, most notably Zika [23, 24].

Genetic differences are additional explanations of individual susceptibility to symptomatic disease, and previous genome-wide association studies (GWAS) and candidate-gene studies have identified genetic factors associated with DENV or WNV disease pathogenesis. To assess the current state of knowledge on genetic variation associated with these flaviviral diseases, and to identify any shared features of anti-viral responses, we conducted a systematic review and meta-analysis of the published associations to date between genetic variants and development of DENV or WNV disease.

Methods

A systematic review of genetic factors and WNV or DENV disease was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Additional file 1) [25].

Search strategy

Medline, PubMed, Embase, and Global Health databases were used to search the literature. Search terms included West Nile or DENV and genetic factors; the same set of text words was used for all databases in conjunction with subject headings that were tailored for each database. The text word search specified West Nile or Dengue in the title, a genetic term in the title or abstract, and a human-related term in the title or abstract (Table 1). A sample search strategy is included in the appendix (Additional file 2). Case-control studies which examined at least one genetic factor associated with either viral disease were included. Studies on non-human (e.g., viral, mosquito) genetics and case reports on single patients were excluded. Reports published prior to May 2017 were included in the review. An ancestry search was done of references of selected studies to collect additional potentially relevant references.

Table 1 Text word selection for search of selected databases. Text words used for the search strategy, with one term from each column required in the title for the viral term, or in the title or abstract for the genetic and human terms
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Study selection and data extraction

Two researchers reviewed the titles and abstracts of all studies and identified potentially relevant articles within Covidence with 98.6% consistency [26]. Discrepancies were resolved through re-review and mutual consensus. Both researchers read the full text of all of the selected potentially relevant articles and identified the final reports to be included in this review. Data sets were extracted without personal identifiers and organized into literature tables. The main fields included authors, year of publication, country, sample size, case and control group definitions, genotyping method, genes and genetic variants analyzed, genotype count data when available, odds ratios (OR), and statistical analysis method.

When two or more studies examined the same variants, we used the raw genotype data to calculate ORs with 95% confidence intervals using the R package Epitools [27]. When the raw genotype data were not available within the published papers, we requested the data sets from corresponding authors of the studies. Of the six authors contacted, three shared data, two indicated they no longer had access to the data, and one did not respond by date of submission. In order to make comparisons across the different DENV phenotypes used in the studies, we compared asymptomatic DENV infections and controls with all symptomatic infections (DENV fever, DENV hemorrhagic fever, and DENV shock syndrome). Using the genotype data, we calculated ORs for each study under a dominant model, recessive model, homozygote mutant versus homozygote wild-type, and heterozygote versus homozygote wild-type. We meta-analyzed the ORs using RevMan [28]. The genetic model with the most significant meta-OR is presented here. When this model was the homozygote mutant versus homozygote wild or the heterozygote versus homozygote wild, we included both of these models for that particular single nucleotide polymorphism (SNP).

Quality assessment

We assessed the quality of each study with the Newcastle-Ottawa Quality Assessment Scale for Case-Control Studies [29], which assesses each study’s selection, comparability, and exposure ascertainment approach.

Results

To identify all published research assessing the role of genetic variation with DENV or WNV disease, we executed the above search strategy and identified 633 published reports (Table 1, Fig. 1). Two researchers independently reviewed the titles and abstracts of these 633 papers and identified 104 papers for further full-text review in this meta-analysis (Additional file 3). One additional paper from 1987 was identified as pertinent during the ancestry search and was added to the review. The final analysis includes data from 87 of the 105 publications, following exclusion of 18 papers for cause (seven repeats, six conference abstracts, and five with an outcome other than disease severity). Reflecting the higher disease burden and longer research history of DENV virus, of these 87 papers selected, 74 studied DENV-infected populations and 13 focused on WNV.

Fig. 1
figure 1

PRISMA Flowchart of strategy to identify papers assessing genetic variation and WNV or DENV disease

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HLA genetic variation associated with disease severity

Notably, 27 separate HLA alleles were examined by two or more research groups for an association with severe DENV disease (Additional file 4). Four research groups analyzed HLA alleles for an association with WNV disease (Additional file 5), however there was no overlap in the alleles studied. Although HLA variants show substantial contribution to disease outcome, significant variations in study design, data analysis platforms, data availability and presentation precluded our in-depth meta-analysis of these data.

Multiple genes are associated with severity of WNV infection

Previous reports of genetic associations with WNV disease severity focused on U.S. or Canadian populations and compared severe and non-severe infections. Overall, these studies identified 12 gene variants and significant findings include SNPs of multiple immune-related genes such as RFC1, SCN1A, and IRF3 (Table 2).

Table 2 Genetic variation significantly associated with West Nile virus disease. We include in this table all variants studied by two or more research groups and variants found to have a significant association by one research group
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OAS1 and CCR5 have significant associations with WNV disease across multiple studies

For genes with genotype count data available for ≥2 studies, we conducted a meta-analysis of genetic association to disease severity. Meta-analysis allows recognition of well-established genetic associations and identification of redundant studies for genes with null associations. We found that SNPs in MX1, OASL, OAS1, RFC1, and CCR5 were studied by multiple research groups for an association with WNV disease (Table 2). To assess the overall association of these SNPs with WNV disease, we calculated a combined OR for each gene based on the genotype counts under four different genetic models. Of these, CCR5 and OAS1 meta-ORs were significant under a dominant model, with meta-OR of 0.83 [95% CI: 0.69–1.00] and 1.29 [1.08–1.53], respectively (Fig. 2). The CCR5 meta-OR was also significant under an allelic model with a meta-OR of 1.22 [95% CI: 1.03–1.44]. The CCR5 delta 32 deletion is associated with more severe disease while the OAS1 allele G was associated with less severe disease.

Fig. 2
figure 2

Significant meta-ORs for associations between OAS1 (rs10774671) and CCR5 (Δ32) and West Nile virus disease. Genotype count data from published reports of WNV subjects were meta-analyzed using RevMan. The meta-odds ratio (OR) for more severe disease is indicated with the genetic model for each gene. For each gene, the allele or genotype is shown which is associated with asymptomatic infection and controls (blue) or severe disease (yellow) outcome

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Multiple genes are associated with severity of DENV infection

Seventy-four studies have examined genetic associations with DENV disease severity and more than 30 genes have been implicated in DENV disease (Additional file 3). SNPs that were studied by only a single research group are presented in Table 3. We also include SNPs studied by multiple research groups, but for which genotype data was unavailable or the comparison groups of multiple studies could not be analyzed together.

Table 3 Genetic variation associated with DENV disease. We include in this table all variants studied by two or more research groups and variants found to have a significant association by one research group
Full size table

Significant associations with DENV disease

Among the DENV studies, the same variant within 17 genes was studied by two or more research groups (Table 3). Four genes had significant meta-ORs (Fig. 3). For a SNP in MBL2 (exon 1), we calculated a meta-OR of 1.54 [1.02–2.31] under a dominant model and 1.65 [1.18–2.32] under an allelic model, with alleles other than the A allele being associated with more severe disease. The T allele for SNP rs2430561 in the IFN-γ gene was associated with severe disease under a recessive model with a meta-OR of 2.48 [0.30–4.71]. For a SNP located within MICB (rs3132468), we found the CC genotype had a significantly greater association with severe disease (meta-OR 2.35 [1.68–3.29]), but the heterozygote genotype showed no significant association with disease severity as compared to the TT genotype (meta-OR = 1.17 [0.86–1.59]). For this SNP, the C allele was also found to be significantly associated with disease as compared to the T allele (meta-OR = 1.35 [1.16–1.57]). For two SNPs located within the PLCE1 gene, every model tested was significant, with the most significant meta-ORs being 0.62 [0.48–0.79] for TT genotype as compared to CC genotype for rs3740360 and 0.55 [0.42–0.71] under a recessive model for rs3765524. TNF-α (rs1800629 and rs361525) was the most studied gene, but none of the models tested provided a significant meta-OR.

Fig. 3
figure 3

Meta-analyzed genetic variation associated with DENV disease. Genotype count data from published reports of WNV subjects were meta-analyzed using RevMan. The meta-odds ratio (OR) for more severe disease is indicated with the genetic model for each gene: MBL2 (a), IFN-γ (b), MICB (c), PLCE1 (d and e). If multiple models were significant, we present the most significant model. The alleles or genotypes associated with asymptomatic infection and controls (blue) or with severe disease (yellow) outcome are shown for each gene

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Quality scores

Based on the Newcastle Ottawa Scoring System, the average quality score was 5.76 (range: 3–7) for the WNV publications and 5.10 (range: 2–7) for the DENV publications (Additional file 6). We also assessed whether the study authors corrected for multiple testing, and found less than half of both WNV and DENV studies provided corrected p-values when appropriate, indicating an inflated type I error rate.

Discussion

We have examined genetic variants that show association with DENV or WNV disease severity. This analysis was undertaken to identify genetic differences that are significant drivers of susceptibility to symptomatic disease that may shed light on mechanisms of immune resistance to these viruses. Among the 87 studies examined, a wide range of genetic targets was found to be significant, with many of the genes unsurprisingly playing a key role in the immune system defense against viral infections (Additional file 7).

Despite the large number of studies, only 27 genes were studied by more than one research group for an association with either disease. Throughout these studies, several key genes rose to the forefront as the most studied and the most significant associations. Many studies focused on the HLA region of the genome, and, although inconsistencies in data presentation preclude a meta-analyze of these results, there were clear signs of the importance of this area for both diseases.

With the central role of HLA for the immune system, polymorphisms in this region have been well studied for associations with disease. The area is highly polymorphic, however, leading to difficulties for comparing the diverse range of alleles. Adding to this complexity, DENV serotypes interact differently with HLA [30]. The regions identified in this systematic review, including DRB1, DQA1, DQB1, A, B, and C, are among the most diverse regions of the HLA region [31]. A recent study examined some of these regions by supertype, and found the B44 supertype could be protective against DHF during secondary infections and that the A02 and A01/03 supertypes could be associated with more severe disease [32].

KIR genes, which are expressed on the surface of natural killer cells, also have wide genetic variability as noted with HLA genes [33]. While several KIR alleles were studied in DENV-infected populations, only one publication to date has examined KIR genotypes in West Nile virus-infected individuals, and this study had a sample size of four [34]. The results suggested a possible association; this, in conjunction with the results of the DENV research in this area and the genes’ highly polymorphic nature, could be an area that should be explored further. Infection with WNV has been shown to lead to diversification of KIR receptor expression [35]. In addition to the research outlined above, researchers have examined the association of KIR genotypes with DENV infection in vitro. Within the in vitro research, the timing of natural killer cell activation has been linked to disease severity and interactions between KIR and HLA have been suggested [36,37,38].

Another key non-HLA gene identified to be associated with WNV disease was OASL, which codes for an enzyme that is induced by type 1 interferon and viruses [39]. OASL was first identified to have a potentially critical role in WNV disease pathogenesis in 2002, when researchers found that mice with a truncated form of the gene were more susceptible to disease [40]. Elevated activity of the OAS genes has also been associated with more severe DENV infection in vitro [41]. This data and the significance of variation within the OAS genes for WNV outcomes highlight the importance of the interferon pathways in response to flavivirus infections and suggest a need for further in depth examination the association of genetic variability within OAS and DENV severity.

CCR5Δ32 was the only gene studied by two or more research groups for each disease. CCR5 was first identified as a co-receptor for HIV in 1996, and CCR5 deficiency, or a homozygous genotype of CCR5Δ32, was found to be protective against HIV infection [42,43,44,45]. In West Nile, CCR5 deficiency is not associated with incidence of infection, but is associated with severity of disease for infected individuals [46]. Subsequent research showed that CCR5 specifically plays a role in the ability of cortical neurons to combat West Nile virus infection of the brain [47]. In DENV, CCR5 deficiency has been linked with increased viral load and disease severity [48]. The study also found that the CCR5 receptor in macrophages is necessary for replication of DENV serotype 2, an early step in the infection process [49]. Given the similarities of these flaviviral diseases and the significant association of CCR5, the only gene looked at by research groups for both diseases, further research could be beneficial to further understanding the role of genetic variation in the development of severe flavivviral disease [50].

When we meta-analyzed the DENV studies, we found significant associations between DENV disease and genetic variation in MBL2, PLCE1, IFN-γ, and MICB. The role of many of these genes in disease pathogenesis has been characterized through in vivo and in vitro studies. MBL2, the mannose-binding lectin 2 gene, encodes a protein with a role in innate immunity and complement pathway, while PLCE1 encodes an enzyme critical to the generation of the inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) messengers [51]. MICB and IFN-y are both critical in the immune response, and thus variations within these genes could have strong effects on the initial response to the viral infection and the subsequent disease pathogenesis [51].

Our study is limited by several factors, most notably by the available literature. To ensure we found as many papers as possible, we constructed a search strategy that involved multiple databases, used both subject headings and text words, was not limited to English articles, and included an ancestry search [52]. Despite our focus on significant results and genes studied by at least two research groups, the wide heterogeneity among the populations studied limited our ability to interpret the meta-analyzed results. Lack of diversity in genetic studies is well-documented [53], and the absence of certain affected populations, particularly in Africa, among the identified studies further demonstrates this unmet research need [54]. The diversity of results among studies that examined the same SNP could be due to population heterogeneity, as well as to differences in study approach, including selection of control and comparison groups. Additionally, previous exposure history, DENV serotype, and WNV or DENV genotype are all factors that can affect disease severity, but were not accounted for in the included studies [4]. The number and type of genes examined varied greatly between studies, and we were limited by what genes researchers chose to sequence and include in publications. The unavailability of comparable genotype data and the incomparability of research groups across some studies preclude a more in depth analysis at present.

Conclusions

The genes found to be significantly associated with WNV or DENV disease pathogenesis varied in function, with most being linked to the immune response. As the regions of the world affected by WNV, DENV, and related viruses such as Zika, continue to expand due in part to climate change, an improved understanding of the association between genetic variation and disease severity will be valuable for all potentially affected populations [55,56,57,58]. Based on the growing incidence of these diseases, the paucity of consistency in the associations found, and the limited overlap in genetic targets studied to date, there is need for continued and deeper studies examining the role of genetic factors in WNV and DENV disease severity. In addition to conducting new studies such as whole-exome sequencing within larger population samples, further analyses could be conducted of existing data, to glean novel findings such as gene-gene or gene-environment interactions, rare and low frequency variants, and pathways of significant determinants of anti-viral resistance.

Abbreviations

DENV:

Dengue virus

DHF:

Dengue Hemorrhagic Fever

DSS:

Dengue Shock Syndrome

GWAS:

genome-wide association studies

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

SNP:

single nucleotide polymorphism

WNV:

West Nile virus

References

  1. Papa A, Karabaxoglou D, Kansouzidou A. Acute West Nile virus neuroinvasive infections: cross-reactivity with dengue virus and tick-borne encephalitis virus. J Med Virol. 2011;83(10):1861–5.

    Article  PubMed  Google Scholar 

  2. Hua RH, Chen NS, Qin CF, Deng YQ, Ge JY, Wang XJ, Qiao ZJ, Chen WY, Wen ZY, Liu WX, et al. Identification and characterization of a virus-specific continuous B-cell epitope on the PrM/M protein of Japanese encephalitis virus: potential application in the detection of antibodies to distinguish Japanese encephalitis virus infection from West Nile virus and dengue virus infections. Virol J. 2010;7:249.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Daep CA, Munoz-Jordan JL, Eugenin EA. Flaviviruses, an expanding threat in public health: focus on dengue, West Nile, and Japanese encephalitis virus. J Neuro-Oncol. 2014;20(6):539–60.

    CAS  Google Scholar 

  4. Gubler DJ. The continuing spread of West Nile virus in the western hemisphere. Clin Infect Dis. 2007;45(8):1039–46.

    Article  PubMed  Google Scholar 

  5. Petersen LR, Brault AC, Nasci RS. West Nile virus: review of the literature. JAMA. 2013;310(3):308–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Symptoms & Treatments [http://www.cdc.gov/westnile/symptoms/index.html].

  7. Coffey LL, Mertens E, Brehin AC, Fernandez-Garcia MD, Amara A, Despres P, Sakuntabhai A. Human genetic determinants of dengue virus susceptibility. Microbes Infect. 2009;11(2):143–56.

    Article  PubMed  CAS  Google Scholar 

  8. Kalayanarooj S. Clinical manifestations and Management of Dengue/DHF/DSS. Trop Med Health. 2011;39(4 Suppl):83–7.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Montgomery RR, Murray KO. Risk factors for West Nile virus infection and disease in populations and individuals. Expert Rev Anti-Infect Ther. 2015;13(3):317–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Whitehorn J, Hubbard S, Anders KL, Quyen NTH, Simmons C. Dengue pathogenesis: host factors. Dengue and Dengue Hemorrhagic Fever, 2nd Edition. 2014:214–28.

  11. James EA, Gates TJ, LaFond RE, Yamamoto S, Ni C, Mai D, Gersuk VH, O'Brien K, Nguyen QA, Zeitner B, et al. Neuroinvasive West Nile infection elicits elevated and atypically polarized T cell responses that promote a pathogenic outcome. PLoS Pathog. 2016;12(1):e1005375.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Qian F, Thakar J, Yuan X, Nolan M, Murray KO, Lee WT, Wong SJ, Meng H, Fikrig E, Kleinstein SH, et al. Immune markers associated with host susceptibility to infection with West Nile virus. Viral Immunol. 2014;27(2):39–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Yao Y, Montgomery RR. Role of immune aging in susceptibility to West Nile virus. Methods Mol Biol. 2016;1435:235–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Cahill ME, Yao Y, Nock D, Armstrong PM, Andreadis TG, Diuk-Wasser MA, Montgomery RR. West Nile Virus Seroprevalence, Connecticut, USA, 2000-2014. Emerg Infect Dis. 2017;23(4):708–10.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Krishnan MN, Sukumaran B, Pal U, Agaisse H, Murray JL, Hodge TW, Fikrig E. Rab 5 is required for the cellular entry of dengue and West Nile viruses. J Virol. 2007;81(9):4881–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Campos RK, Wong B, Xie XP, Lu YF, Shi PY, Pompon J, Garcia-Blanco MA, Bradrick SS. RPLP1 and RPLP2 are essential Flavivirus host factors that promote early viral protein accumulation. J Virol. 2017;91(4)

  17. Gack MU, Diamond MS. Innate immune escape by dengue and West Nile viruses. Curr Opin Virol. 2016;20:119–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Chaturvedi UC, Agarwal R, Elbishbishi EA, Mustafa AS. Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol Med Microbiol. 2000;28(3):183–8.

    Article  PubMed  CAS  Google Scholar 

  19. Kumar M, Verma S, Nerurkar VR. Pro-inflammatory cytokines derived from West Nile virus (WNV)-infected SK-N-SH cells mediate neuroinflammatory markers and neuronal death. J Neuroinflammation. 2010;7:73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Rossini G, Landini MP, Gelsomino F, Sambri V, Varani S. Innate host responses to West Nile virus: implications for central nervous system immunopathology. World J Virol. 2013;2(2):49–56.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol. 2009;78(6):539–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Mackenzie JS, Gubler DJ, Petersen LR. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med. 2004;10(12):S98–S109.

    Article  PubMed  CAS  Google Scholar 

  23. Hotez PJ, Murray KO. Dengue, West Nile virus, chikungunya, Zika - and now Mayaro? PLoS Negl Trop Dis. 2017;11(8): e0005462.

  24. Yun SI, Lee YM. Zika virus: An emerging flavivirus. J Microbiol. 2017;55(3):204–19.

    Article  PubMed  CAS  Google Scholar 

  25. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Covidence systematic review software. www.covidence.org.

  27. Tomas J. Aragon MPF, Daniel Wollschlaeger, Adam Omidpanah: epitools: Epidemiology Tools. In.; 2017.

  28. Review Manager (RevMan). In., 5.3 EDN Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2014.

  29. Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, Tugwell P: The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. In.; 2000.

  30. Gan CS, Yusof R, Othman S. Different serotypes of dengue viruses differently regulate the expression of the host cell antigen processing machinery. Acta Trop. 2015;149:8–14.

    Article  PubMed  CAS  Google Scholar 

  31. Shiina T, Hosomichi K, Inoko H, Kulski JK. The HLA genomic loci map: expression, interaction, diversity and disease. J Hum Genet. 2009;54(1):15–39.

    Article  PubMed  CAS  Google Scholar 

  32. Vejbaesya S, Thongpradit R, Kalayanarooj S, Luangtrakool K, Luangtrakool P, Gibbons RV, Srinak D, Ngammthaworn S, Apisawes K, Yoon IK, et al. HLA class I Supertype associations with clinical outcome of secondary dengue virus infections in ethnic Thais. J Infect Dis. 2015;212(6):939–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Uhrberg M. The KIR gene family: life in the fast lane of evolution. Eur J Immunol. 2005;35(1):10–5.

    Article  PubMed  CAS  Google Scholar 

  34. Spiroski M, Milenkovic Z, Petlichkovski A, Ivanovski L, Topuzovska IK, Djulejic E. Killer cell immunoglobulin-like receptor genes in four human West Nile virus infections reported 2011 in the republic of Macedonia. Hum Immunol. 2013;74(3):389–94.

    Article  PubMed  CAS  Google Scholar 

  35. Strauss-Albee DM, Fukuyama J, Liang EC, Yao Y, Jarrell JA, Drake AL, Kinuthia J, Montgomery RR, John-Stewart G, Holmes S, et al. Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility. Sci Transl Med. 2015;7(297):297ra115.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Azeredo EL, De Oliveira-Pinto LM, Zagne SM, Cerqueira DI, Nogueira RM, Kubelka CF. NK cells, displaying early activation, cytotoxicity and adhesion molecules, are associated with mild dengue disease. Clin Exp Immunol. 2006;143(2):345–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Townsley E, O'Connor G, Cosgrove C, Woda M, Co M, Thomas SJ, Kalayanarooj S, Yoon IK, Nisalak A, Srikiatkhachorn A, et al. Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells. Clin Exp Immunol. 2016;183(3):419–30.

    Article  PubMed  CAS  Google Scholar 

  38. Yao Y, Strauss-Albee DM, Zhou JQ, Malawista A, Garcia MN, Murray KO, Blish CA, Montgomery RR. The natural killer cell response to West Nile virus in young and old individuals with or without a prior history of infection. PLoS One. 2017;12(2):e0172625.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. OASL - 2′-5′-oligoadenylate synthase-like protein. http://www.uniprot.org/uniprot/Q15646.

  40. Mashimo T, Lucas M, Simon-Chazottes D, Frenkiel MP, Montagutelli X, Ceccaldi PE, Deubel V, Guenet JL, Despres P. A nonsense mutation in the gene encoding 2′-5′-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice. Proc Natl Acad Sci U S A. 2002;99(17):11311–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Simon-Loriere E, Lin RJ, Kalayanarooj SM, Chuansumrit A, Casademont I, Lin SY, Yu HP, Lert-Itthiporn W, Chaiyaratana W, Tangthawornchaikul N, et al. High anti-dengue virus activity of the OAS gene family is associated with increased severity of dengue. J Infect Dis. 2015;212(12):2011–20.

    Article  PubMed  CAS  Google Scholar 

  42. Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996;272(5270):1955–8.

    Article  PubMed  CAS  Google Scholar 

  43. Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996;381(6584):661–6.

    Article  PubMed  CAS  Google Scholar 

  44. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996;381(6584):667–73.

    Article  PubMed  CAS  Google Scholar 

  45. Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, MacDonald ME, Stuhlmann H, Koup RA, Landau NR. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996;86(3):367–77.

    Article  PubMed  CAS  Google Scholar 

  46. Lim JK, McDermott DH, Lisco A, Foster GA, Krysztof D, Follmann D, Stramer SL, Murphy PM. CCR5 deficiency is a risk factor for early clinical manifestations of West Nile virus infection but not for viral transmission. J Infect Dis. 2010;201(2):178–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Durrant DM, Daniels BP, Pasieka T, Dorsey D, Klein RS. CCR5 limits cortical viral loads during West Nile virus infection of the central nervous system. J Neuroinflammation. 2015;12:233.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Marques RE, Guabiraba R, Del Sarto JL, Rocha RF, Queiroz AL, Cisalpino D, Marques PE, Pacca CC, Fagundes CT, Menezes GB, et al. Dengue virus requires the CC-chemokine receptor CCR5 for replication and infection development. Immunology. 2015;145(4):583–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Chen YC, Wang SY. Activation of terminally differentiated human monocytes/macrophages by dengue virus: productive infection, hierarchical production of innate cytokines and chemokines, and the synergistic effect of lipopolysaccharide. J Virol. 2002;76(19):9877–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Loeb M. Genetic susceptibility to West Nile virus and dengue. Public Health Genomics. 2013;16(1–2):4–8.

    Article  PubMed  CAS  Google Scholar 

  51. Gene. https://www.ncbi.nlm.nih.gov/gene/.

  52. Akobeng AK. Understanding systematic reviews and meta-analysis. Arch Dis Child. 2005;90(8):845–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Popejoy AB, Fullerton SM. Genomics is failing on diversity. Nature. 2016;538(7624):161–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Were F. The dengue situation in Africa. Paediatr Int Child Health. 2012;32(Suppl 1):18–21.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Ebi KL, Nealon J. Dengue in a changing climate. Environ Res. 2016;151:115–23.

    Article  PubMed  CAS  Google Scholar 

  56. Paz S. Climate change impacts on West Nile virus transmission in a global context. Philos Trans R Soc Lond Ser B Biol Sci. 2015;370(1665)

  57. Carlson CJ, Dougherty ER, Getz W. An ecological assessment of the pandemic threat of Zika virus. PLoS Negl Trop Dis. 2016;10(8):e0004968.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Lessler J, Chaisson LH, Kucirka LM, Bi Q, Grantz K, Salje H, Carcelen AC, Ott CT, Sheffield JS, Ferguson NM, et al. Assessing the global threat from Zika virus. Science. 2016;353(6300):aaf8160.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Loeb M, Eskandarian S, Rupp M, Fishman N, Gasink L, Patterson J, Bramson J, Hudson TJ, Lemire M. Genetic variants and susceptibility to neurological complications following West Nile virus infection. J Infect Dis. 2011;204(7):1031–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Danial-Farran N, Eghbaria S, Schwartz N, Kra-Oz Z, Bisharat N. Genetic variants associated with susceptibility of Ashkenazi Jews to West Nile virus infection. Epidemiology & Infection. 2015;143(4):857–63.

    Article  CAS  Google Scholar 

  61. Long D, Deng X, Singh P, Loeb M, Lauring AS, Seielstad M. Identification of genetic variants associated with susceptibility to West Nile virus neuroinvasive disease. Genes & Immunity. 2016;17(5):298–304.

    Article  CAS  Google Scholar 

  62. Bigham AW, Buckingham KJ, Husain S, Emond MJ, Bofferding KM, Gildersleeve H, Rutherford A, Astakhova NM, Perelygin AA, Busch MP et al: Host genetic risk factors for West Nile virus infection and disease progression. PLoS One 2011, 6 (9) (no pagination)(e24745).

  63. Glass WG, McDermott DH, Lim JK, Lekhong S, Yu SF, Frank WA, Pape J, Cheshier RC, Murphy PM. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med. 2006;203(1):35–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Das R, Loughran K, Murchison C, Qian F, Leng L, Song Y, Montgomery RR, Loeb M, Bucala R. Association between high expression macrophage migration inhibitory factor (MIF) alleles and West Nile virus encephalitis. Cytokine. 2016;78:51–4.

    Article  PubMed  CAS  Google Scholar 

  65. Yakub I, Lillibridge KM, Moran A, Gonzalez OY, Belmont J, Gibbs RA, Tweardy DJ. Single nucleotide polymorphisms in genes for 2′-5′-oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infection. J Infect Dis. 2005;192(10):1741–8.

    Article  PubMed  CAS  Google Scholar 

  66. Lim JK, Lisco A, McDermott DH, Huynh L, Ward JM, Johnson B, Johnson H, Pape J, Foster GA, Krysztof D, et al. Genetic variation in OAS1 is a risk factor for initial infection with West Nile virus in man. PLoS Pathog. 2009;5(2):e1000321.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Dang TN, Naka I, Sa-Ngasang A, Anantapreecha S, Wichukchinda N, Sawanpanyalert P, Patarapotikul J, Tsuchiya N, Ohashi J. Association of BAK1 single nucleotide polymorphism with a risk for dengue hemorrhagic fever. BMC Medical Genetics. 2016;17(1):43.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Brestovac B, Halicki LA, Harris RP, Sampson I, Speers DJ, Mamotte C, Williams D. Primary acute dengue and the deletion in chemokine receptor 5 (CCR5DELTA32). Microbes & Infection. 2014;16(6):518–21.

    Article  CAS  Google Scholar 

  69. Xavier-Carvalho C, Gibson G, Brasil P, Ferreira RX, de Souza Santos R, Goncalves Cruz O, de Oliveira SA, de Sa Carvalho M, Pacheco AG, Kubelka CF, et al. Single nucleotide polymorphisms in candidate genes and dengue severity in children: a case-control, functional and meta-analysis study. Infection, Genetics & Evolution. 2013;20:197–205.

    Article  CAS  Google Scholar 

  70. Alagarasu K, Damle IM, Bachal RV, Mulay AP, Shah PS, Dayaraj C. Association of promoter region polymorphisms of CD209 gene with clinical outcomes of dengue virus infection in western India. Infection, Genetics & Evolution. 2013;17:239–42.

    Article  CAS  Google Scholar 

  71. Noecker CA, Amaya-Larios IY, Galeana-Hernandez M, Ramos-Castaneda J, Martinez-Vega RA. Contrasting associations of polymorphisms in FcgammaRIIa and DC-SIGN with the clinical presentation of dengue infection in a Mexican population. Acta Trop. 2014;138:15–22.

    Article  PubMed  CAS  Google Scholar 

  72. Oliveira LF, Lima CP, Azevedo Rdo S, Mendonca DS, Rodrigues SG, Carvalho VL, Pinto EV, Maia AL, Maia MH, Vasconcelos JM, et al. Polymorphism of DC-SIGN (CD209) promoter in association with clinical symptoms of dengue fever. Viral Immunol. 2014;27(5):245–9.

    Article  PubMed  CAS  Google Scholar 

  73. Sakuntabhai A, Turbpaiboon C, Casademont I, Chuansumrit A, Lowhnoo T, Kajaste-Rudnitski A, Kalayanarooj SM, Tangnararatchakit K, Tangthawornchaikul N, Vasanawathana S, et al. A variant in the CD209 promoter is associated with severity of dengue disease. Nat Genet. 2005;37(5):507–13.

    Article  PubMed  CAS  Google Scholar 

  74. Silva LK, Blanton RE, Parrado AR, Melo PS, Morato VG, Reis EA, Dias JP, Castro JM, Vasconcelos PF, Goddard KA, et al. Dengue hemorrhagic fever is associated with polymorphisms in JAK1. Eur J Hum Genet. 2010;18(11):1221–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Wang L, Chen RF, Liu JW, Lee IK, Lee CP, Kuo HC, Huang SK, Yang KD. DC-SIGN (CD209) promoter −336 a/G polymorphism is associated with dengue hemorrhagic fever and correlated to DC-SIGN expression and immune augmentation. PLoS Neglected Tropical Diseases [electronic resource]. 2011;5(1):e934.

    Article  CAS  Google Scholar 

  76. Kraivong R, Vasanawathana S, Limpitikul W, Malasit P, Tangthawornchaikul N, Botto M, Screaton GR, Mongkolsapaya J, Pickering MC. Complement alternative pathway genetic variation and dengue infection in the Thai population. Clinical & Experimental Immunology. 2013;174(2):326–34.

    CAS  Google Scholar 

  77. Pastor AF, Rodrigues Moura L, Neto JW, Nascimento EJ, Calzavara-Silva CE, Gomes AL, Silva AM, Cordeiro MT, Braga-Neto U, Crovella S, et al. Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression. Hum Immunol. 2013;74(9):1225–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Alagarasu K, Bachal RV, Tillu H, Mulay AP, Kakade MB, Shah PS, Cecilia D. Association of combinations of interleukin-10 and pro-inflammatory cytokine gene polymorphisms with dengue hemorrhagic fever. Cytokine. 2015;74(1):130–6.

    Article  PubMed  CAS  Google Scholar 

  79. Alagarasu K, Memane RS, Shah PS. Polymorphisms in the retinoic acid-1 like-receptor family of genes and their association with clinical outcome of dengue virus infection. Arch Virol. 2015;160(6):1555–60.

    Article  PubMed  CAS  Google Scholar 

  80. Alagarasu K, Bachal RV, Damle I, Shah PS, Cecilia D. Association of FCGR2A p.R131H and CCL2 c.-2518 A>G gene variants with thrombocytopenia in patients with dengue virus infection. Hum Immunol. 2015;76(11):819–22.

    Article  PubMed  CAS  Google Scholar 

  81. Garcia G, Sierra B, Perez AB, Aguirre E, Rosado I, Gonzalez N, Izquierdo A, Pupo M, Danay Diaz DR, Sanchez L, et al. Asymptomatic dengue infection in a Cuban population confirms the protective role of the RR variant of the FcgammaRIIa polymorphism. American Journal of Tropical Medicine & Hygiene. 2010;82(6):1153–6.

    Article  Google Scholar 

  82. Loke H, Bethell D, Phuong CX, Day N, White N, Farrar J, Hill A. Susceptibility to dengue hemorrhagic fever in Vietnam: evidence of an association with variation in the vitamin d receptor and fc gamma receptor IIa genes. American Journal of Tropical Medicine & Hygiene. 2002;67(1):102–6.

    Article  CAS  Google Scholar 

  83. Mohsin SN, Mahmood S, Amar A, Ghafoor F, Raza SM, Saleem M. Association of FcgammaRIIa polymorphism with clinical outcome of dengue infection: first insight from Pakistan. American Journal of Tropical Medicine & Hygiene. 2015;93(4):691–6.

    Article  CAS  Google Scholar 

  84. Soundravally R, Hoti SL. Immunopathogenesis of dengue hemorrhagic fever and shock syndrome: role of TAP and HPA gene polymorphism. Hum Immunol. 2007;68(12):973–9.

    Article  PubMed  CAS  Google Scholar 

  85. Feitosa RNM, Vallinoto ACR, Vasconcelos PFDC, Azevedo RDSDS, Azevedo VN, MacHado LFA, Lima SS, Ishak MDOG, Ishak R. Gene polymorphisms and serum levels of pro- and anti-inflammatory markers in dengue viral infections. Viral Immunol. 2016;29(7):379–88.

    Article  PubMed  CAS  Google Scholar 

  86. Fernandez-Mestre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens. 2004;64(4):469–72.

    Article  PubMed  CAS  Google Scholar 

  87. Perez AB, Sierra B, Garcia G, Aguirre E, Babel N, Alvarez M, Sanchez L, Valdes L, Volk HD, Guzman MG. Tumor necrosis factor-alpha, transforming growth factor-beta1, and interleukin-10 gene polymorphisms: implication in protection or susceptibility to dengue hemorrhagic fever. Hum Immunol. 2010;71(11):1135–40.

    Article  PubMed  CAS  Google Scholar 

  88. Cansancao IF, do Carmo AP, Leite RD, Portela RD, de Sa Leitao Paiva Junior S, de Queiroz Balbino V, Rabenhorst SH. Association of genetic polymorphisms of IL1beta −511 C>T, IL1RN VNTR 86 bp, IL6–174 G>C, IL10–819 C>T and TNFalpha −308 G>A, involved in symptomatic patients with dengue in Brazil. Inflamm Res. 2016;65(11):925–32.

    Article  PubMed  CAS  Google Scholar 

  89. Sa-Ngasang A, Ohashi J, Naka I, Anantapreecha S, Sawanpanyalert P, Patarapotikul J. Association of IL1B -31C/T and IL1RA variable number of an 86-bp tandem repeat with dengue shock syndrome in Thailand. J Infect Dis. 2014;210(1):138–45.

    Article  PubMed  CAS  Google Scholar 

  90. Moreira ST, Cardoso DM, Visentainer JE, Fonzar UJV, Moliterno RA. The possible protective role of the Il6<sup>-174GC</sup> genotype in Dengue Fever. Open Tropical Medicine Journal. 2008;1:87–91.

    Article  CAS  Google Scholar 

  91. Sam SS, Teoh BT, Chinna K, AbuBakar S. High producing tumor necrosis factor alpha gene alleles in protection against severe manifestations of dengue. Int J Med Sci. 2015;12(2):177–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Fernando AN, Malavige GN, Perera KL, Premawansa S, Ogg GS, De Silva AD. Polymorphisms of transporter associated with antigen presentation, tumor necrosis factor-alpha and Interleukin-10 and their implications for protection and susceptibility to severe forms of dengue fever in patients in Sri Lanka. J Global Infect Dis. 2015;7(4):157–64.

    Article  CAS  Google Scholar 

  93. Acioli-Santos B, Segat L, Dhalia R, Brito CA, Braga-Neto UM, Marques ET, Crovella S. MBL2 gene polymorphisms protect against development of thrombocytopenia associated with severe dengue phenotype. Hum Immunol. 2008;69(2):122–8.

    Article  PubMed  CAS  Google Scholar 

  94. Figueiredo GG, Cezar RD, Freire NM, Teixeira VG, Baptista P, Cordeiro M, Carmo RF, Vasconcelos LR, Moura P. Mannose-binding lectin gene (MBL2) polymorphisms related to the mannose-binding lectin low levels are associated to dengue disease severity. Hum Immunol. 2016;77(7):571–5.

    Article  PubMed  CAS  Google Scholar 

  95. Dang TN, Naka I, Sa-Ngasang A, Anantapreecha S, Chanama S, Wichukchinda N, Sawanpanyalert P, Patarapotikul J, Tsuchiya N, Ohashi J. A replication study confirms the association of GWAS-identified SNPs at MICB and PLCE1 in Thai patients with dengue shock syndrome. BMC Medical Genetics. 2014;15:58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Khor CC, Chau TN, Pang J, Davila S, Long HT, Ong RT, Dunstan SJ, Wills B, Farrar J, Van Tram T, et al. Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1. Nat Genet. 2011;43(11):1139–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Whitehorn J, Chau TN, Nguyet NM, Kien DT, Quyen NT, Trung DT, Pang J, Wills B, Van Vinh Chau N, Farrar J, et al. Genetic variants of MICB and PLCE1 and associations with non-severe dengue. PLoS ONE [Electronic Resource]. 2013;8(3):e59067.

    Article  CAS  Google Scholar 

  98. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, Oliveira M, Cavadas B, Regnault B, Alvarez M, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS Pathog. 2017;13(2):e1006220.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Soundravally R, Hoti SL. Significance of transporter associated with antigen processing 2 (TAP2) gene polymorphisms in susceptibility to dengue viral infection. J Clin Immunol. 2008;28(3):256–62.

    Article  PubMed  CAS  Google Scholar 

  100. Alagarasu K, Bachal RV, Memane RS, Shah PS, Cecilia D. Polymorphisms in RNA sensing toll like receptor genes and its association with clinical outcomes of dengue virus infection. Immunobiology. 2015;220(1):164–8.

    Article  PubMed  CAS  Google Scholar 

  101. Garcia-Trejo AR, Falcon-Lezama JA, Juarez-Palma L, Granados J, Zuniga-Ramos J, Rangel H, Barquera R, Vargas-Alarcon G, Ramos C. Tumor necrosis factor alpha promoter polymorphisms in Mexican patients with dengue fever. Acta Trop. 2011;120(1–2):67–71.

    Article  PubMed  CAS  Google Scholar 

  102. Alagarasu K, Mulay AP, Singh R, Gavade VB, Shah PS, Cecilia D. Association of HLA-DRB1 and TNF genotypes with dengue hemorrhagic fever. Hum Immunol. 2013;74(5):610–7.

    Article  PubMed  CAS  Google Scholar 

  103. Chuansumrit A, Anantasit N, Sasanakul W, Chaiyaratana W, Tangnararatchakit K, Butthep P, Chunhakan S, Yoksan S. Tumour necrosis factor gene polymorphism in dengue infection: association with risk of bleeding. Paediatrics and International Child Health. 2013;33(2):97–101.

    Article  PubMed  Google Scholar 

  104. Djamiatun K, Ferwerda B, Netea MG, van der Ven AJ, Dolmans WM, Faradz SM. Toll-like receptor 4 polymorphisms in dengue virus-infected children. American Journal of Tropical Medicine & Hygiene. 2011;85(2):352–4.

    Article  CAS  Google Scholar 

  105. Swati S, Singh SK, Kavita K, Nikky N, Dhole TN, Rajesh K, Saba H. Analysis of TLR4 (Asp299 Gly and Thr399Ile) gene polymorphisms and mRNA level in patients with dengue infection: a case-control study. Infect Genet Evol. 2016;43:412–7.

    Article  CAS  Google Scholar 

  106. Alagarasu K, Honap T, Mulay AP, Bachal RV, Shah PS, Cecilia D. Association of vitamin D receptor gene polymorphisms with clinical outcomes of dengue virus infection. Hum Immunol. 2012;73(11):1194–9.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to many colleagues for valuable advice, and particularly wish to thank Ms. Xiaomei Wang for technical input, Ms. Kate Nyhan, MLS, (Yale University Cushing/Whitney Medical Library) for guidance in the development of the search strategy, and Dr. Marina Antillón for translating Spanish-language articles during the full text review.

Funding

MEC & RRM: AI 089992; SC: Self and Family Management T32 NR008346. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Authors and Affiliations

  1. Yale University School of Public Health, New Haven, CT, USA

    Megan E. Cahill & Andrew T. DeWan

  2. Yale University School of Nursing, West Haven, CT, USA

    Samantha Conley

  3. Yale University School of Medicine, New Haven, CT, USA

    Ruth R. Montgomery

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  1. Megan E. Cahill
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Contributions

Conceptualization (MEC, ATD, RRM); project administration (MEC, RRM); data curation (MEC, SC); methodology (MEC, SC, ATD); formal analysis (MEC); writing – original draft preparation (MEC); writing – review and editing (MEC, SC, ATD, RRM). All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ruth R. Montgomery.

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Ethics approval and consent to participate

Not applicable. Data sets were extracted without personal identifiers and organized into literature tables.

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Additional files

Additional file 1:

PRISMA Checklist. This systematic review of genetic factors and WNV or dengue disease was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines outlined in this checklist. (DOC 95 kb)

Additional file 2:

Sample Search Strategy for the Embase Database. Medline, PubMed, Embase, and Global Health databases were used to search the literature. Search terms included West Nile or Dengue and genetic factors; the same set of text words was used for all databases in conjunction with subject headings that were tailored for each database. As an example, this search strategy for the Embase database is provided. These subject headings, in conjunction with the text search (Table 1), were used to find relevant literature in Embase. (DOCX 13 kb)

Additional file 3:

Included Papers. All publications included in this review are listed, with study details on authors, year of publication, country, sample size, case and control group definitions, and genotyping method. (XLSX 54 kb)

Additional file 4:

HLA Associations with DENV Disease Severity. HLA alleles studied by two or more research groups for association with DENV disease severity. (DOCX 311 kb)

Additional file 5:

HLA Associations with WNV Disease Severity. All examined targets from the analyzed publications are listed, with significant associations shown in bold. (XLSX 9 kb)

Additional file 6:

Quality Scores. The quality of each study was evaluated with the Newcastle-Ottawa Quality Assessment Scale for Case-Control Studies, which assesses each study’s selection, comparability, and exposure ascertainment approach. (XLSX 16 kb)

Additional file 7:

Extracted Data from Included Studies. All genotype data extracted from the manuscripts or collected from study authors is provided. (XLSX 54 kb)

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Cahill, M.E., Conley, S., DeWan, A.T. et al. Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis 18, 282 (2018). https://doi.org/10.1186/s12879-018-3186-6

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BMC Infectious Diseases

ISSN: 1471-2334

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