Skip to main content

Association of the rs4646994 in ACE gene with susceptibility to tuberculosis in a region of the Brazilian Amazon

Abstract

Background

Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis and represents an important global public health issue. Single-nucleotide polymorphisms and INDELs are common genetic variations that can be located in genes associated with immune response and, therefore, they may have direct implications over the phenotype of susceptibility to infections like tuberculosis. This study aimed to investigate the association between the 17 genetic polymorphisms and susceptibility to tuberculosis in a Brazilian population.

Methods

This case-control study enrolled 283 individuals with active tuberculosis and 145 health care workers. Four INDELs and 13 single nucleotide polymorphisms and were genotyped using Multiplex PCR method and TaqMan SNP Genotyping Assays. Group comparisons for categorical variables were performed using the chi-squared test, whilst the t-Student test was used to analyze the continuous variables. Multiple logistic regression analyses were performed to estimate the odds ratio (OR) with 95% confidence intervals (CI). Deviation from Hardy-Weinberg equilibrium was assessed using chi-squared tests with Bonferroni correction. The results were analyzed comparing the genotypic distributions adopting the dominant model and the estimated values ​​of p corrected for multiple tests through FDR (False Discovery Rate) test.

Results

The HWE test confirmed that the genotypic frequencies for polymorphisms were balanced. The frequency of Del allele was 73 and 75%, in cases and controls respectively. Frequency of Del allele was significantly higher in the control group than TB group. The homozygous Del/Del genotype was present in 51.6% of cases and 58.6% of controls. The rare Ins/Ins genotype was present in only 7.6% of controls and 6% of cases. The ACE Del/Del genotype was significantly higher in the cases than in controls revealing significant protection for TB in the domain model (OR = 0.465; p < 0.005).

Conclusions

The Del/Del genotype of the rs4646994 in ACE gene was associated with susceptibility to tuberculosis. The identification of genetic variants responsible for susceptibility to tuberculosis will allow the development of new diagnostic tools for tuberculosis infection. These studies will help improve control and the future eradication of this disease.

Introduction

Despite the BCG vaccination and chemotherapy with an effective four-drug treatment regimen, tuberculosis is the leading cause of death from a single infectious disease agent worldwide, exceeding the human immunodeficiency virus. The World Health Organization estimates that there are about 10.4 million new cases and 1.8 million deaths from TB each year. Latent tuberculosis infection affects one-third of the human population, but only 10% of infected individuals will develop active tuberculosis. Individuals with compromised immune systems have a higher risk of falling ill [1, 2].

The early reports showed that diabetes, smoking, alcohol use, drug use, and pathogen characteristics were risk factors for tuberculosis infection and active tuberculosis [3, 4]. Variations in the Angiotensin-converting enzyme (ACE) may be one among many contributing factors for tuberculosis. Interactions between the ACE I/D polymorphism and other risk factors can therefore influence the risk for tuberculosis disease. In the present study, we focused on the angiotensin-converting enzyme (ACE) Del/Del genotype that was once reported to be associated with progression of the severe acute respiratory syndrome (SARS) and COVID-19 [5, 6].

The ACE Ins/Del polymorphism has been one of the most studied genetic variations. The Angiotensin-converting enzyme (ACE) has a role in blood pressure regulation via the renin-angiotensin-aldosterone system (RAAS), in fertility, immunity, hematopoiesis, and diseases such as obesity, fibrosis, and Alzheimer’s dementia. The ACE is rich in microvascular endothelium and is involved in angiopathy of the lung. However, the total extent of the ACE influence on human health and disease is, however, still unknown [7,8,9].

The genotype and allele frequency of this polymorphism has been reported to be associated with several diseases including COVID-19 [10], cardiovascular disease [11], cancer [12], and diabetes mellitus and renal disease [13] in humans. In the present study, we aim to evaluate the association between ACE (Ins/Del) polymorphism and risk of tuberculosis in an admixture population such as the Brazilian population. These findings may be useful and provide basic information regarding our understanding of genetic predisposition and tuberculosis.

Materials and methods

Subjects

Blood samples were obtained from 283 Brazilian patients affected by active pulmonary tuberculosis. TB was diagnosed based on radiographic and clinical presentation, positive of acid-fast-bacilli on a sputum smear and culture for M. tuberculosis. A control group was composed of 145 health care workers without tuberculosis infection. Demographic and clinical characteristics of individuals were presented in Table 1. The study was approved by the Ethical Committee of João Barros Barreto Hospital, and all subjects provided written informed consent (protocol n° 350507).

Table 1 Demographic and clinical characteristics of individuals with tuberculosis and control group

DNA isolation and polymorphism genotyping

Seventeen genetic variants, INDEL, and SNP, in immune-related genes were investigated (Table 2). Genomic DNA was isolated from peripheral blood leukocytes using the phenol extraction method [14]. Four SNPs were genotyped using TaqMan® SNP Genotyping Assays (Applied Biosystems, Foster City, USA). Thirteen INDELs polymorphisms were genotyped by a single multiplex reaction with Master Mix QIAGEN® Multiplex PCR kit (Qiagen, Hilden, Germany) and the primers. Multiplex PCR products were separated and analyzed by capillary electrophoresis on the ABI 3130 Genetic Analyzer instrument (Applied Biosystems), using GS-500 LIX as a pattern of molecular weight (Applied Biosystems), G5 virtual filter matrix, and POP7 (Applied Biosystems). After data collection, samples were analyzed in GeneMapper®3.7 software (Applied Biosystems).

Table 2 Description of polymorphisms analyzed

Ancestry informative markers (AIMs)

AIMs were used to adjust for population admixture, controlling population stratification and avoiding spurious associations in case-control studies. Genetic ancestry contributions of European, African, and Amerindian ancestry was investigated using a set of 61 autosomal AIMs described by Santos et al. 2010 and Ramos et al. [15, 16].

Statistical analyses

Statistical analyses were performed using the RStudio v.1.3 software. Group comparisons for categorical variables were performed using the chi-squared test, whilst the t-Student test was used to analyze the continuous variables. Multiple logistic regression analyses were performed to estimate the odds ratio (OR) with 95% confidence intervals (CI). These analyses were adjusted for confounding variables including gender, comorbidities, smoking, genetic ancestry. A 5% significance level was used for the analyses. Deviation from Hardy-Weinberg equilibrium was assessed using chi-squared tests with Bonferroni correction. The results were analyzed comparing the genotypic distributions adopting the dominant model and they estimated values ​​of p corrected for multiple tests through FDR (False Discovery Rate) test.

Results

We evaluated the association of 13 INDEL and four SNPs variants and susceptibility of tuberculosis in an Amazon region with a high degree of interethnic admixture. Demographic and clinical characteristics of individuals with tuberculosis and healthy controls were presented in Table 1. The mean age of participants was 50 ± 16.84 in the case and 52 ± 9.15 years old in controls. The differences in control and TB groups were statistically significant for gender, comorbidity, smoking, and ancestry. In the tuberculosis group, 47.7% of participants were male and 52.3% were female, in contrast with the control group, in which 17.3% were male and 82.7% were female. For the case group, 107 out of 283 cases had comorbidities, which were primarily cancer, diabetes, non-drug hepatitis, and autoimmune diseases. Smoking habits were higher in case groups (31.7%) than in the control group (20.7%).

Populational ancestry was evaluated using three reference populations: European, African, and Amerindian. The ethnic composition of the case group was 25.4%% African, 40.9% European, and 33.7% Amerindian, while in the control group composition was 21.5% African, 49.6% European, and 28.9% Amerindian. The population structure results showed a lower European contribution and a higher African and Amerindian contribution in the cases when compared to the control group.

The associations between 17 polymorphisms and tuberculosis risk were presented in Table 3. The association of genotypes was performed through logistic regression with adjustment for potential confounding factors including age, gender, comorbidity, smoking, and genetic ancestry. The polymorphisms investigated in this study were in accordance with the Hardy–Weinberg equilibrium test. Allele and genotypes of several polymorphisms studied were not associated with tuberculosis risk, except rs4646994 in the ACE gene.

Table 3 Association between groups for the 17 polymorphisms investigated

Only the rs4646994 polymorphism in the ACE gene showed significant differences between the cases and controls. For this SNP, the Ins/Del alleles in the case group were 27% for Ins and 73% for Del, and the Ins/Del alleles in the control group were 25% for Ins and 75% for Del. The frequency of Del allele (rs4646994) was higher in control than tuberculosis group. Moreover, the homozygous Del/Del genotype for this SNP was present in 51.6% of cases and 58.6% of controls. The rare Ins/Ins genotype (rs4646994) was present in only 6% of cases and 7.6% of controls. The results showed that ACE Del/Del genotype was associated with protection to tuberculosis development, in the domain model (OR = 0.465; p < 0.005). Figure 1 provided a visual illustration of the differences between genotypic frequencies for ACE Ins/Del polymorphism (rs4646994).

Fig. 1
figure 1

Distribuição das frequências genotípicas para o marcador rs4646994 (ACE) no grupo de pacientes de TB e grupo controle

Discussion

Tuberculosis remains a major health problem worldwide. Several studies suggested the association of host genetic factors to TB susceptibility in various ethnic populations. The prevalence of tuberculosis disease was higher in males in this study. In the study of Hertz and Schneider (2019) and Ben et al. (2020), the tuberculosis infection was significantly higher in men than in women, a phenomenon reported in several countries [17, 18]. There is a lack of information on the role of gender in this disease. Although, there are some potential explanations why male had an increased odds of developing tuberculosis infection. Some researchers suggest the influence of sex-specific determinants of immunity, which include effects of sex steroid hormones and sex chromosome-encoded genes and miRNAs [19]. In addition, men are more exposed to factors that can compromise immunity, such as illicit drugs, smoking, and comorbidities such as diabetes and HIV [17, 20, 21].

Comorbidities and smoking are also two important risk factors widely associated with TB, with their deleterious effect especially relevant in countries with a high prevalence of the disease [22], and our work corroborates that these two variables are linked to susceptibility to the disease in the Amazonian population. It is known that patients with comorbidities are at greater risk of developing TB compared to people without comorbidities due to changes in the immune response, with HIV, diabetes, and hepatitis being the most common comorbidities in patients with TB [23, 24]. Smoking has a harmful effect on the lungs since it decreases the phosphorylation of transcriptional factors that regulate the expression of IFN-g [25], altering the immune response and also hindering the functioning of immune cells such as macrophages, monocytes, and CD4 lymphocytes [26, 27].

We also have explored the association between ACE polymorphisms and tuberculosis in the Amazonian Brazilian population, which is characterized by a genetic background of three parental populations (European, African, and Amerindians). Similar results from our ancestry analysis were found by Leal et al. where the Amerindian contribution was significantly higher and the European contribution was significantly lower in the Tuberculosis group in the Brazilian Amazon population [27].

One of the primary physiological roles of ACE is in both innate and adaptive responses by modulating macrophage and neutrophil function. In particular, macrophages that overexpress ACE are more effective against tumors and infections. Neutrophils that overexpress ACE have an increased production of superoxide, which increases their ability to kill bacteria [28]. Recent studies point to the functionality of ACE in promoting the maturation of myelocytic lineage cells and to improve the effective phagocytosis capacity and consequent self-limitation of Mtb infection [29, 30]. In this context, individuals with Del/Del genotype would have greater gene expression that would have a crucial role in the innate effective immune response.

We found Del/Del genotype of the ACE gene (rs4646994) showed significant association by setting up a protective factor for the development of tuberculosis. To our knowledge, few studies evaluated the correlation between ACE polymorphisms and the risk of tuberculosis. Ogarkov et al. investigated the occurrence of frequencies of ACE genotype in Russian individuals with tuberculosis The-Ins/Del polymorphism of the gene ACE was studied and the Del/Del genotype (ACE) was significantly higher in the group of TB patients when compared to controls [31]. However, Zhang et al. also analyze the Ins/Del polymorphism and development of tuberculosis. The results showed that the Ins/Del polymorphism studied was not associated with susceptibility to TB in the Chinese population [32]. The study by Ogarkov et al. [31] and Zhang et al. [32] found different results than our results. The reason may be differential susceptibility to TB can vary significantly between ethnic populations, due to genetic factors such as genomic ancestry, and environmental factors, such as poverty, unequal access to health, and the environment [33].

Many data indicate the association between ACE polymorphism, particularly the homozygote variant (Del/Del), might contribute to the risk of chronic obstructive pulmonary disease (COPD) and COPD with pulmonary hypertension among Asians [8]. Similar findings were described by Gomez et al., who found that the ACE Del/Del polymorphism was statistically higher in the severe COVID-19 group than in the mild disease group [6]. Furthermore, Dmitrenko et al. found that the Del/Del genotypes were associated with increased risk of pregnancy complication in gestational diabetes mellitus women, increasing its risk by 2,96 [11]. Zmorzynski et al. observed the association between Del/DEl genotype and more than 2-fold risk of multiple myeloma [34]. The Del/Del genotype was significantly more frequent in coronary heart disease (CHD) patients with type2 diabetes mellitus (T2DM) compared to each of CHD patients without T2DM and control populations [35].

Interestingly, the ACE polymorphism and tuberculosis protection in Amazon populations were significantly associated, however larger studies are necessary to deepen the relationship between the ACE gene and its potential protective factor for tuberculosis infection in the Amazonia population. Further studies are necessary to validate these findings for other ethnic populations. It is important, as well, to investigate other genetic markers like polymorphisms in the immune response genes in this population.

Conclusion

In conclusion, host genetic factors may play a role in tuberculosis disease, influencing susceptibility to infection. Our case-control study suggests that the Del/Del genotype of the rs4646994 in ACE gene was associated with protective factors to tuberculosis. The identification of genetic variants responsible for susceptibility to tuberculosis may help develop new and improved diagnostic tools for tuberculosis infection. This genetic study can help improve TB control and the future eradication of this disease.

Availability of data and materials

The datasets are available in https://figshare.com/s/0af7c9a15996be56a062 or DOI https://doi.org/10.6084/m9.figshare.14551035.

References

  1. Yang T, Ge B. miRNAs in immune responses to mycobacterium tuberculosis infection. Cancer Lett. 2018;431:22–30. https://doi.org/10.1016/j.canlet.2018.05.028.

    CAS  Article  PubMed  Google Scholar 

  2. WHO. Global tuberculosis report 2020. Geneva: World Health Organization; 2020.

  3. Silva DR, Muñoz-Torrico M, Duarte R, Galvão T, Bonini EH, Arbex FF, et al. Risk factors for tuberculosis: diabetes, smoking, alcohol use, and the use of other drugs. J Bras Pneumol. 2018;44:145–52. https://doi.org/10.1590/s1806-37562017000000443.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Huang L, Nazarova EV, Russell DG. Mycobacterium tuberculosis : bacterial fitness within the host macrophage. Microbiol Spectr. 2019;BAI-0001-2019(7). https://doi.org/10.1128/microbiolspec.

  5. Itoyama S, Keicho N, Quy T, Phi NC, Long HT, Ha LD, et al. ACE1 polymorphism and progression of SARS. Biochem Biophys Res Commun. 2004;323:1124–9. https://doi.org/10.1016/j.bbrc.2004.08.208.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Gómez J, Albaiceta GM, García-Clemente M, López-Larrea C, Amado-Rodríguez L, Lopez-Alonso I, et al. Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene. 2020;762:145102. https://doi.org/10.1016/j.gene.2020.145102.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Hubert C, Houot AM, Corvol P, Soubrier F. Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J Biol Chem. 1991;266:15377–83.

    CAS  Article  Google Scholar 

  8. Ma Y, Tong X, Liu Y, Liu S, Xiong H, Fan H. ACE gene polymorphism is associated with COPD and COPD with pulmonary hypertension: a meta-analysis. COPD. 2018;13:2435–46. https://doi.org/10.2147/COPD.S168772.

    CAS  Article  Google Scholar 

  9. Lubbe L, Cozier GE, Oosthuizen D, Acharya KR, Sturrock ED. ACE2 and ACE: structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV. Clin Sci. 2020;134:2851–71. https://doi.org/10.1042/CS20200899.

    CAS  Article  Google Scholar 

  10. Zheng H, Cao JJ. Angiotensin-converting enzyme gene polymorphism and severe lung injury in patients with coronavirus disease 2019. Am J Pathol. 2020;190:2013–7. https://doi.org/10.1016/j.ajpath.2020.07.009.

    CAS  Article  PubMed  Google Scholar 

  11. Dmitrenko OP, Karpova NS, Nurbekov MK, Papysheva OV. I/D polymorphism gene ACE and risk of preeclampsia in women with gestational diabetes mellitus. Dis Markers. 2020;2020:1–7. https://doi.org/10.1155/2020/8875230.

    CAS  Article  Google Scholar 

  12. Xiao Y, Dong Z, Zhu J, You J, Fan J. Association between ACE A240T polymorphism and cancer risk: a meta-analysis. J Int Med Res. 2019;47:5917–25. https://doi.org/10.1177/0300060519882559.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Shen W, Jiang X-X, Li Y-W, He Q. I/D polymorphism of ACE and risk of diabetes-related end-stage renal disease: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2019;23:1652–60. https://doi.org/10.26355/eurrev_201902_17126.

    CAS  Article  PubMed  Google Scholar 

  14. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. USA: Cold Spring Harbor Laboratory Press; 1989.

    Google Scholar 

  15. Ramos BR de A, D’Elia MPB, Amador MAT, Santos NPC, Santos SEB, da Cruz Castelli E, et al. Neither self-reported ethnicity nor declared family origin are reliable indicators of genomic ancestry. Genetica. 2016;144:259–65. https://doi.org/10.1007/s10709-016-9894-1.

  16. Santos NPC, Ribeiro-Rodrigues EM, Ribeiro-Dos-Santos AKC, Pereira R, Gusmão L, Amorim A, et al. Assessing individual interethnic admixture and population substructure using a 48-insertion-deletion (INSEL) ancestry-informative marker (AIM) panel. Hum Mutat. 2010;31:184–90. https://doi.org/10.1002/humu.21159.

    CAS  Article  PubMed  Google Scholar 

  17. Hertz D, Schneider B. Sex differences in tuberculosis. Semin Immunopathol. 2019;41:225–37. https://doi.org/10.1007/s00281-018-0725-6.

    Article  PubMed  Google Scholar 

  18. Ben Jmaa M, Ben Ayed H, Koubaa M, Hammami F, Damak J, Ben JM. Is there gender inequality in the epidemiological profile of tuberculosis? Tunis Med. 2020;98:232–40.

    PubMed  Google Scholar 

  19. Sex differences in the C57BL/6 model of Mycobacterium tuberculosis infection | Scientific Reports. [cited 14 Mar 2022]. Available: https://www.nature.com/articles/s41598-017-11438-z.

  20. Galdas PM, Cheater F, Marshall P. Men and health help-seeking behaviour: literature review. J Adv Nurs. 2005;49:616–23. https://doi.org/10.1111/j.1365-2648.2004.03331.x.

    Article  PubMed  Google Scholar 

  21. Chaves EC, Carneiro IC, do RS, Santos MIP de O, Sarges N de A, Neves EOS das. Aspectos epidemiológicos, clínicos e evolutivos da tuberculose em idosos de um hospital universitário em Belém, Pará. Rev Bras Geriatr Gerontol. 2017;20:45–55. https://doi.org/10.1590/1981-22562017020.160069.

    Article  Google Scholar 

  22. Tobacco and tuberculosis: a qualitative systematic review and meta-analysis - PubMed. [cited 14 Mar 2022]. Available: https://pubmed.ncbi.nlm.nih.gov/17945060/.

  23. Duarte R, Lönnroth K, Carvalho C, Lima F, Carvalho ACC, Muñoz-Torrico M, et al. Tuberculosis, social determinants and co-morbidities (including HIV). Pulmonology. 2018;24:115–9. https://doi.org/10.1016/j.rppnen.2017.11.003.

    CAS  Article  PubMed  Google Scholar 

  24. Narasimhan P, Wood J, Macintyre CR, Mathai D. Risk factors for tuberculosis Pulm Med. 2013;2013:828939. https://doi.org/10.1155/2013/828939.

    Article  PubMed  Google Scholar 

  25. Ferrara G, Murray M, Winthrop K, Centis R, Sotgiu G, Migliori GB, et al. Risk factors associated with pulmonary tuberculosis: smoking, diabetes and anti-TNFα drugs. Curr Opin Pulm Med. 2012;18:233–40. https://doi.org/10.1097/MCP.0b013e328351f9d6.

    CAS  Article  PubMed  Google Scholar 

  26. Loddenkemper R, Brönnecke M, Castell S, Diel R. Tuberculosis and tobacco smoking. Pneumologie. 2016;70:17–22. https://doi.org/10.1055/s-0041-109601.

    CAS  Article  PubMed  Google Scholar 

  27. VB LDF d, Santana da Silva MN, DCR de O F, JCG R, MC da C B, PD do C P, et al. Amerindian genetic ancestry as a risk factor for tuberculosis in an amazonian population. PLoS One. 2020;15:e0236033. https://doi.org/10.1371/journal.pone.0236033.

    CAS  Article  Google Scholar 

  28. Bernstein KE, Khan Z, Giani JF, Cao D-Y, Bernstein EA, Shen XZ. Angiotensin-converting enzyme in innate and adaptive immunity. Nat Rev Nephrol. 2018;14:325–36. https://doi.org/10.1038/nrneph.2018.15.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Guerra FE, Borgogna TR, Patel DM, Sward EW, Voyich JM. Epic immune battles of history: neutrophils vs. Staphylococcus aureus Front Cell Infect Microbiol 2017;7:286. https://doi.org/10.3389/fcimb.2017.00286.

  30. Bernstein KE, Khan Z, Giani JF, Zhao T, Eriguchi M, Bernstein EA, et al. Overexpression of angiotensin-converting enzyme in myelomonocytic cells enhances the immune response. F1000Res. 2016;5. https://doi.org/10.12688/f1000research.7508.1.

  31. Ogarkov OB, Sin’kov VV, Medvedeva TV, Gutnikova MI, Nekipelov OM, Raevskaia LI, et al. Polymorphism of genes of the renin-angiotensin system ACE, AT1R, and AT2R in patients with pulmonary tuberculosis. Mol Gen Mikrobiol Virusol 2008:12–18.

  32. Zhang Y, Li X, Wu Z, Fan H. Association between ACE I/D polymorphism and pulmonary tuberculosis in Chinese population. Mol Biol Rep. 2014;41:3187–9. https://doi.org/10.1007/s11033-014-3178-6.

    CAS  Article  PubMed  Google Scholar 

  33. Rotimi CN, Jorde LB. Ancestry and disease in the age of genomic medicine. N Engl J Med. 2010;363:1551–8. https://doi.org/10.1056/NEJMra0911564.

    Article  PubMed  Google Scholar 

  34. Zmorzynski S, Szudy-Szczyrek A, Popek-Marciniec S, Korszen-Pilecka I, Wojcierowska-Litwin M, Luterek M, et al. ACE insertion/deletion polymorphism (rs4646994) is associated with the increased risk of multiple myeloma. Front Oncol. 2019;9:44. https://doi.org/10.3389/fonc.2019.00044.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Hemeed RN, Al-Tu’ma FJ, Al-Koofee DAF, Al-Mayali AH. Relationship of angiotensin converting enzyme (I/D) polymorphism (rs4646994) and coronary heart disease among a male Iraqi population with type 2 diabetes mellitus. J Diabetes Metab Disord. 2020;19:1227–32. https://doi.org/10.1007/s40200-020-00632-y.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors wish to thank all the participants of the study for their collaboration. This study was supported by the Brazilian National Research Council (CNPq), the Coordination for Higher Education Personnel Training (CAPES), the Amazonian Research Foundation (FAPESPA), and the Research and Extension faculties of the Federal University of Pará (PROPESP/PROEX/UFPA). None of these organizations had any role in the design of the study, collection or analysis of the data, the decision to publish the manuscript, or its preparation. The contents of this study are the sole responsibility of the authors.

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq (CNPq), and Pró-Reitoria de Pesquisa e Pós-Graduação (PROPESP/UFPA). Dr. Ney Santos is supported by CNPq/Produtividade (CNPQ 309999/2021–9).

Author information

Authors and Affiliations

Authors

Contributions

Experimental study design, article writing: DCRFP, DFVBL, MNSS; statistical analysis: LCBS, PDCP; literature review: GEC, MCCB, ASCA; the acquisition of data: ACOB, CHBS; interpretation of data: AHCP, CAS, PPA; revised the manuscript: ARS, SEBS, MRF; and coordination: NPCS. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Ney P. C. dos Santos.

Ethics declarations

Ethics approval and consent to participate

The ethics committee of João Barros Barreto Hospital/UFPA approved this study, and the committee’s reference number is 350507. Volunteers signed an Informed Consent Form to participate in this study.

Consent for publication

Not Applicable.

Competing interests

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Porchera, D.C.R.F., Leal, D.F.V.B., Braga, A.C.O. et al. Association of the rs4646994 in ACE gene with susceptibility to tuberculosis in a region of the Brazilian Amazon. transl med commun 7, 10 (2022). https://doi.org/10.1186/s41231-022-00116-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s41231-022-00116-6

Keywords

  • Tuberculosis
  • Susceptibility
  • INDEL
  • Polymorphisms
  • ACE