Could malaria explain the global distribution of the angiotensin converting enzyme I/D polymorphism? A systematic review and ecological study

Chris Kenyon; Anna Rosanas

doi:10.12688/f1000research.26719.1

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Systematic Review

Could malaria explain the global distribution of the angiotensin converting enzyme I/D polymorphism? A systematic review and ecological study

[version 1; peer review: 2 approved with reservations, 3 not approved]

Chris Kenyon ¹, Anna Rosanas¹

PUBLISHED 06 Oct 2020

Author details Author details

¹ Institute of Tropical Medicine, Antwerp, Antwerp, 2000, Belgium

Chris Kenyon
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Anna Rosanas
Roles: Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing

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Abstract

Background: The D-allele of the angiotensin converting enzyme (ACE1) has been linked to an increased risk of certain diseases including hypertension and COVID-19 but a decreased risk of cerebral malaria. We hypothesized that malaria played a role in determining variations in the global distribution of ACE1 I/D polymorphism.
Methods: A systematic review was conducted to summarize the frequency of ID/DD genotypes in all countries with available data.
Results: The ID/DD genotype frequency was found to be highest in Africa (86.4%, IQR 83.6-94.7%) and Eastern Mediterranean (median 84.5%, IQR 78.3-89.8%) and lowest in South East Asia (55%, 49.5-67.8%) and Western Pacific (61.1%, IQR 55.0-67.2%). Linear regression revealed positive associations between ID/DD genotype frequency and the incidence of malaria, malaria mortality as well as hemoglobin S allele frequency (all P<0.05).
Conclusions: Our findings are compatible with the hypothesis that malaria played a role in establishing the differential frequency of the D-allele.

Keywords

Malaria, ACE, polymorphism

Corresponding author: Chris Kenyon

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2020 Kenyon C and Rosanas A. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Kenyon C and Rosanas A. Could malaria explain the global distribution of the angiotensin converting enzyme I/D polymorphism? A systematic review and ecological study [version 1; peer review: 2 approved with reservations, 3 not approved]. F1000Research 2020, 9:1205 (https://doi.org/10.12688/f1000research.26719.1) First published: 06 Oct 2020, 9:1205 (https://doi.org/10.12688/f1000research.26719.1) Latest published: 06 Oct 2020, 9:1205 (https://doi.org/10.12688/f1000research.26719.1)

Summary

The D-allele of the angiotensin converting enzyme (ACE1) has been linked to a number of diseases including hypertension, obesity and most recently COVID-19. Previous research has suggested that the prevalence of this allele may vary between world regions. Because the D-allele has been shown to be protective against cerebral malaria, we hypothesized that malaria played a role in determining variations in the global distribution of ACE1 I/D polymorphism. We conducted a systematic review of published literature to estimate the prevalence of the D-allele by country and World Health Organization region. The D-allele was found to be most prevalent in Africa and least prevalent in the Western Pacific. A positive association was found between the prevalence of the D-allele and three markers of malaria burden of disease. Our findings are thus compatible with the hypothesis that malaria played a role in establishing the differential frequency of the D-allele.

Introduction

The renin-angiotensin system plays an important role in the regulation of cardiovascular, renal and immune physiology^1–3. The angiotensin converting enzyme-1 (ACE1) converts angiotensin I to angiotensin II which is a key effector molecular in this system². The ACE1 gene insertion (I) and a 287 bp Alu repeat deletion (D) polymorphism explain a large proportion of the individual variation in ACE1 levels both in serum and tissue². ACE1 DD homozygotes and ID heterozygotes have approximately 65% and 30%, respectively, higher ACE1 levels in serum ACE1 than II homozygote individuals^3,4. It is unknown why the frequency of this polymorphism varies between different populations around the world^5,6.

This increased ACE1 expression is thought to partly explain the association between the D-allele and an increased risk for diseases such as hypertension, heart failure, cerebrovascular disease, diabetic nephropathy, arthritis, various cancers, asthma, acute respiratory distress syndrome (ARDS) and possibly COVID-19 incidence and mortality^3,5,7,8. Increased ACE1 in D-allele carriers generates higher angiotensin II levels, whose stimulation of the AT2₁ receptor then activates vasoconstriction as well as a number of pro-inflammatory and fibrotic pathways which increase the risk of these conditions^3,7–10. The D-allele has been found to be associated in case-control studies with protection against progression to severe malaria^11–13. In vitro and in vivo studies have demonstrated that angiotensin II can reduce the entry of plasmodia into erythrocytes and protect the blood-brain barrier against invasion by plasmodia^12–15. These findings have led a number of authors to propose that differential intensity in malaria exposure may have driven variations in the prevalence of the D-allele^13,14 in a similar way to how malaria influenced the prevalence of haemoglobin S (HbS), and other polymorphisms associated with different susceptibility to malaria¹⁶. In this study, we aimed to assess the association between D allele frequency and malaria using three indicators of malaria exposure: malaria incidence, malaria mortality and the prevalence of the HbS allele¹².

To do this we first conducted a systemic review of the frequency of the ID/DD genotypes in different countries around the world. A prior systematic review measured D allele frequencies by ethnicity, sex and age and reported D allele frequencies of 56.2% in “whites’, 60.3% in ‘Blacks’ (60.3%) and the lowest (39.1%) in ‘Asians’⁶. Results were similar for when DD genotype was measured. This study did not evaluate the geographical variation of the I/D polymorphism.

Methods

Systematic review of ACE1 DD and ID/DD prevalence

In April 2020, we used PubMed and Google Scholar to conduct a systematic review with the objective of obtaining country-level ACE1 estimates of DD and ID+DD frequency. We used the following MeSH terms: 'ACE' OR 'angiotensin-converting enzyme' AND ('polymorphism' OR 'deletion' OR 'insertion'). The following inclusion criteria were used: sample size of at least 50; published in English and the population could be considered representative of the general population (the studies were typically the control groups of case control studies evaluating the associations between I/D polymorphisms and specific diseases). Studies from previous systematic reviews of associations between D-allele frequency and various diseases could be included if they met the entry criteria. No date restrictions were used. Duplicate studies were removed (Figure 1). The data was extracted by a single author (CK), and manually checked for accuracy. Risk of bias was not assessed. The principle summary measure used was the prevalence of the genotype of interest expressed as a percentage. The PRISMA guidelines were followed for the manuscript (see Extended data, STable 1¹⁷).

Figure 1. PRISMA flowchart.

HbS: The HbS allele frequency (expressed as a percentage) was obtained from a study that estimated national HbS allele frequencies for 190 countries¹⁸.

Malaria incidence: The national incidence of malaria per 1,000 population at risk for the year 2000 (the earliest year with available data), was obtained from the World Health Organization (WHO), Global Health Observatory Data Repository. A value of zero cases per 1,000 was used for countries classified as having eliminated malaria in 2000.

Malaria mortality. The age-standardized national number of deaths from malaria per 100,000 individuals. The data was obtained from the International Health Metrics and Evaluation Global Burden of Diseases study for the year 1990 – the first year with available data.

Geographical grouping. For the global analyses, countries were classified into 6 regions according to the WHO system.

A previous study limited to European countries found an ecological association between COVID-19 incidence and D-allele frequency, with both having higher values in Southern European countries⁵. This provided the motivation to compare the ID/DD prevalence between European regions. We used the four European Regions as defined by the United Nations Geoscheme for Europe for this purpose.

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Statistical analysis. Linear regression was used to evaluate the country-level association between the prevalence of ID/DD genotypes and the three measures of intensity of malaria exposure. Differences in ID/DD genotype prevalence between world regions were assessed via the Wilcoxon rank-sum test. The analyses were performed in STATA version 16 (Stata Corp, College Station, Tx). The maps were produced with Data Wrapper v2.

Results

Systematic review of ACE1 DD and ID/DD prevalence

Searches of the literature identified 5099 references. The application of the selection criteria restricted the total to 248 informative references published between 1993 and 2020, providing 253 prevalence estimates from 71 countries (Figure 1; Extended data, STable 2¹⁷). Of these, 7 were located in the Americas, 15 in Eastern Mediterranean, 26 in Europe, 8 in sub Saharan Africa, 5 in South East Asia and 10 in Western Pacific (Table 2).

The ID/DD frequency was found to be highest in Africa (86.4%, IQR 83.6-94.7%) and Eastern Mediterranean (84.5%, IQR 78.3-89.8%) and lowest in South East Asia (55%, 49.5-67.8%) and Western Pacific (61.1%, IQR 55.0-67.2%; Figure 2 & Figure 5; Table 1). Within Europe, the prevalence was highest in Southern Europe (85.3%, IQR 84.3-88.2%) and lowest in Northern Europe (75.7%, IQR 73.9-76.7%; Table 2).

Figure 2. Boxplots of the prevalence of ACE1 ID/DD genotypes according to World Health Organization regions.

Table 1. Prevalence of the ID/DD genotypes according to World Health Organization regions.

Region	Number of studies^b	Median Prevalence, % (IQR)	P-value
Europe	26	79.2% (76.1-82.0)	Ref^a
Africa	8	86.4% (83.6-94.7%)	0.0005
Americas	7	74.0% (64.1-79.2%)	0.0798
Eastern Mediterranean	15	84.5% (78.3-89.8%)	0.1093
South East Asia	5	55% (49.5-67.8%)	>0.0001
Western Pacific	10	61.1% (55.0-67.2%)	<0.0001

^a Europe was used as the reference category as it had the largest sample size.

^b The number of studies used to generate the median prevalence estimates

Table 2. Prevalence of the ID/DD genotypes in four European sub-regions.

Sub-region	Number of studies^b	Median Prevalence, % (IQR)	P-value
Northern Europe	7	75.7% (73.9-76.7%)	Ref^a
Eastern Europe	6	77.6% (76.1-79.7%)	0.0478
Southern Europe	4	85.3% (84.3-88.2%)	0.0061
Western Europe	6	80.4% (78.6-81.0%)	0.0478

^a Northern Europe was used as the reference category as it had the largest sample size.

^b The number of studies used to generate the median prevalence estimates

Linear regression revealed positive associations between ID/DD frequency and the incidence of malaria (coef. 4.96, 95% confidence interval [CI] 1.73- 8.20; N=63; Table 3 and Figure 3), malaria mortality (coef. 0.69, 95% CI 0.20- 1.19; N=70) as well as HbS allele frequency (coef. 0.12, 95% CI 0.04- 0.19; N=68). Results were similar when these regressions were run with DD frequency as the outcome variable (Extended data, STable 4¹⁷).

Table 3. Linear regression assessing the country-level association between the frequency of the ACE1 ID/DD genotypes and malaria incidence per 1,000, malaria mortality per 100,000 and the allele frequency of hemoglobin S (HbS).

	N	Coef.	95% CI	P-value
Malaria incidence	63	4.96	1.73-8.20	0.003
Malaria mortality	71	0.69	0.20-1.19	0.006
HbS	68	0.12	0.04-0.19	0.002

Figure 3.

Scatter plots of the associations between prevalence of the ACE1 ID/DD genotypes and malaria incidence per 1,000 people (a), malaria deaths per 100,000 people and allele frequency of the hemoglobin S allele (c).

Discussion

Differential exposure to malaria has been found to play a role in driving the large geographical variations in the prevalence of various haemoglobinopathies, thalassemias, glucose 6-phosphate dehydrogenase deficiencies, erythrocyte membranopathies and various mediators of inflammation and immunity^19,20. We found country- and regional-level differences in the prevalence of the ACE1 D-allele that were associated with malaria incidence and mortality and HbS allele. These findings add into previous individual-level studies showing protection against severe malaria by the D allele, suggesting that malaria may have played a role in the global variations in D-allele frequency.

An important weakness of the study is our use of malaria incidence and mortality data from 1990 and 2000. Although this was the earliest data we had available, it underestimates the historical burden of malaria for much of the world’s population up to the beginning/mid-20^th century as shown in Figure 4²⁰. This figure of malaria prevalence from the preintervention period (around 1900) was produced by Lysenko in 1968. Unfortunately it has not been translated into estimated numerical values of national prevalence that could be used to test numerical associations²¹. Although we did not test this statistically, it does appear that a number of the countries with high D-allele prevalence but low malaria incidence in 2000 in our analysis had a high malaria prevalence in 1900 (Figure 3 and Figure 4)²⁰. For example, all 10 countries with ID/DD prevalence of above 81% and malaria incidence of 0 in 2000 were classified as being at least hypoendemic for malaria transmission in 1900 according to Lysenko²¹. Our finding of higher prevalence of the D-allele in Southern than Northern Europe is also commensurate with the higher historical prevalence of malaria in this part of Europe^20,21.

Figure 4. The map global malaria endemicity originally produced by Lysenko et al.²¹ and reproduced by Hay et al. ²⁰.

Endemicity as defined by Lysenko is according to the parasite rate in the 2–10-year age cohort (hypoendemic <0.1; mesoendemic 0.11–0.5; hyperendemic 0.51–0.75) except the holoendemic class (0.75) where the PR refers to the 1-year age group. The black line was added by Hay et al. to delineate the 2002 limit of malaria risk²⁰.

Figure 5. The country level prevalence of the ACE1 ID/DD genotypes (in percentages) according to the data produced by the current systematic review.

Another weakness of our study is the small number of countries with data for D-allele frequency and malaria burden of disease. We also acknowledge the fact that some of the differences in ID/DD frequency between studies and countries may be attributed to differences in how control groups were selected, differences in age distribution and in the methodology used to genotype individuals⁶. It is also important to note that recent genome wide association studies have not found the ACE1 I/D polymorphism to be associated with severe malaria^22,23. The lack of an association in these studies may however be related to the high prevalence of the D-allele in malaria endemic areas, as well as the high level of genetic diversity and weak linkage disequilibrium in Africans compared to elsewhere²². The association between malaria and the D-allele could be explained by confounding. It is possible that the actual driver of the D-allele is an environmental factor such as another infection that is associated with malaria. Finally, not all studies we drew our data from reported if the I- and D-alleles were in Hardy-Weinberg equilibrium. Including data from studies where these alleles were not in Hardy-Weinberg equilibrium would, however, be expected to introduce a non-differential misclassification bias into the analysis²⁴. This would be expected to dilute the strength of association between the prevalence of the D-allele and malaria severity.

Given these concerns, we can only conclude that our data is compatible with the hypothesis that malaria played a role in establishing frequency distribution of the D-allele. This association could provide a potential evolutionary explanation for the commonly observed higher prevalence of hypertension in individuals with African genetic background^25,26. If the association between the D-allele and COVID-19 incidence/morbidity is confirmed, our mapping of D-allele prevalence could assist with estimating morbidity and mortality in different populations.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Extended data

Figshare: Could malaria explain the global distribution of the angiotensin converting enzyme I/D polymorphism? A systematic review and ecological study. https://doi.org/10.6084/m9.figshare.12982112.v2¹⁷.

This project contains the following extended data:

STable 1. PRISMA checklist.
STable 2. Study characteristics of studies included in systematic review, including frequency of II, ID and DD genotypes of ACE1, arranged according to country and year of study.
STable 3. Study references for STable 2.
STable 4. Linear regression assessing the country-level association between the prevalence of the DD genotypes of the ACE1 gene and malaria incidence per 1,000, malaria mortality per 100,000 and the allele frequency of hemoglobin S.

Extended data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Authors contributions

CK conceptualized the study, was responsible for the acquisition, analysis and interpretation of data including the systematic review and wrote the analysis up as a manuscript. AR assisted with the study design and analysis. Both authors contributed to and approved the final draft.

Faculty Opinions recommended

References

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Version 1

VERSION 1 PUBLISHED 06 Oct 2020

Author details Author details

¹ Institute of Tropical Medicine, Antwerp, Antwerp, 2000, Belgium

Chris Kenyon
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Anna Rosanas
Roles: Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

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https://doi.org/10.12688/f1000research.26719.1

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Kenyon C and Rosanas A. Could malaria explain the global distribution of the angiotensin converting enzyme I/D polymorphism? A systematic review and ecological study [version 1; peer review: 2 approved with reservations, 3 not approved]. F1000Research 2020, 9:1205 (https://doi.org/10.12688/f1000research.26719.1)

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Reviewer Report 13 Feb 2025

Hassen Mamo, Department of Microbial, Cellular and Molecular Biology, Addis Ababa University, Addis Ababa, Ethiopia

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https://doi.org/10.5256/f1000research.29501.r356306

I. General Comment
The manuscript is of interest to experts in the field of human genetic factors related to susceptibility or resistance to malaria, as well as its evolutionary significance and current public health implications for more effective malaria ... Continue reading

I. General Comment
The manuscript is of interest to experts in the field of human genetic factors related to susceptibility or resistance to malaria, as well as its evolutionary significance and current public health implications for more effective malaria control, elimination, and eventual eradication by integrating all available means. However, substantial effort is required to strengthen the manuscript to that level. Extensive revisions are needed in all sections of the systematic review, including the title.

II. Section-by-section Report
Below is a comprehensive section-by-section report.

1. Title
The manuscript summarizes existing literature and lacks original ecological data, rendering the current title misleading. The use of "and" suggests the inclusion of both elements, which is not accurate. A more appropriate title that would reflect the content can be ‘The role of malaria in the global distribution of angiotensin-converting enzyme gene polymorphism: A systematic review of ecological associations’. This revision clarifies the emphasis on the systematic review aspect without implying the presence of original ecological research findings.

2. Abstract
The abstract introduces the ACE1 D-allele and its disease associations, clearly stating the hypothesis linking malaria to the ACE1 I/D polymorphism distribution. It briefly outlines the systematic review and the focus on genotype frequencies, summarizing results with specific data points. The conclusion ties back to the hypothesis, suggesting malaria's potential role in shaping D-allele frequency. However, the methods part lacks crucial details on the search strategy, inclusion/exclusion criteria, and data analysis, which are essential for evaluating the review's robustness. While the results present key findings, they could better connect to the hypothesis. For instance, reiterating the hypothesis before the results and using phrases like "These results support our hypothesis that malaria influences ACE1 polymorphism distribution" would clarify the link. Additionally, the mention of "all P<0.05" needs clarification on clinical significance and comparison to prior studies, possibly including effect sizes or confidence intervals (CIs). The conclusion could be more assertive by suggesting implications for further research or public health. Finally, the inclusion of keywords like "genetic polymorphism" or "epidemiology" could improve the visibility of the review.

3. Summary
The summary has notable strengths, such as introducing the ACE1 D-allele and its links to various diseases, clearly articulating the hypothesis connecting malaria to the ACE1 I/D polymorphism distribution, and highlighting geographic variations in D-allele prevalence. However, there are significant deficiencies. Specific prevalence rates for the D-allele in different regions would clarify the data. The summary lacks details on study selection and analysis methods, which are crucial for assessing credibility. The phrase "three markers of malaria burden of disease" is vague; specifying these markers, such as malaria incidence and mortality rates, would improve clarity. Additionally, a brief discussion on the implications of the findings for public health policies or future research directions is needed. Quantifying terms like "most prevalent" and "least prevalent" would improve impact, and the repeated phrasing regarding the hypothesis could be streamlined for conciseness.

4. Introduction
The introduction rightly outlines the role of the renin-angiotensin system and ACE1 in various physiological processes, laying a strong foundation for the manuscript. It provides a rationale for investigating the ACE1 D-allele, linking it to numerous diseases and emphasizing its clinical significance. Relevant citations support claims about the D-allele’s associations with diseases and its potential protective role against severe malaria, demonstrating engagement with existing research. The objectives are clearly stated, logically progressing from background information to specific aims, while highlighting the need to understand the variation in ACE1 polymorphism frequency across populations.

However, the section has significant deficiencies. The flow between sentences and sections could be improved, particularly the transition from ACE1’s role in diseases to the D-allele’s protective effects against malaria, which feels abrupt. More transitional phrases would help. Additionally, some sentences repeat similar ideas about the D-allele's protective role, and streamlining these sections would improve clarity and conciseness. The inconsistent use of "D-allele" and "D allele" should be standardized throughout the text. While a prior systematic review is cited, the introduction does not sufficiently how this one differs from or builds upon that review regarding geographical variation, which would highlight its novelty. Specific statistics (e.g., D allele frequencies by ethnicity) are presented without visual aids or tables to support these claims, which could improve understanding. Overall, while the introduction is informative, addressing these deficiencies will improve the clarity, flow, and overall readability of the manuscript.

5. Methods
Utilizing PubMed and Google Scholar for literature searches is appropriate, as these are reputable sources for biomedical research. The inclusion criteria (sample size, language, representativeness) are well-defined, ensuring the quality of the studies included. The mention of a single author (CK) responsible for data extraction, along with manual accuracy checks, indicates a methodical approach, though this has its limitations. The statistical methods employed (linear regression and Wilcoxon rank-sum test) are suitable for analyzing associations and differences in genotype prevalence.

However, this section has also significant weaknesses. Not assessing the risk of bias in the included studies or quality is a major oversight, as this is crucial for evaluating the reliability of findings in systematic reviews. While sources for malaria incidence and mortality are mentioned, more detail on how these data were selected or validated is missing. The literature search strategy lacks comprehensiveness; specifying the search time frame and how duplicates were identified and removed would strengthen the methodology. Including only studies with a sample size of at least 50 raises the risk of selection bias by excluding smaller but relevant studies. The choice of specific years for malaria incidence and mortality data (e.g., 2000 and 1990) is not justified; explaining why these years were chosen over more recent data would be beneficial. Additionally, while geographical classification is mentioned, more explanation is needed regarding how this impacts the analysis and interpretation of results. In conclusion, addressing these deficiencies, particularly the lack of bias assessment and the need for greater transparency in data sources will increase the review's contribution to the literature on ACE1 polymorphism and malaria.

6. Results
The results indicate a thorough literature search, yielding a substantial number of references (5,099) before applying selection criteria, demonstrating a rigorous approach. The findings are presented, with specific prevalence estimates for ACE1 genotypes across various regions, facilitating an understanding of geographic variations. The inclusion of linear regression analysis to explore associations adds robustness, while CIs for the coefficients boost the credibility of the statistical findings and convey the precision of the estimates. The geographic breakdown of prevalence estimates further aids the understanding of the data and its implications for public health.

However, there are important concerns. The section lacks context regarding how prevalence estimates compare to previous findings or their significance in the literature. There is no mention of the quality or reliability of the included studies, which is crucial for interpreting the results. There is little synthesis of the summaries of the papers assessed and important details. Additionally, the analysis does not address potential confounding variables that could influence associations between ID/DD frequency and malaria-related outcomes. While figures and tables are referenced, they lack contextual explanation, which would help readers better understand the data. More detail about the regression model, including checks for assumptions and model fit, would also increase the analysis's transparency and depth.

7. Discussion
The discussion presents the review's findings within the broader context of research on genetic variations influenced by malaria, linking the ACE1 D-allele to historical malaria exposure patterns. The authors candidly address significant limitations, such as reliance on outdated malaria incidence and mortality data, enhancing transparency and credibility. Referencing historical malaria prevalence data (e.g., from Lysenko) adds depth, offering a perspective on historical influences on D-allele frequency. The acknowledgment of potential confounding factors shows a better awareness of the complexities in genetic epidemiology. Additionally, the discussion suggests implications for public health, particularly concerning hypertension and COVID-19, guiding future research directions.

However, certain issues are evident in this section as well. While some literature is referenced, the discussion could be strengthened by integrating more studies to support claims and provide a broader perspective. There is minimal discussion about the statistical robustness of the findings or how limitations might affect interpretation; for instance, addressing the impact of sample size could be beneficial. Although confounding is acknowledged, the exploration of alternative explanations for the observed associations, such as environmental or other genetic factors, could be more thorough. The authors also do not provide concrete recommendations for future research or public health strategies, which would enhance the practical application of the findings. Overall, while the discussion offers valuable insights and addresses limitations, it requires further integration of literature, deeper exploration of alternative explanations, and clearer recommendations for future research. Addressing these issues would significantly strengthen the review's conclusions.

8. Conclusion
The conclusion summarizes the key findings of the systematic review but it could be improved in several ways. Strengthening the language from "we can only conclude that our data is compatible" to "the data suggest a possible role" would convey a more assertive tone without overstating the findings. Additionally, while it links the D-allele to higher hypertension prevalence in individuals with an African genetic background, a brief explanation of how malaria might influence this association would clarify the connection. Mentioning COVID-19 implications could be more explicit by outlining how mapping D-allele prevalence could inform public health strategies or interventions, providing concrete examples for better applicability. Suggesting areas for further research would present a balanced view and guide future studies. Finally, concluding with a stronger statement that emphasizes the review's contribution to genetic epidemiology would increase the overall impact.

9. References
The references cited in the manuscript predominantly focus on the ACE I/D polymorphism, which is central to the review’s hypothesis and findings. They encompass a range of studies covering topics such as the implications of ACE1 in various diseases, genetic variability, and the role of malaria, enriching the discussion. Notably, the inclusion of recent studies related to COVID-19 and other contemporary health issues demonstrates the authors’ efforts. This diverse selection provides an across-the-board view of the topic, drawing insights from epidemiology, genetics, and public health. However, the list includes a limited number of malaria-specific studies, which is crucial for the systematic review's central theme. While there are references discussing ACE1 polymorphisms, fewer studies focus specifically on the relationship between malaria and genetic polymorphisms. Some references related to COVID-19 may not be directly relevant to the focus on malaria's influence on ACE1 polymorphism distribution.

Additionally, studies addressing the historical prevalence of malaria and its impact on genetic variations over time, which could strengthen the discussion on evolutionary aspects, are missing. Important foundational studies that explore the relationship between malaria and genetic polymorphisms are also less visible, limiting the review's breadth. Furthermore, references discussing systematic review methodologies or bias assessment in genetic epidemiology are notably missing, which would increase the methodological rigor of the review. While the references provide a concrete foundation for the systematic review, they could be made more comprehensive by incorporating more specific studies on malaria, balancing the focus on ACE1, and including historical and methodological perspectives. It is surprising that the authors claimed to have analyzed a significant number of articles but failed to provide adequate citations or a reference list, aside from the supplementary files. It is generally inappropriate for a systematic review manuscript to assert the selection and analysis of 248 articles without citing, explaining, or listing them.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Partly
Is the statistical analysis and its interpretation appropriate?

Partly
Are the conclusions drawn adequately supported by the results presented in the review?

Partly
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Malaria biology, immunology, epidemiology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Reviewer Report 03 Feb 2025

Abhinav Sinha, ICMR-National Institute of Malaria Research, Dwarka, New Delhi, India

Aparna Tiwari, ICMR-National Institute of Malaria Research, Delhi, India

Not Approved

https://doi.org/10.5256/f1000research.29501.r359145

The authors take up a very intriguing but complex hypothesis for the systematic review. The rationale behind the systematic review is very good but it appears that there are multiple confusions in the understanding of this complex evolutionary relationship between ... Continue reading

The authors take up a very intriguing but complex hypothesis for the systematic review. The rationale behind the systematic review is very good but it appears that there are multiple confusions in the understanding of this complex evolutionary relationship between malaria and hypertension.
There are two hypotheses that are put forth to explain the above relation that malaria is associated with hypertension - direct and indirect. Although the authors hint towards the indirect association but it is not explicitly stated anywhere in the manuscript.
Further, if we presume that the authors take up the indirect hypothesis, it must be made very clear that exposure pressure to severe malaria (and not malaria) predisposes them to the genetic risk of hypertension (and not directly increased blood pressure). Therefore, correlation with malaria incidence, mortality, blood pressure and HbS may not be the most appropriate way to address this hypothesis..

Other major negative issues relate to the lack of clarity on multiple aspects such as reasons for choosing the WHO regions, why the DD and ID genotypes were not separately analyzed, errors in citing references, issues about representativeness of population, choice of regression analysis, incomplete PRISMA flow chart, not registering the systematic review on PROSPERO, misinterpretation of p-values, inadequate information on selected allele of HbS, and many more minor mistakes.

Overall, there is no doubt that authors selected a very pertinent rationale but were unable to do justice with the intricate hypothesis.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Partly
Are sufficient details of the methods and analysis provided to allow replication by others?

No
Is the statistical analysis and its interpretation appropriate?

No
Are the conclusions drawn adequately supported by the results presented in the review?

No
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Molecular epidemiology, malaria, molecular parasitology, epidemiology, public health

We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Reviewer Report 21 Jun 2021

Rasheedunnisa Begum, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujurat, India

Mitesh Dwivedi, C.G. Bhakta Institute of Biotechnology, Uka Tarsadia University, Surat, India

Approved with Reservations

https://doi.org/10.5256/f1000research.29501.r86865

The authors have tried to present a systematic review to study the role of Malaria in ACE I/D genotype distribution. The review is novel and interesting as ACE I/D polymorphism might be associated with malaria and COVID-19 susceptibility as suggested ... Continue reading

The authors have tried to present a systematic review to study the role of Malaria in ACE I/D genotype distribution. The review is novel and interesting as ACE I/D polymorphism might be associated with malaria and COVID-19 susceptibility as suggested by the authors. However, there seems to be a few reservations for the article and concluding the association of Malaria with ACE I/D genotype distribution.

Comments:

How do the authors justify the effect of Malaria on distribution of ACE I/D genotypes in the studied population? In fact ACE I/D polymorphism might be a susceptibility factor for malaria in these populations. To confirm this, respective analysis should be carried out and if the ACE I/D polymorphism is found to be a susceptibility factor to malaria then, the conclusion “malaria played a role in establishing frequency distribution of the D-allele” must be revised as “ACE I/D polymorphism may have a role in malaria susceptibility”.
In the introduction the authors have mentioned that previous case-control studies suggest that the D-allele is associated with protection against progression to severe malaria but in the current review they have found positive association for malaria incidence, malaria mortality and D allele which is contradictory and they must justify this. Moreover, the authors should carry out a meta-analysis for the association of ACE I/D polymorphism with Malaria susceptibility and severity.
It is important to study the association of ACE protein levels with malaria incidence, malaria mortality.
Additionally, the article lacks the following crucial points in the systematic review, which could be included:

Risk of publication bias and sensitivity analyses.
The authors must screen the studies before inclusion of studies in the systematic review to avoid any bias.
The methodology part lacks the exclusion criteria for the studies.
Table 2 (Supplementary) lacks the crucial data like HWE, age, gender, ACE protein levels.
Quality assessment for the included studies should be done.
The accession number (rs number) of the ACE I/D polymorphism has not been mentioned anywhere in the article.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

No
Is the statistical analysis and its interpretation appropriate?

Partly
Are the conclusions drawn adequately supported by the results presented in the review?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Immunogenetics, disease biology, vitiligo, autoimmunity, case-control studies

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.

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Reviewer Report 26 Jan 2021

Alfred Amambua-Ngwa, Medical Research Council Unit, London School of Hygiene and Tropical Medicine, London, UK

Approved with Reservations

https://doi.org/10.5256/f1000research.29501.r76910

The authors present a somewhat systematic review of publications to determine the relationship between ACE1 ID/DD alleles and malaria. The authors used malaria incidence rather than prevalence information as well as the distribution of Hbs and malaria mortality. The review ... Continue reading

The authors present a somewhat systematic review of publications to determine the relationship between ACE1 ID/DD alleles and malaria. The authors used malaria incidence rather than prevalence information as well as the distribution of Hbs and malaria mortality. The review has a strong rationale given the suspected role of ACE1 in COVID-19 and associations with high blood pressure in populations of African descent. However, there are several limitations with the data gathering and analysis process that does not render full credibility to the conclusions of malaria being a contributing factor to the prevalence of the ID/DD alleles:

Data curation by a single author is not in line with standards for systematic reviews.
The authors have not clearly stated the number of different publication types that were included, short communications, letters, posters, reviews, and conference abstracts. The method seemed limited by the number of databases or sources used for the search and the numbers in the flow chat need further clarification on how some publications were eliminated. For example, why were only 312 texts assessed for eligibility out of the 402 texts obtained after screening? Why were the final 248 texts included after excluding 90 out of the 312 assessed?
Both first (Title/abstract) and second (full text) screening were done by one author which might have biased the screening strategy. Moreover, the author CK seems to have done everything in the manuscript, and this questions the contribution(s) of the second author.
It is not clear how the authors assessed the criteria of “the population being a representative of the general population” in the selected 248 articles. This is important because allele frequencies depend on census sizes from the population. Yet the authors did not provide country-level information on the number of samples. This reflects a general flaw in the statistics as results are presented per sub-region. Country-level malaria incidence for example can be widely different within sub-regions and so country-level data would have been more informative. Given that the frequency of the D allele is almost fixed in most of Africa and equally high in malaria-free regions, the regression in my opinion cannot be robust. No explanation for example was given for the lower frequency in South East Asia where there is historically a higher prevalence of malaria than in Europe.
From figure 3 there is a higher prevalence of the D allele in higher malaria prevalence regions, but the relationship is far from linear. Hence the coefficients presented cannot be accurate.
The authors should consider adding a reference for the WHO system mentioned in the geographical grouping section of the methods.
In the first paragraph of the results, the authors are referring to table 2 instead of table 1 and in the second paragraph, they refer the reader to table 1 instead of table 2.
The author should consider rearrangement of figures for easy flow. Changing figure 5 to figure 3 will enable a better understanding of the second paragraph of the results section by the reader.
The authors might consider capturing the P-values in figure 2.
The limitation of drawing data from studies without a report that I and D alleles are in Hardy-Weinberg equilibrium can and should be corrected. Withdrawing data from such studies in a review on polymorphism can create big bias in the analysis and conclusions drawn. I herein suggest the authors go back to all included 248 papers, sort out those without reports that the I and D alleles are in Hardy-Weinberg equilibrium, and then do additional analysis on data from only studies with reports on Hardy-Weinberg equilibrium. This will enable the authors to present results of data drawn from studies with and without reports from Hardy-Weinberg equilibrium as well as results with data drawn from only studies with reports on I and D alleles being in Hardy-Weinberg equilibrium, hence reducing bias in the analysis and final conclusion(s).

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

No
Is the statistical analysis and its interpretation appropriate?

Partly
Are the conclusions drawn adequately supported by the results presented in the review?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: parasitology, genomics, genetics, epidemiology, transmission, drug resistance

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Reviewer Report 24 Nov 2020

Bin Pei, Evidence-Based Medicine Center and The Third Ward of Orthopedic, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China

Not Approved

https://doi.org/10.5256/f1000research.29501.r74480

In this study, the authors performed a systematic review to analyze the association between ACE1 I/D polymorphism and malaria. The topic is novel, but there are some serious defects that cannot be ignored.

This study included previous systematic

In this study, the authors performed a systematic review to analyze the association between ACE1 I/D polymorphism and malaria. The topic is novel, but there are some serious defects that cannot be ignored.

This study included previous systematic reviews regarding ACE1 I/D, which is inconsistent with the scientificity of a systematic review. Besides, the search strategy and databases could not ensure the comprehensiveness of the researches included in this study, and the included 248 literatures were neither listed in this paper nor in the supplement. The data was extracted by only a single author, this is inconsistent with the basic requirement of data extracting method in systematic reviews. Moreover, the author did not evaluate the publication bias and method quality of the included studies, which may influence the reliability of the conclusion.
For the systematic review of gene polymorphism, Hardy-Weinberg test was not performed in this study. Whether the included researches meets Hardy-Weinberg test is important to reflect the representativeness of the population.
There are defects in statistical analysis. Linear regression was used to evaluate the country-level association between the prevalence of ID/DD genotypes and the three measures of intensity of malaria. However, the scatter plots (Figure 3) could not reflect the feasibility of linear regression, and the authors did not explain whether the data meet the assumption of linear regression. Besides, the prevalence of the ACE1 ID/DD genotypes should be obtained only from the healthy population, but the authors did not display the data resource in the figures or tables. Additionally, in Table 1 and Table 2, there is a methodological error to analyze the association between gene polymorphisms and malaria in other regions based on the region with the largest sample size, which may obtain fundamentally wrong results and conclusions.
The results of ID/DD genotype were analyzed in the study. Although it was mentioned in the last sentence of the results section that “Results were similar when these regressions were run with DD frequency as the outcome variable”, it could not be concluded that the D allele is associated with malaria. It is suggested that on the basis of overcoming the above problems, the authors should separately study the correlation between I allele and malaria and the correlation between D allele and malaria.
The research on gene polymorphism is always divided by race rather than region.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Partly
Is the statistical analysis and its interpretation appropriate?

No
Are the conclusions drawn adequately supported by the results presented in the review?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Evidence-based medicine, clinical epidemiology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Bin Pei, Hubei University of Medicine, Xiangyang, China
Alfred Amambua-Ngwa, London School of Hygiene and Tropical Medicine, London, UK
Rasheedunnisa Begum, The Maharaja Sayajirao University of Baroda, Vadodara, India

Mitesh Dwivedi, Uka Tarsadia University, Surat, India
Abhinav Sinha, ICMR-National Institute of Malaria Research, Dwarka, India

Aparna Tiwari, ICMR-National Institute of Malaria Research, Delhi, India
Hassen Mamo, Addis Ababa University, Addis Ababa, Ethiopia

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13 Feb 2025 | for Version 1

Hassen Mamo, Department of Microbial, Cellular and Molecular Biology, Addis Ababa University, Addis Ababa, Ethiopia

4 Views Cite this report Responses(0)

Not Approved

I. General Comment
The manuscript is of interest to experts in the field of human genetic factors related to susceptibility or resistance to malaria, as well as its evolutionary significance and current public health implications for more effective malaria control, elimination, and eventual eradication by integrating all available means. However, substantial effort is required to strengthen the manuscript to that level. Extensive revisions are needed in all sections of the systematic review, including the title.

II. Section-by-section Report
Below is a comprehensive section-by-section report.

1. Title
The manuscript summarizes existing literature and lacks original ecological data, rendering the current title misleading. The use of "and" suggests the inclusion of both elements, which is not accurate. A more appropriate title that would reflect the content can be ‘The role of malaria in the global distribution of angiotensin-converting enzyme gene polymorphism: A systematic review of ecological associations’. This revision clarifies the emphasis on the systematic review aspect without implying the presence of original ecological research findings.

2. Abstract
The abstract introduces the ACE1 D-allele and its disease associations, clearly stating the hypothesis linking malaria to the ACE1 I/D polymorphism distribution. It briefly outlines the systematic review and the focus on genotype frequencies, summarizing results with specific data points. The conclusion ties back to the hypothesis, suggesting malaria's potential role in shaping D-allele frequency. However, the methods part lacks crucial details on the search strategy, inclusion/exclusion criteria, and data analysis, which are essential for evaluating the review's robustness. While the results present key findings, they could better connect to the hypothesis. For instance, reiterating the hypothesis before the results and using phrases like "These results support our hypothesis that malaria influences ACE1 polymorphism distribution" would clarify the link. Additionally, the mention of "all P<0.05" needs clarification on clinical significance and comparison to prior studies, possibly including effect sizes or confidence intervals (CIs). The conclusion could be more assertive by suggesting implications for further research or public health. Finally, the inclusion of keywords like "genetic polymorphism" or "epidemiology" could improve the visibility of the review.

3. Summary
The summary has notable strengths, such as introducing the ACE1 D-allele and its links to various diseases, clearly articulating the hypothesis connecting malaria to the ACE1 I/D polymorphism distribution, and highlighting geographic variations in D-allele prevalence. However, there are significant deficiencies. Specific prevalence rates for the D-allele in different regions would clarify the data. The summary lacks details on study selection and analysis methods, which are crucial for assessing credibility. The phrase "three markers of malaria burden of disease" is vague; specifying these markers, such as malaria incidence and mortality rates, would improve clarity. Additionally, a brief discussion on the implications of the findings for public health policies or future research directions is needed. Quantifying terms like "most prevalent" and "least prevalent" would improve impact, and the repeated phrasing regarding the hypothesis could be streamlined for conciseness.

4. Introduction
The introduction rightly outlines the role of the renin-angiotensin system and ACE1 in various physiological processes, laying a strong foundation for the manuscript. It provides a rationale for investigating the ACE1 D-allele, linking it to numerous diseases and emphasizing its clinical significance. Relevant citations support claims about the D-allele’s associations with diseases and its potential protective role against severe malaria, demonstrating engagement with existing research. The objectives are clearly stated, logically progressing from background information to specific aims, while highlighting the need to understand the variation in ACE1 polymorphism frequency across populations.

However, the section has significant deficiencies. The flow between sentences and sections could be improved, particularly the transition from ACE1’s role in diseases to the D-allele’s protective effects against malaria, which feels abrupt. More transitional phrases would help. Additionally, some sentences repeat similar ideas about the D-allele's protective role, and streamlining these sections would improve clarity and conciseness. The inconsistent use of "D-allele" and "D allele" should be standardized throughout the text. While a prior systematic review is cited, the introduction does not sufficiently how this one differs from or builds upon that review regarding geographical variation, which would highlight its novelty. Specific statistics (e.g., D allele frequencies by ethnicity) are presented without visual aids or tables to support these claims, which could improve understanding. Overall, while the introduction is informative, addressing these deficiencies will improve the clarity, flow, and overall readability of the manuscript.

5. Methods
Utilizing PubMed and Google Scholar for literature searches is appropriate, as these are reputable sources for biomedical research. The inclusion criteria (sample size, language, representativeness) are well-defined, ensuring the quality of the studies included. The mention of a single author (CK) responsible for data extraction, along with manual accuracy checks, indicates a methodical approach, though this has its limitations. The statistical methods employed (linear regression and Wilcoxon rank-sum test) are suitable for analyzing associations and differences in genotype prevalence.

However, this section has also significant weaknesses. Not assessing the risk of bias in the included studies or quality is a major oversight, as this is crucial for evaluating the reliability of findings in systematic reviews. While sources for malaria incidence and mortality are mentioned, more detail on how these data were selected or validated is missing. The literature search strategy lacks comprehensiveness; specifying the search time frame and how duplicates were identified and removed would strengthen the methodology. Including only studies with a sample size of at least 50 raises the risk of selection bias by excluding smaller but relevant studies. The choice of specific years for malaria incidence and mortality data (e.g., 2000 and 1990) is not justified; explaining why these years were chosen over more recent data would be beneficial. Additionally, while geographical classification is mentioned, more explanation is needed regarding how this impacts the analysis and interpretation of results. In conclusion, addressing these deficiencies, particularly the lack of bias assessment and the need for greater transparency in data sources will increase the review's contribution to the literature on ACE1 polymorphism and malaria.

6. Results
The results indicate a thorough literature search, yielding a substantial number of references (5,099) before applying selection criteria, demonstrating a rigorous approach. The findings are presented, with specific prevalence estimates for ACE1 genotypes across various regions, facilitating an understanding of geographic variations. The inclusion of linear regression analysis to explore associations adds robustness, while CIs for the coefficients boost the credibility of the statistical findings and convey the precision of the estimates. The geographic breakdown of prevalence estimates further aids the understanding of the data and its implications for public health.

However, there are important concerns. The section lacks context regarding how prevalence estimates compare to previous findings or their significance in the literature. There is no mention of the quality or reliability of the included studies, which is crucial for interpreting the results. There is little synthesis of the summaries of the papers assessed and important details. Additionally, the analysis does not address potential confounding variables that could influence associations between ID/DD frequency and malaria-related outcomes. While figures and tables are referenced, they lack contextual explanation, which would help readers better understand the data. More detail about the regression model, including checks for assumptions and model fit, would also increase the analysis's transparency and depth.

7. Discussion
The discussion presents the review's findings within the broader context of research on genetic variations influenced by malaria, linking the ACE1 D-allele to historical malaria exposure patterns. The authors candidly address significant limitations, such as reliance on outdated malaria incidence and mortality data, enhancing transparency and credibility. Referencing historical malaria prevalence data (e.g., from Lysenko) adds depth, offering a perspective on historical influences on D-allele frequency. The acknowledgment of potential confounding factors shows a better awareness of the complexities in genetic epidemiology. Additionally, the discussion suggests implications for public health, particularly concerning hypertension and COVID-19, guiding future research directions.

However, certain issues are evident in this section as well. While some literature is referenced, the discussion could be strengthened by integrating more studies to support claims and provide a broader perspective. There is minimal discussion about the statistical robustness of the findings or how limitations might affect interpretation; for instance, addressing the impact of sample size could be beneficial. Although confounding is acknowledged, the exploration of alternative explanations for the observed associations, such as environmental or other genetic factors, could be more thorough. The authors also do not provide concrete recommendations for future research or public health strategies, which would enhance the practical application of the findings. Overall, while the discussion offers valuable insights and addresses limitations, it requires further integration of literature, deeper exploration of alternative explanations, and clearer recommendations for future research. Addressing these issues would significantly strengthen the review's conclusions.

8. Conclusion
The conclusion summarizes the key findings of the systematic review but it could be improved in several ways. Strengthening the language from "we can only conclude that our data is compatible" to "the data suggest a possible role" would convey a more assertive tone without overstating the findings. Additionally, while it links the D-allele to higher hypertension prevalence in individuals with an African genetic background, a brief explanation of how malaria might influence this association would clarify the connection. Mentioning COVID-19 implications could be more explicit by outlining how mapping D-allele prevalence could inform public health strategies or interventions, providing concrete examples for better applicability. Suggesting areas for further research would present a balanced view and guide future studies. Finally, concluding with a stronger statement that emphasizes the review's contribution to genetic epidemiology would increase the overall impact.

9. References
The references cited in the manuscript predominantly focus on the ACE I/D polymorphism, which is central to the review’s hypothesis and findings. They encompass a range of studies covering topics such as the implications of ACE1 in various diseases, genetic variability, and the role of malaria, enriching the discussion. Notably, the inclusion of recent studies related to COVID-19 and other contemporary health issues demonstrates the authors’ efforts. This diverse selection provides an across-the-board view of the topic, drawing insights from epidemiology, genetics, and public health. However, the list includes a limited number of malaria-specific studies, which is crucial for the systematic review's central theme. While there are references discussing ACE1 polymorphisms, fewer studies focus specifically on the relationship between malaria and genetic polymorphisms. Some references related to COVID-19 may not be directly relevant to the focus on malaria's influence on ACE1 polymorphism distribution.

Additionally, studies addressing the historical prevalence of malaria and its impact on genetic variations over time, which could strengthen the discussion on evolutionary aspects, are missing. Important foundational studies that explore the relationship between malaria and genetic polymorphisms are also less visible, limiting the review's breadth. Furthermore, references discussing systematic review methodologies or bias assessment in genetic epidemiology are notably missing, which would increase the methodological rigor of the review. While the references provide a concrete foundation for the systematic review, they could be made more comprehensive by incorporating more specific studies on malaria, balancing the focus on ACE1, and including historical and methodological perspectives. It is surprising that the authors claimed to have analyzed a significant number of articles but failed to provide adequate citations or a reference list, aside from the supplementary files. It is generally inappropriate for a systematic review manuscript to assert the selection and analysis of 248 articles without citing, explaining, or listing them.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Partly
Is the statistical analysis and its interpretation appropriate?

Partly
Are the conclusions drawn adequately supported by the results presented in the review?

Partly
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Malaria biology, immunology, epidemiology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Reviewer Report

15 Views

03 Feb 2025 | for Version 1

Abhinav Sinha, ICMR-National Institute of Malaria Research, Dwarka, New Delhi, India

Aparna Tiwari, ICMR-National Institute of Malaria Research, Delhi, India

15 Views Cite this report Responses(0)

Not Approved

The authors take up a very intriguing but complex hypothesis for the systematic review. The rationale behind the systematic review is very good but it appears that there are multiple confusions in the understanding of this complex evolutionary relationship between malaria and hypertension.
There are two hypotheses that are put forth to explain the above relation that malaria is associated with hypertension - direct and indirect. Although the authors hint towards the indirect association but it is not explicitly stated anywhere in the manuscript.
Further, if we presume that the authors take up the indirect hypothesis, it must be made very clear that exposure pressure to severe malaria (and not malaria) predisposes them to the genetic risk of hypertension (and not directly increased blood pressure). Therefore, correlation with malaria incidence, mortality, blood pressure and HbS may not be the most appropriate way to address this hypothesis..

Other major negative issues relate to the lack of clarity on multiple aspects such as reasons for choosing the WHO regions, why the DD and ID genotypes were not separately analyzed, errors in citing references, issues about representativeness of population, choice of regression analysis, incomplete PRISMA flow chart, not registering the systematic review on PROSPERO, misinterpretation of p-values, inadequate information on selected allele of HbS, and many more minor mistakes.

Overall, there is no doubt that authors selected a very pertinent rationale but were unable to do justice with the intricate hypothesis.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Partly
Are sufficient details of the methods and analysis provided to allow replication by others?

No
Is the statistical analysis and its interpretation appropriate?

No
Are the conclusions drawn adequately supported by the results presented in the review?

No
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Molecular epidemiology, malaria, molecular parasitology, epidemiology, public health

We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Reviewer Report

9 Views

21 Jun 2021 | for Version 1

Rasheedunnisa Begum, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujurat, India

Mitesh Dwivedi, C.G. Bhakta Institute of Biotechnology, Uka Tarsadia University, Surat, India

9 Views Cite this report Responses(0)

Approved With Reservations

The authors have tried to present a systematic review to study the role of Malaria in ACE I/D genotype distribution. The review is novel and interesting as ACE I/D polymorphism might be associated with malaria and COVID-19 susceptibility as suggested by the authors. However, there seems to be a few reservations for the article and concluding the association of Malaria with ACE I/D genotype distribution.

Comments:

How do the authors justify the effect of Malaria on distribution of ACE I/D genotypes in the studied population? In fact ACE I/D polymorphism might be a susceptibility factor for malaria in these populations. To confirm this, respective analysis should be carried out and if the ACE I/D polymorphism is found to be a susceptibility factor to malaria then, the conclusion “malaria played a role in establishing frequency distribution of the D-allele” must be revised as “ACE I/D polymorphism may have a role in malaria susceptibility”.
In the introduction the authors have mentioned that previous case-control studies suggest that the D-allele is associated with protection against progression to severe malaria but in the current review they have found positive association for malaria incidence, malaria mortality and D allele which is contradictory and they must justify this. Moreover, the authors should carry out a meta-analysis for the association of ACE I/D polymorphism with Malaria susceptibility and severity.
It is important to study the association of ACE protein levels with malaria incidence, malaria mortality.
Additionally, the article lacks the following crucial points in the systematic review, which could be included:

Risk of publication bias and sensitivity analyses.
The authors must screen the studies before inclusion of studies in the systematic review to avoid any bias.
The methodology part lacks the exclusion criteria for the studies.
Table 2 (Supplementary) lacks the crucial data like HWE, age, gender, ACE protein levels.
Quality assessment for the included studies should be done.
The accession number (rs number) of the ACE I/D polymorphism has not been mentioned anywhere in the article.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

No
Is the statistical analysis and its interpretation appropriate?

Partly
Are the conclusions drawn adequately supported by the results presented in the review?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Immunogenetics, disease biology, vitiligo, autoimmunity, case-control studies

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.

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Reviewer Report

7 Views

26 Jan 2021 | for Version 1

Alfred Amambua-Ngwa, Medical Research Council Unit, London School of Hygiene and Tropical Medicine, London, UK

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Approved With Reservations

The authors present a somewhat systematic review of publications to determine the relationship between ACE1 ID/DD alleles and malaria. The authors used malaria incidence rather than prevalence information as well as the distribution of Hbs and malaria mortality. The review has a strong rationale given the suspected role of ACE1 in COVID-19 and associations with high blood pressure in populations of African descent. However, there are several limitations with the data gathering and analysis process that does not render full credibility to the conclusions of malaria being a contributing factor to the prevalence of the ID/DD alleles:

Data curation by a single author is not in line with standards for systematic reviews.
The authors have not clearly stated the number of different publication types that were included, short communications, letters, posters, reviews, and conference abstracts. The method seemed limited by the number of databases or sources used for the search and the numbers in the flow chat need further clarification on how some publications were eliminated. For example, why were only 312 texts assessed for eligibility out of the 402 texts obtained after screening? Why were the final 248 texts included after excluding 90 out of the 312 assessed?
Both first (Title/abstract) and second (full text) screening were done by one author which might have biased the screening strategy. Moreover, the author CK seems to have done everything in the manuscript, and this questions the contribution(s) of the second author.
It is not clear how the authors assessed the criteria of “the population being a representative of the general population” in the selected 248 articles. This is important because allele frequencies depend on census sizes from the population. Yet the authors did not provide country-level information on the number of samples. This reflects a general flaw in the statistics as results are presented per sub-region. Country-level malaria incidence for example can be widely different within sub-regions and so country-level data would have been more informative. Given that the frequency of the D allele is almost fixed in most of Africa and equally high in malaria-free regions, the regression in my opinion cannot be robust. No explanation for example was given for the lower frequency in South East Asia where there is historically a higher prevalence of malaria than in Europe.
From figure 3 there is a higher prevalence of the D allele in higher malaria prevalence regions, but the relationship is far from linear. Hence the coefficients presented cannot be accurate.
The authors should consider adding a reference for the WHO system mentioned in the geographical grouping section of the methods.
In the first paragraph of the results, the authors are referring to table 2 instead of table 1 and in the second paragraph, they refer the reader to table 1 instead of table 2.
The author should consider rearrangement of figures for easy flow. Changing figure 5 to figure 3 will enable a better understanding of the second paragraph of the results section by the reader.
The authors might consider capturing the P-values in figure 2.
The limitation of drawing data from studies without a report that I and D alleles are in Hardy-Weinberg equilibrium can and should be corrected. Withdrawing data from such studies in a review on polymorphism can create big bias in the analysis and conclusions drawn. I herein suggest the authors go back to all included 248 papers, sort out those without reports that the I and D alleles are in Hardy-Weinberg equilibrium, and then do additional analysis on data from only studies with reports on Hardy-Weinberg equilibrium. This will enable the authors to present results of data drawn from studies with and without reports from Hardy-Weinberg equilibrium as well as results with data drawn from only studies with reports on I and D alleles being in Hardy-Weinberg equilibrium, hence reducing bias in the analysis and final conclusion(s).

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

No
Is the statistical analysis and its interpretation appropriate?

Partly
Are the conclusions drawn adequately supported by the results presented in the review?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

parasitology, genomics, genetics, epidemiology, transmission, drug resistance

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Reviewer Report

10 Views

24 Nov 2020 | for Version 1

Bin Pei, Evidence-Based Medicine Center and The Third Ward of Orthopedic, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China

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Not Approved

In this study, the authors performed a systematic review to analyze the association between ACE1 I/D polymorphism and malaria. The topic is novel, but there are some serious defects that cannot be ignored.

This study included previous systematic reviews regarding ACE1 I/D, which is inconsistent with the scientificity of a systematic review. Besides, the search strategy and databases could not ensure the comprehensiveness of the researches included in this study, and the included 248 literatures were neither listed in this paper nor in the supplement. The data was extracted by only a single author, this is inconsistent with the basic requirement of data extracting method in systematic reviews. Moreover, the author did not evaluate the publication bias and method quality of the included studies, which may influence the reliability of the conclusion.
For the systematic review of gene polymorphism, Hardy-Weinberg test was not performed in this study. Whether the included researches meets Hardy-Weinberg test is important to reflect the representativeness of the population.
There are defects in statistical analysis. Linear regression was used to evaluate the country-level association between the prevalence of ID/DD genotypes and the three measures of intensity of malaria. However, the scatter plots (Figure 3) could not reflect the feasibility of linear regression, and the authors did not explain whether the data meet the assumption of linear regression. Besides, the prevalence of the ACE1 ID/DD genotypes should be obtained only from the healthy population, but the authors did not display the data resource in the figures or tables. Additionally, in Table 1 and Table 2, there is a methodological error to analyze the association between gene polymorphisms and malaria in other regions based on the region with the largest sample size, which may obtain fundamentally wrong results and conclusions.
The results of ID/DD genotype were analyzed in the study. Although it was mentioned in the last sentence of the results section that “Results were similar when these regressions were run with DD frequency as the outcome variable”, it could not be concluded that the D allele is associated with malaria. It is suggested that on the basis of overcoming the above problems, the authors should separately study the correlation between I allele and malaria and the correlation between D allele and malaria.
The research on gene polymorphism is always divided by race rather than region.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Partly
Is the statistical analysis and its interpretation appropriate?

No
Are the conclusions drawn adequately supported by the results presented in the review?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Evidence-based medicine, clinical epidemiology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Could malaria explain the global distribution of the angiotensin converting enzyme I/D polymorphism? A systematic review and ecological study

Abstract

Keywords

Summary

Introduction

Methods

Systematic review of ACE1 DD and ID/DD prevalence

Figure 1. PRISMA flowchart.

Results

Systematic review of ACE1 DD and ID/DD prevalence

Figure 2. Boxplots of the prevalence of ACE1 ID/DD genotypes according to World Health Organization regions.

Table 1. Prevalence of the ID/DD genotypes according to World Health Organization regions.

Table 2. Prevalence of the ID/DD genotypes in four European sub-regions.

Table 3. Linear regression assessing the country-level association between the frequency of the ACE1 ID/DD genotypes and malaria incidence per 1,000, malaria mortality per 100,000 and the allele frequency of hemoglobin S (HbS).

Figure 3.

Discussion

Figure 4. The map global malaria endemicity originally produced by Lysenko et al.21 and reproduced by Hay et al. 20.

Figure 5. The country level prevalence of the ACE1 ID/DD genotypes (in percentages) according to the data produced by the current systematic review.

Data availability

Underlying data

Extended data

Authors contributions

References

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Figure 4. The map global malaria endemicity originally produced by Lysenko et al.²¹ and reproduced by Hay et al. ²⁰.