Effect of rs4646994 polymorphism of angiotensin-converting enzyme on the risk of nonischemic cardiomyopathy

Abstract Background: Angiotensin-converting enzyme (ACE) gene polymorphisms have recently been shown to be associated with risk of developing left ventricular hypertrophy (LVH). However, the results were controversial. We aimed to conduct this meta-analysis to further confirm the association between ACE rs4646994 polymorphism and hypertrophic cardiomyopathy (HCM)/dilated cardiomyopathy (DCM). Methods: PubMed, Embase, the Chinese National Knowledge Information, and Wanfang databases were searched for eligible studies. The Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of included studies. Then we evaluated the association between ACE gene mutation and HCM/DCM by calculating odds ratios (ORs) and 95% confidence intervals (95% CIs). Subgroup analysis was further performed to explore situations in specialized subjects. Sensitivity analysis and publication bias was assessed to confirm the study reliability. Results: There were 13 studies on DCM (2004 cases and 1376 controls) and 16 studies on HCM (2161 controls and 1192 patients). ACE rs4646994 polymorphism was significantly associated with DCM in all genetic models. However, in HCM, four genetic models (allele model, homozygous model, heterozygous model, and dominant model) showed significant association between ACE rs4646994 polymorphism and DCM. In subgroup analysis, we found that ACE rs4646994 polymorphism was significantly associated with DCM/HCM in Asian population. Finally, we also conducted a cumulative meta-analysis, which indicates that the results of our meta-analysis are highly reliable. Conclusion: ACE rs4646994 polymorphism increases the risk of DCM/HCM in Asians, but not in Caucasians. More case–control studies are needed to strengthen our conclusions and to assess the gene–gene and gene–environment interactions between ACE rs4646994 polymorphism and DCM/HCM.


Rationale
3 Describe the rationale for the review in the context of existing knowledge. 4 Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses. 5

METHODS
Eligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses. 5 Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.

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Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used. 5 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

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Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

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Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

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10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.
6 Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

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Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results. 6-7 Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

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13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

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13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. 6-7 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

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13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression). 6-7 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. 6-7 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases). 6-7 Certainty assessment

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

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16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. 7 Study characteristics 17 Cite each included study and present its characteristics. 7 Risk of bias in studies 18 Present assessments of risk of bias for each included study. 7

Results of individual studies
19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots. 7

Results of syntheses
20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. 7-10 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect.

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20c Present results of all investigations of possible causes of heterogeneity among study results. 7-10 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. 7-10 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed. 11 Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed. 7-11

Discussion
23a Provide a general interpretation of the results in the context of other evidence. 11 23b Discuss any limitations of the evidence included in the review. 12 23c Discuss any limitations of the review processes used. 12 23d Discuss implications of the results for practice, policy, and future research. 13

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. 13 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. 5 24c Describe and explain any amendments to information provided at registration or in the protocol. 5 Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review. 14 Competing interests 26 Declare any competing interests of review authors. 14 Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.