Abstract
BACKGROUND: The mutant allele (*2) of aldehyde dehydrogenase type 2 (ALDH2) caused by a single nucleotide variant (rs671) inhibits enzymatic activity and is associated with multiple diseases. In recent years, an explosive number of original studies and meta-analyses have been conducted to examine the associations of ALDH2 rs671 polymorphism with diseases. Due to conflicting results, the overall associations of ALDH2 rs671 polymorphism and multiple diseases remain unclear. METHODS: A quantitative umbrella review will be conducted on meta-analyses of genetic association studies to examine the pleiotropic effects of ALDH2 rs671, mainly including cardio-cerebral vascular disease, diabetes mellitus, cancer, neurodegenerative disease, and alcohol-induced medical disease. A search of relevant literature according to comprehensive search strategies will be performed on studies published before July 1st, 2022 in PubMed, MEDLINE Ovid, Embase, Cochrane Database of Systematic Reviews, and Web of Science. Study selection, data extraction, methodology quality assessment, and strength of evidence assessment will be conducted by two reviewers independently and in duplicate. Included meta-analyses will be grouped by outcomes. Data conflicts and overlap between meta-analyses will be managed through updated standardized and customized methods including the calculation of CCA for study selection reference, application of Doi plots to assess small-study effects and others. Evidence from included meta-analyses will be quantitatively synthesized by overlap-corrected analyses and meta-analysis using primary studies. DISCUSSION: This umbrella review is expected to generate systematic evidence on the association between ALDH2 rs671 and diseases. Specific approaches were developed to address key challenges in conducting an umbrella review, including assessment tools of methodology and evidence quality of meta-analyses, methods to manage overlap between meta-analyses, a "stop-light" plot to summarize key findings. These approaches provide applicable methods for future umbrella reviews of meta-analyses on genetic association studies. TRIAL REGISTRATION: CRD42021223812.