Context-Dependent Associations of the APOA1 rs670 Polymorphism with Apolipoprotein A1 and HDL Cholesterol: A Systematic Review and Meta-Analysis

Abstract

The APOA1 rs670 (−75 G>A) polymorphism has been implicated in lipid metabolism and susceptibility to metabolic syndrome (MetS). However, individual studies have reported inconsistent associations with circulating apolipoprotein A1 (Apo A1) and lipid parameters, and no meta-analysis has comprehensively evaluated these associations stratified by metabolic disorder status. We therefore quantified the associations between APOA1 rs670 and serum Apo A1 and lipid parameters, and determined whether these associations are modified by metabolic disorder status. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched from inception to March 2026. Eligible studies reported APOA1 rs670 genotype data with quantitative lipid measurements. Forty studies involving 22,175 participants met the inclusion criteria. Pooled effect sizes were estimated as standardized mean differences (SMDs) with 95% confidence intervals (CIs) using random-effects models. This review was registered in PROSPERO (CRD420261333145). A allele carriers had significantly higher serum Apo A1 (SMD, 0.20; p < 0.001) and HDL-C levels (SMD, 0.14; p < 0.001) than GG homozygotes. Subgroup analyses stratified by metabolic disorder status revealed that the associations with Apo A1 (SMD, 0.53 vs. 0.11) and HDL-C (SMD, 0.23 vs. 0.08) were substantially stronger among individuals with metabolic disorders than among metabolically healthy individuals. No significant associations were observed for LDL-C or triglyceride levels. The APOA1 rs670 polymorphism is associated with higher circulating Apo A1 and HDL-C levels, with stronger associations in individuals with metabolic disorders. These findings suggest that metabolic status modifies the phenotypic effects of rs670 on the Apo A1–HDL pathway.