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

Q: What are the key findings of this study?

Carriers of the APOA1 rs670 A allele had significantly higher serum Apo A1 levels (SMD 0.197) and HDL-C levels than GG homozygotes, with the effect amplified in those with metabolic disorders.

Q: What is the clinical evidence from this study?

Study design: Meta-Analysis. Population: Metabolic syndrome and lipid metabolism (n=22175). Intervention: APOA1 rs670 A allele (GA or AA genotypes) vs. APOA1 rs670 GG genotype. Primary outcome: Serum Apolipoprotein A1 (Apo A1) levels (SMD 0.197, 95% CI 0.095-0.299, p=<0.001).

Q: What does this research mean for the field?

The APOA1 rs670 polymorphism is associated with higher circulating Apo A1 and HDL-C levels, an effect that is substantially stronger in individuals with metabolic disorders compared to metabolically healthy individuals. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To assess the quantitative associations of the APOA1 rs670 (−75 G>A) polymorphism with serum apolipoprotein A1 and circulating lipid levels, and evaluate whether metabolic disorder status modifies these associations.

Chien‐Yi Chan; Yi-Chen Huang; Ming-Fen Lee; Chuyi Huang; Wen‐Chieh Wu

doi:10.3390/ijms27177622

August 25, 2026International Journal of Molecular SciencesOpen Access

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

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Key result

APOA1 rs670 A allele is linked to higher Apo A1 and HDL-C levels.

SMD +0.197
95% CI 0.095-0.299
P<0.001
n=22,175

Why the study?

Does the APOA1 rs670 A allele polymorphism improve Apo A1 and HDL-C levels in individuals with and without metabolic disorders?

Key Points

To assess the quantitative associations of the APOA1 rs670 (−75 G>A) polymorphism with serum apolipoprotein A1 and circulating lipid levels, and evaluate whether metabolic disorder status modifies these associations.
Searched PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov through March 2026, identifying 40 eligible studies across Asia, the Middle East, Europe, South America, the USA, and Australia with 22,175 participants (PROSPERO CRD420261333145).
Calculated pooled standardized mean differences (SMDs) with 95% confidence intervals using random-effects models, comparing A allele carriers (GA or AA) to GG homozygotes across lipid traits and stratifying by metabolic disorder status.
Carriers of the rs670 A allele had significantly higher levels of serum Apo A1 (SMD, 0.197; 95% CI, 0.095–0.299; p < 0.001) and HDL-C (SMD, 0.139; 95% CI, 0.068–0.211; p < 0.001) compared with GG homozygotes.
Stratification by metabolic status showed significantly larger effect sizes in individuals with metabolic disorders versus healthy individuals for Apo A1 (SMD, 0.533; 95% CI, 0.021–1.046; p = 0.041 vs. SMD, 0.106; 95% CI, 0.054–0.157; p < 0.001) and HDL-C (SMD, 0.233; 95% CI, 0.076–0.390; p = 0.004 vs. SMD, 0.082; 95% CI, 0.018–0.147; p = 0.012).
No statistically significant associations were found with LDL-C (SMD, 0.069; 95% CI, −0.003–0.141; p = 0.059) or triglycerides (SMD, −0.035; 95% CI, −0.109–0.039; p = 0.352).

Study Design

Type

Meta-Analysis (n=22,175)

Multicenter

Yes

Structured PICO

Does the APOA1 rs670 A allele polymorphism improve Apo A1 and HDL-C levels in individuals with and without metabolic disorders?

P

Population

22,175 participants from 40 pooled studies assessing the association between the APOA1 rs670 genotype and quantitative lipid measurements.

E

Exposure

APOA1 rs670 A allele carrier (GA or AA genotype)

C

Comparator

APOA1 rs670 GG homozygote

O

Outcome

Serum Apolipoprotein A1 (Apo A1) and HDL-C levelssurrogate

Main Result

Standardized Mean Difference: 0.197 (95% CI 0.095–0.299)

p-value: p=<0.001

Limitations

Most studies conducted in Asian and European populations, limiting generalizability
Inconsistent reporting of environmental modifiers like diet and smoking
Based on aggregate study-level data, precluding assessment of individual-level interactions
Substantial between-study heterogeneity, particularly among participants with metabolic disorders
Inability to examine atherogenic lipid ratios due to lack of available data
Predominantly Asian and European populations
Environmental modifiers (diet, smoking, activity) not systematically evaluated
Relies on aggregate study-level data rather than individual participant data
Substantial heterogeneity in the metabolic syndrome subgroup
Atherogenic lipid ratios could not be examined

Implication

The APOA1 rs670 A allele is significantly associated with higher serum Apo A1 and HDL-C levels, an effect that is substantially amplified under conditions of metabolic dysregulation.

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.

Discussion

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Cite This Study

Chan et al. (2026) conducted a meta-analysis in Metabolic syndrome and lipid metabolism (n=22,175). APOA1 rs670 A allele (GA or AA genotypes) vs. APOA1 rs670 GG genotype was evaluated on Serum Apolipoprotein A1 (Apo A1) levels (SMD 0.197, 95% CI 0.095-0.299, p=<0.001). Carriers of the APOA1 rs670 A allele had significantly higher serum Apo A1 levels (SMD 0.197) and HDL-C levels than GG homozygotes, with the effect amplified in those with metabolic disorders.

synapsesocial.com/papers/6a8fe9ad10c91c1e92621797 https://doi.org/10.3390/ijms27177622

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

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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