Aug 2026· International Journal of Molecular Sciences· Vol 27, pp. 7622· 0 citations· 61 references
TL;DR
It is suggested that metabolic status modifies the phenotypic effects of rs670 on the Apo A1–HDL pathway.
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.
Background Alzheimer’s disease (AD) and vascular dementia (VaD) have become significant global health challenges. Recent research evidence indicates a close comorbidity between AD and cerebral small vessel disease. The C677T (rs1801133, also known as c.665C > T) and A1298C (rs1801131) polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene have been associated with both conditions, though conclusions vary across studies. Methods We conducted a systematic search of PubMed, Embase, Web of Science and the Cochrane Library, covering the period from the inception of these databases to January 2026. Studies reporting the distribution of MTHFR C677T and/or A1298C genotypes were included. A fixed-effects model was used to calculate the pooled odds ratio (OR) and its 95% confidence interval (CI). Sensitivity analyses using random-effects models were also performed to test the robustness of the findings. Subgroup analyses were performed according to type of dementia and ethnicity. Results A total of 26 C677T studies and 8 A1298C studies were included. In the allele contrast model (T vs. C), C677T was significantly associated with dementia (OR = 1.40, 95% CI 1.05–1.87, p = 0.021) and AD (OR = 1.40, 95% CI 1.01–1.93, p = 0.043), but no statistically significant association was observed for VaD (OR = 1.42, 95% CI 0.76–2.66, p = 0.266). C677T showed no significant association under homozygous, heterozygous, dominant, or recessive inheritance models. No significant heterogeneity in association was observed across racial subgroups. A1298C showed no significant association with dementia under any genetic model. Conclusion This meta-analysis showed that the MTHFR C677T T allele is associated with the risk of AD in an allele-dependent model, with a similar but non-significant trend for VaD. The A1298C polymorphism shows no association with either type of dementia. These findings suggest that C677T genotyping may aid AD risk stratification in research, but it requires prospective validation and gene-environment studies before clinical use.
Yu-Yao He, Yandan Shi, Jin-Hua Hu et al.· Frontiers in Aging Neuroscie...· 0 citations
Epidemiological and Mendelian randomization studies have reported an inverse relationship between lipoprotein(a) [Lp(a)] concentration and type 2 diabetes (T2D), although findings have not been uniform across studies. We hypothesized that genetic variation at the
LPA
locus may contribute to T2D development beyond circulating Lp(a) concentration alone, and therefore aimed to investigate the association between common
LPA
variation and incident T2D.
We analysed 5058 male participants from the Aragon Workers’ Health Study with approximately 15 years of follow-up. T2D was defined as the presence of antidiabetic treatment or HbA1c ≥ 6.5%. Common
LPA
single-nucleotide variants (SNVs) with a minor allele frequency ≥ 1% were selected. Several weighted
LPA
genetic scores were constructed, with the 15-SNV score defined as the primary
LPA
genetic score and alternative and more restricted scores evaluated in sensitivity analyses. Associations of single
LPA
variants and
LPA
genetic scores with incident T2D were assessed using multivariable logistic regression models adjusted for age, body mass index, ln-transformed Lp(a), and a T2D polygenic risk score. False discovery rate correction was applied to account for multiple testing. Robustness was assessed using leave-one-out analyses and Cox proportional hazards models.
Among 4744 participants free of T2D at baseline, 578 (12.2%) developed incident T2D. Baseline Lp(a) concentrations were lower in participants who developed incident T2D than in those who remained free of T2D (12.6 [5.0–32.5] versus 17.0 [6.1–40.0] mg/dL;
p
< 0.001). No individual
LPA
SNV remained significantly associated with incident T2D. In contrast, the primary 15-SNV
LPA
genetic score was associated with incident T2D after adjustment for measured baseline Lp(a) concentration (odds ratio per one-standard-deviation increase 1.17, 95% confidence interval 1.07–1.29;
p
= 0.001). The 13-SNV, 12-SNV, 10-coding/splice, and 2-SNV raising-Lp(a) scores were also significantly associated with incident T2D after false discovery rate correction. The association with the 15-SNV
LPA
genetic score was supported by leave-one-out and Cox analyses.
A 15-SNV
LPA
genetic score was associated with incident T2D after adjustment for measured baseline Lp(a) concentration and a T2D polygenic risk score. These findings suggest that common
LPA
variation represented by the 15-SNV genetic score may contribute to T2D risk through mechanisms not fully captured by circulating Lp(a) concentration alone.
P. Corredoira, Daniel Bello Álvarez, Itziar Lamiquiz Moneo et al.· Cardiovascular Diabetology· 0 citations
The low-density lipoprotein receptor-related protein 5 (
LRP5
) gene is a key regulator of bone mineral density and skeletal metabolism. The rs3736228 (Ala1330Val) polymorphism in
LRP5
has been firmly established as a genome-wide significant locus for bone mineral density and fracture risk in large-scale GWAS. However, demographic and clinical subgroups that are frequently underrepresented in GWAS cohorts, such as sex, menopausal status and ethnicity, may have different impact sizes and ideal genetic models. Previous candidate-gene meta-analyses, while informative, did not systematically evaluate these subgroup-specific effects, owing to limited sample sizes and incomplete stratification. Therefore, we conducted this updated systematic review and meta-analysis to provide granular, subgroup-stratified risk estimates that complement existing GWAS evidence.
This systematic review was conducted in accordance with PRISMA guidelines. A comprehensive electronic search was performed across five databases: PubMed, Embase, Cochrane Library, Web of Science, and Ovid. The literature search was conducted using a combination of Medical Subject Headings(MeSH)terms, such as"osteoporosis, “fracture, “
LRP5
,“and"polymorphism,“along with their related synonyms. We also manually screened reference lists of retrieved articles to identify additional relevant studies. To address heterogeneity, we employed both the Cochran’s Q test and the I²statistic. A fixed-effects model was used when I²<50%and
P
≥ 0.05; otherwise, a random-effects model was applied. All analyses were performed using STATA software version 17.0, and the odds ratios(ORs)and their corresponding 95%confidence interval(CI)values were calculated using fixed effects or random effects model. We carried out a subgroup analysis to explore the source of heterogeneity according to gender, race, disease, genotyping methods, control resources, female menopause, and HWE balance.
The current meta-analysis involved 14 studies, comprising 16 independent comparisons, including 1,549 patients and 3,345 control subjects. The analyses revealed a significant association between
LRP5
rs3736228 polymorphism and an increased risk of osteoporosis and fractures. Specifically,in the overall analysis, the polymorphism showed a higher likelihood of osteoporosis and fractures in the allelic model [OR=1.17, 95%CI(1.04-1.31),
P
=0.011], homozygous model [OR=1.47, 95%CI(1.07-2.01),
P
=0.018], dominant model [OR=1.44, 95%CI(1.05-2.97),
P
=0.023], and recessive model [OR=1.16, 95%CI(1.01-1.33),
P
=0.017]but not in the heterozygous model [OR=1.34, 95%CI(0.96-1.88),
P
=0.09]. Subgroup analyses showed that the polymorphism was associated with increased risk in males under the allelic(OR = 1.59, 95% CI 1.06–2.39,
P
= 0.026)and dominant models(OR = 1.74, 95% CI 1.11–2.73,
P
= 0.016). In females, risk was elevated in the homozygous(OR = 1.50, 95% CI 1.05–2.14,
P
= 0.027)and recessive models(OR = 1.48, 95% CI 1.04–2.09,
P
= 0.030). In population-based controls, significant associations were observed in the allelic(OR = 1.21, 95% CI 1.06–1.39,
P
= 0.005), homozygous(OR = 1.49, 95% CI 1.06–2.10,
P
= 0.021), dominant(OR = 1.22, 95% CI 1.03–1.43,
P
= 0.017), and recessive models(OR = 1.46, 95% CI 1.04–2.04,
P
= 0.027). No significant associations were found in the hospital-based subgroup. Heterogeneity was partly explained by disease type, publication year, and control source(
P
< 0.05 in multivariate meta-regression).
This updated meta-analysis confirms that the LRP5 rs3736228 polymorphism is significantly associated with osteoporosis and fracture risk, consistent with GWAS evidence, while further providing risk estimates stratified by sex and menopausal status, which are not readily obtainable from GWAS-level summary statistics alone.Notably, the observed associations appeared less robust in males, and premenopausal females, although these subgroup findings should be interpreted with caution owing to limited sample sizes. Nevertheless, further large-scale, prospective studies are warranted to validate these subgroup-specific estimates and to evaluate their potential utility in clinical risk stratification.
Chi Zhang, Wuhua Liu, Youhua Wang et al.· BMC Musculoskeletal Disorder...· 0 citations
Introduction: Homocysteine (HCY) is an important risk factor for chronic diseases and is associated with an unfavorable body composition status. Aerobic exercise can serve as a non-pharmacological intervention affecting these indicators; however, the available evidence is limited and inconsistent. The aim of this study was to conduct a systematic review and meta-analysis of the effects of aerobic exercise on HCY levels and body composition indices in adults with and without chronic disease.
Materials and Methods: The databases PubMed, Web of Science, Scopus, Magiran, IranDoc, NoorMags, and SID were systematically searched up to (19 March 2025). To calculate effect sizes, the standardized mean difference (SMD) with 95% confidence intervals was analyzed using a random-effects model in CMA2 software. Statistical heterogeneity was assessed using the I² index, and publication bias was evaluated using funnel plot analysis and Egger’s test.
Results: A total of 22 studies with 609 adult participants, both with and without chronic diseases, were included in the meta-analysis. The results showed that aerobic exercise interventions were associated with a significant reduction in HCY [P=0.001, SMD=-0.784 (95% CI: -1.322 to -0.246)], BMI [P=0.004, SMD=-0.379 (95% CI: -1.120 to -0.639)], WHR [P=0.002, SMD=-0.678 (95% CI: -1.111 to -0.245)] and BF [P=0.001, SMD=-0.982 (95% CI: -1.692 to -0.271)] compared to the control group in adults with and without chronic diseases.
Conclusion: Aerobic training in adults, with or without chronic disease, leads to a significant reduction in HCY, BMI, WHR, and BF. These findings suggest that regular aerobic exercise can be effective in improving individuals’ metabolic profile and plays an important role in the prevention and management programs for obesity and related chronic diseases.
O. Zafarmand, A. Saremi· Occupational Medicine· 0 citations
Background Dysregulation of lipid metabolism has been implicated in Parkinson’s disease (PD), yet causal relationships remain unclear due to confounding factors inherent in observational studies. Most Mendelian randomization studies on lipid-PD relationships have been conducted in European populations, leaving the causal association in East Asian populations largely unexplored. Methods We conducted a bidirectional Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data from the Integrative Epidemiology Unit (IEU) Open GWAS project for East Asian populations to assess the causal associations between four lipid traits — triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)—and PD. The primary MR analyses were conducted using the inverse-variance weighted (IVW) method. Sensitivity analyses included Cochran’s Q test, MR-Egger regression, and leave-one-out analyses. We further conducted colocalization analysis to assess whether the four lipid traits and PD shared common genetic variants. Finally, we complemented the findings using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Results Genetically predicted higher levels of TC (OR = 0.476, 95% CI = 0.269–0.843, p = 0.011) and LDL-C (OR = 0.494, 95% CI = 0.289–0.845, p = 0.010) were associated with a reduced risk of PD. No causal relationship was observed between TG or HDL-C and PD. Reverse MR analysis indicated no causal effect of PD on any of the lipid traits. Colocalization analysis did not support shared genetic variants between the lipid traits and PD (all PP.H4 < 0.8). In MPTP-induced PD mice, both TC and LDL-C levels were significantly lower than in controls. Conclusion This study provides genetic evidence supporting a genetically predicted inverse association of TC and LDL-C with PD risk among East Asian populations. The underlying mechanisms and any therapeutic implications warrant further experimental investigation.
Yanzi Bao, huaxin Huang, Wei Feng et al.· Frontiers in Aging Neuroscie...· 0 citations
Rs3764261 modified the association between vegetarian diet status and HDL-C levels, supporting evidence for gene–diet interactions in precision nutrition approaches to lipid risk management.
Ying-Hsiang Chou, Y. Tyan, Shih-Tsung Chang et al.· Frontiers in Nutrition· 0 citations
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