The PCSK6-CORIN Polygenic Risk Score and Ischemic Stroke: The Dose-Response Association and Partial Mediation by Hypertension.

Exploration of the causal relationship between inflammatory cytokines and type 2 diabetes via mendelian randomization and polygenic score

Background To investigate the potential causal relationship between inflammatory cytokines and type 2 diabetes (T2D) using two-sample Mendelian randomization (MR) and to explore the transferability of inflammatory genetic susceptibility in a Mongolian population through polygenic score (PGS) analysis. Methods A two-sample MR analysis was conducted using genome-wide association study (GWAS) summary statistics. Inflammatory cytokine data were obtained from protein quantitative trait locus GWAS datasets (GCST90274758–GCST90274848), and T2D summary statistics were derived from the IEU Open GWAS database (ebi-a-GCST006867). The inverse variance weighted method was used as the primary MR approach, complemented by sensitivity analyses. In an independent Mongolian cohort (N = 351), a PGS was constructed from directly genotyped cytokine-associated SNPs. We assessed PGS-T2D associations using logistic regression adjusted for age, sex, and principal components (PCs), with sensitivity analyses to determine the optimal PC number. Results In the European population, genetically predicted higher FGF-21 levels were associated with an increased risk of T2D (OR = 1.141, 95% CI: 1.032–1.261, P = 0.010), and IL-5 also showed a positive association with T2D risk (OR = 1.114, 95% CI: 1.004–1.237, P = 0.042). In contrast, ARTN, CD5, CSF-1, CXCL10, CXCL9, FGF-19, and SLAMF1 were associated with lower T2D risk. In the Mongolian population, the PGS for inflammation-related cytokine levels demonstrated a significant association with T2D status across models adjusting for 0 to 6 principal components (all P< 0.05). In the full model (adjusted for age, sex, and the first 4 PCs), each 1-SD increase in the PGS corresponded to a 25.4% increase in the odds of T2D (OR = 1.254, 95% CI: 1.005–1.575, P = 0.048; AUC = 0.625). These findings are suggestive and exploratory, necessitating further validation in independent cohorts. Conclusion This study identified nine inflammatory cytokines with potential causal associations with T2D in European populations. Notably, in a Mongolian cohort, a PGS for genetically predicted cytokine levels showed a modest yet independent association with T2D risk after controlling for population stratification. These cross-population findings warrant replication in larger-scale studies.

Examining the potential causal relationships among smoking, blood DNA methylation, and type 2 diabetes development: A Mendelian randomization study

INTRODUCTION Type 2 diabetes (T2D) is a major global health burden with rising prevalence and significant morbidity and mortality. Smoking has been recognized as an independent risk factor for T2D, but the exact underlying mechanisms are not yet fully understood. METHODS We conducted a two-sample Mendelian randomization (MR) study to investigate the effects of smoking behaviors and smoking-related DNA methylation on type 2 diabetes (T2D) risk. This secondary analysis was based on publicly available summary statistics. Smoking traits were obtained from a large meta-GWAS of over 1.2 million individuals of European ancestry. DNA methylation data were derived from the CHARGE Consortium EWAS (n=15907) and mQTLs from the GoDMC (n=27750). T2D outcome data were obtained from a European GWAS including 74124 cases and 824006 controls. Replication was performed in FinnGen (17268 cases, 184778 controls) and BioBank Japan (40250 cases, 170615 controls). Stringently selected genetic instruments were applied, and causal effects were estimated primarily using two-sample MR with inverse-variance weighted analysis, complemented by MR-Egger and weighted median approaches, and further validated by colocalization analysis. RESULTS In our genomic analysis, we presented convincing evidence supporting the association between genetically predicted smoking initiation and an increased susceptibility to T2D. In epigenetic analysis, we identified methylation at 21 smoking-related CpG sites associated with T2D risk. Subsequently, 14 of these CpG sites were validated using the FinnGen dataset, and 12 of them were validated using the BBJ dataset. Furthermore, we observed strong colocalization evidence for four CpG sites, including cg23756272 (BCL2), cg03864215 (KCNJ11), cg09861057 (TDRD10) and cg10672416 (C12orf65), and T2D risk. CONCLUSIONS This research provides novel findings of the impact of smoking on T2D susceptibility, highlighting the role of epigenetic DNA methylation.

LPA genetic variation is associated with type 2 diabetes after adjustment for lipoprotein(a) concentration: results of the Aragon Workers’ health study

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.

Polygenic risk scores predict blood pressure changes independent of dietary intervention: a secondary analysis of the NUPRESS trial

This study aimed to investigate whether genetic variability, assessed through polygenic risk scores (PRSs), predicts blood pressure (BP) changes in individuals with systemic arterial hypertension (SAH), and to explore potential interactions between genetic risk and dietary interventions. This study represents a secondary analysis of data from the Brazilian multicentre trial (NUPRESS), which compared a Dietary Approach to Stop Hypertension (DASH) diet (control group) with a multicomponent intervention (intervention group) over 180 days in adults with SAH. Participants underwent anthropometric assessment, cardiovascular risk evaluation, dietary assessment, and genotyping using a genomic microarray. Single nucleotide polymorphisms (SNPs) associated with BP changes were identified and used to construct PRSs. Multiple linear regression models were employed to examine associations between PRSs, dietary interventions, and changes in systolic (ΔSBP) and diastolic BP (ΔDBP). A total of 114 SNPs were associated with ΔSBP and 101 with ΔDBP. The resulting PRSs showed strong correlations with both ΔSBP (r = 0.85; p < 0.0001) and ΔDBP (r = 0.84; p < 0.0001). No significant effect of dietary intervention on BP changes was observed, and no interaction was identified between PRSs and dietary approach for ΔSBP (p = 0.98) or ΔDBP (p = 0.13). PRSs derived from BP-associated SNPs were strong predictors of BP changes over six months, independent of dietary intervention. These findings support the potential utility of genetic profiling in predicting individual variability in BP response, although replication in independent cohorts is warranted. Main study trial registration number NCT03793881 on ClinicalTrials.gov.

Association of PCSK9 and CCL22 gene polymorphisms with myocardial infarction in a South Indian population

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

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.