Aug 2026· International Journal of Epidemiology· Vol 55· 0 citations· 42 references
Medicine
TL;DR
The authors' study identified putative actionable proteins that could reduce the elevated T2D risk attributable to childhood adiposity in Europeans, but their relevance in Asian populations requires further investigation.
Abstract
Abstract Background Increased childhood adiposity contributes to higher type 2 diabetes (T2D) risk, but the underlying mechanisms remain unclear. Furthermore, whether these mechanistic pathways are shared across ethnic groups has not been explored. Methods We conducted a two-step Mendelian randomization (MR) using European-based summary statistics from genome-wide association studies of childhood body mass index (BMI) (n = 61 111), adulthood proteomics (n = 35 559), and later life T2D (cases: 242 283; controls: 1 569 734). We also conducted a recall-by-genotype (RbG) study in a Chinese birth cohort (n = 250) to assess whether childhood BMI was associated with the identified proteomic signals in an East Asian population. Analyses included multi-instrument MR methods (inverse variance weighted and MR-Egger) and, for single-instrument proteins, cis-MR using the Wald ratio, with colocalization validation. Multiple testing was adjusted using false discovery rate (FDR). Results Higher genetically predicted childhood BMI was associated with 1299 proteins (FDR-adjusted P < .05), of which 36 proteins were associated with higher T2D risk. Six proteins were supported by colocalization (PPH4 > 80%). Genetically predicted higher childhood BMI was positively associated with GCKR, RBP1, ENTPD6, and GST A1-1, and inversely associated with PRSS27 and SHBG. The proportion of the BMI-T2D effect mediated by these proteins ranged from 1.87% to 12.92%. However, only SHBG was replicated in Asians in the RbG study. Conclusions Our study identified putative actionable proteins that could reduce the elevated T2D risk attributable to childhood adiposity in Europeans, but their relevance in Asian populations requires further investigation.
This network Mendelian randomisation study delineates protein-mediated pathways linking cluster-stratified T2D genetic predisposition to cardiovascular risk, which can inform preventive strategies by stratifying individuals based on distinct biological pathways represented by these genetic clusters.
Shuang Liao, Gabriel Chun Yin Sung, Yiwen Liang et al.· Diabetes, obesity and metabo...· 0 citations
These findings implicate lipid metabolism, body weight regulation, and central nervous system mechanisms in antipsychotic-associated metabolic changes and may inform future precision medicine approaches to risk prediction and treatment selection.
H. Kazemi, J. E. Drake, S. Bacanu et al.· medRxiv· 0 citations
New SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population are identified, including a missense variant in an olfactory receptor gene linked to MCP-1, which may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.
J. Leite, G. F. L. Pascoal, G. B. S. Duarte et al.· Frontiers in Immunology· 0 citations
Insulin resistance (IR) is a hallmark feature of Type 2 Diabetes Mellitus and a well-established risk factor for coronary heart disease (CHD), yet the pathways through which IR contributes to CHD remain incompletely understood. To comprehensively describe the genetic architecture of IR, we collected three direct IR indicators--- fasting insulin (N = 151,013), the Modified Stumvoll insulin sensitivity index (N = 53,657), and pro-insulin (N = 45,861), and conducted joint analysis on them using Linkage Disequilibrium (LD) Score Regression and factor analysis. A single latent IR factor was generated which captures 60.5% of the shared genetic variance. Based on the IR factor, a multivariate GWAS was conducted within Genomic Structural Equation Modelling and then we built a polygenic risk score (PRS) of IR for the UK Biobank European cohort (N = 407,767; 55,729 CHD cases and 352,038 controls). Then we performed the association study to quantify the relationship between genetically predicted IR and CHD. Causal mediation analyses were also performed through 2,923 plasma proteins (Olink) and 168 metabolites (Nightingale NMR), followed by serial-mediation models (IR -> protein -> metabolite -> CHD) over all prescreened pairs. Single-mediator screening nominated 938 proteins and 159 metabolites; this yielded 3,669 significant "protein -> metabolite -> CHD" serial-mediation pathways, from which 33 broadly-acting core mediating proteins were prioritized. These acted predominantly through the large and very large high-density lipoprotein (HDL) particle subclasses: 30 of the 33 core proteins and all 14 HDL-subclass metabolites formed 306 pathways, of which 303 (99.0%) amplify the CHD risk. These results map a proteomic and metabolomic axis linking the genetic component of IR to CHD and highlight HDL lipoprotein-subclass biology as a candidate therapeutic and biomarker space.
R. Dong, J. Fu, B. Zhang et al.· medRxiv· 0 citations
Childhood obesity is a major global health concern, yet the long-term effects of early-life adiposity on adult fat distribution and underlying biological pathways remain poorly understood. In particular, it is unclear whether childhood BMI differentially influences specific adipose tissue depots and whether circulating proteins mediate these relationships. We conducted a Mendelian randomisation study using genetic instruments for childhood BMI across 12 timepoints from ages 3 to 18 years. Two-sample MR was applied to five MRI-derived adult fat depots (abdominal subcutaneous (ASAT), gluteofemoral (GFAT), visceral (VAT), liver, and pancreatic fat) in UK Biobank. We further implemented a two-step MR framework to assess whether 2,940 circulating plasma proteins (Olink) mediate observed associations, integrating temporal, statistical, and directional evidence across childhood. Genetically predicted higher childhood BMI from approximately age 7 years onwards was associated with increased ASAT and GFAT in adulthood, but showed little evidence of association with visceral, liver, or pancreatic fat, with effects persisting into adolescence. Two-step MR identified 140 proteins influenced by childhood BMI during a developmentally sensitive window, of which seven showed directionally consistent evidence of mediation. These proteins included ACAN, CCL7, and CLIC5 for abdominal subcutaneous fat, and CLIC5, BMP10, CLEC10A, KIT, and IGSF3 for gluteofemoral fat, highlighting partially distinct biological pathways across depots. Childhood BMI exerts depot-specific effects on adult fat distribution, particularly influencing subcutaneous adipose tissue. Circulating proteins provide evidence of potential mediating pathways, supporting the existence of developmentally sensitive biological mechanisms linking early-life adiposity to adult body composition. These findings underscore childhood as a critical period for shaping long-term adipose tissue distribution and highlight potential molecular targets for future intervention strategies.
B. Hayes, E. Hazelwood, G. Power et al.· medRxiv· 0 citations
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.
Cong Zhang, Yanping Zhao, Hui Pang et al.· Frontiers in Immunology· 0 citations
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