Jul 2026· Journal of the American College of Cardiology· Vol 88, pp. 1107-1120· 1 citation· 48 references
Medicine
TL;DR
A role for lipid-driven chronic inflammation in IHD etiology is supported, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.
Abstract
Background
Most drugs target proteins, and proteome-wide genetic analyses in diverse populations could discover potential novel and repurposed targets for improved prevention and treatment of ischemic heart disease (IHD) beyond statin therapy.
Objectives
The purposes of this study were to use cis-acting single nucleotide polymorphisms (cis-pQTLs) identified for plasma proteins in East Asians and Europeans to discover and validate potential drug targets for IHD.
Methods
We measured plasma levels of 9,520 (Olink/SomaScan: 2,923/7,297) proteins in a case-cohort study of IHD (1,976 incident cases and 2,001 subcohort controls) in statin-free individuals in the prospective China Kadoorie Biobank (CKB). Genome-wide association studies identified 2,895 (Olink/SomaScan: 1,301/1,594) cis-pQTLs for these proteins in CKB. Two-sample Mendelian randomization (MR) and colocalization analyses assessed associations of all available cis-pQTLs for these proteins with IHD in East Asians (n = 29,319 cases), with further replication in Europeans (n = 181,522 cases) and comparison with findings in previous MR studies.
Results
In CKB observational analyses, a total of 959 (Olink/SomaScan: 426/533) proteins were associated at false discovery rate-corrected P < 0.05 with IHD after adjusting for major IHD risk factors. Two-sample MR analyses provided genetic support for 54 unique (Olink/SomaScan: 36/28) proteins in IHD etiology. Colocalization analyses confirmed shared gene-protein-IHD associations (posterior probability of hypothesis 4 [PPH4] ≥0.8) for 15 unique (Olink/SomaScan: 10/10) proteins, including 8 lipid-related, 3 inflammation-related, 1 blood pressure-related, and 3 alcohol-related proteins in East Asians. In Europeans, MR analyses of 12 non-alcohol-related proteins showed directionally concordant results for 8 proteins, with 5 having strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8), including 4 lipid-related (proprotein convertase subtilisin/kexin type 9, LPA, APOE, cadherin-1) and 1 systolic blood pressure-related (fibroblast growth factor 5) protein. However, 4 proteins showed directionally discordant MR results, including 2 lipid-related (APOA5, SORT1) and 1 inflammation-related (transforming growth factor beta 1) proteins with strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8). Comparison with previous MR studies revealed little consistency across studies in the number and identity of target proteins for IHD beyond well-established lipid-related (low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides) or inflammation-related (interleukin-6) protein targets.
Conclusions
The findings support a role for lipid-driven chronic inflammation in IHD etiology, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.
Background Coronary atherosclerosis (CA) is a leading cause of cardiovascular morbidity and mortality worldwide. This study is aimed at identifying candidate plasma proteins and potential therapeutic targets for CA. Methods We performed a proteome‐wide Mendelian randomization (MR) analysis using integrated protein quantitative trait loci (pQTLs) and genome‐wide association study (GWAS) summary data. Forward two‐sample MR was first performed using cis‐pQTLs from the UK Biobank Pharma Proteomics Project (UKB‐PPP), followed by reverse MR analysis to exclude potential reverse causality. Bayesian colocalization analysis was conducted to ensure that the associations between proteins and CA were driven by shared genetic variants. Summary‐data‐based MR (SMR) combined with HEIDI testing was used to prioritize proteins and eliminate linkage bias. Significant proteins were cross‐referenced with a curated druggable genome to identify their potential therapeutic relevance. Cross‐platform validation was performed using the SomaScan‐based pQTL dataset from deCODE genetics. An oxidized low‐density lipoprotein (ox‐LDL)–induced human umbilical vein endothelial cell (HUVEC) injury model was used for the evaluation of prioritized proteins. Results Forward MR analysis using UKB‐PPP cis‐pQTL data identified 45 CA‐associated proteins (23 protective, 22 risk‐related; FDR < 0.05), with no reverse causality observed. Five proteins—PARP1, SDCCAG8, FST, FOLH1, and NCAN—were prioritized through MR (FDR < 0.05), colocalization analysis (PP.H4 > 0.50), and SMR analysis with HEIDI filtering (p_SMR < 0.05; p_HEIDI > 0.05). All five proteins were included in the druggable genome list, supporting their potential therapeutic relevance. PARP1 showed consistent associations across Olink and SomaScan platforms and was upregulated in an ox‐LDL‐induced HUVEC model as assessed by western blot. Conclusions This study identified PARP1, SDCCAG8, FST, FOLH1, and NCAN as genetically prioritized candidate proteins for CA, with PARP1 showing the most consistent evidence across analyses. Further validation and mechanistic studies are warranted.
Da Gao, Hai-Yan Lin, Sheng-Jie Wang et al.· Cardiovascular Therapeutics· 0 citations
Blood proteins may play causal roles in cardiovascular diseases (CVDs) such as heart failure (HF) and peripheral artery disease (PAD). Proteome-wide Mendelian randomization (MR) has been widely used to prioritize drug targets for CVD in European populations, but its application to non-European populations remains limited. We conducted a proteome-wide MR analysis to evaluate the potential causal effects of 2,922 plasma proteins on five CVDs—atrial fibrillation (AF), coronary artery disease (CAD), HF, ischemic heart disease (IHD), and PAD. Analyses were performed across African (n = 931), East Asian (n = 262), and European (n = 10,840) populations using genetic instrument data from the UK Biobank cohort. Significant associations were further examined with genetic colocalization to strengthen causal inference. Using MR and colocalization analyses, we identified 53 significant protein–CVD associations across multi-populations, including 16 in African, six in East Asian, and 31 in European populations, respectively. Cross-population comparisons revealed four protein–CVD associations unique to African population and another four specific to East Asian population. Integration with clinical trial data prioritized 14 protein–disease pairs as promising candidates for therapeutic development or drug repurposing. Our findings highlight the value of proteome-wide MR in evaluating drug target applicability across populations. Several protein–disease associations were population-specific, emphasizing the need for inclusive genetic research to inform precision medicine in CVD prevention and treatment.
Hua Zhong, Jingjing Zhu, Shuai Liu et al.· Zeitschrift für Induktive Ab...· 0 citations
Background Despite multiple clinical trials, disease-modifying treatments for COPD are currently limited. Since many drugs target proteins, identifying causality between proteins and lung function informs understanding of COPD pathophysiology and may suggest novel targets. We used Mendelian randomisation (MR) to prioritise proteins as potentially causal for imparied lung function. For prioritised proteins, we explored their potential suitability as drug targets by predicting their effects on a range of clinical outcomes. Methods We used genome-wide association study (GWAS) data on 2923 proteins (n=48 195, UK Biobank) to identify single genetic variants (protein quantitative trait loci (cis-pQTLs)) associated with protein levels (p≤5×10−9, variant ≤100 kb of a transcription start site). We performed cis-pQTL-MR analyses of four spirometric traits (n=149 166, 36 independent cohorts). Sensitivity analyses included colocalisation and reverse direction MR. We report associations between cis-pQTLs for prioritised proteins and multiple clinical respiratory outcomes, and use phenome-wide analysis to explore potential adverse effects or drug repurposing opportunities. Findings 1841 proteins had a suitable cis-pQTL. We implicated 16 proteins as potentially causal for lung function (p<1.71×10−5): seven proteins have not been implicated by previous lung function GWAS or MR (CCND2, DTD1, PILRA, PTPRK, TDRKH, GRHPR, NUDT5), and we provide corroborative evidence for 10 proteins. We add to the literature identifying surfactant protein D (SFTPD) as a candidate, yet predict that integrin subunit alpha V (ITGAV) inhibition could impair some lung function measures, mimicking adverse results from a recent trial. Interpretation Our approach identifies proteins (some novel) that are potentially therapeutic targets for respiratory disease, and which warrant follow-up for utility and safety.
Jing Chen, N. Shrine, Kayesha Coley et al.· ERJ Open Research· 0 citations
INTRODUCTION
Pharmacological targets supported by genetic evidence demonstrate significantly higher success rates in clinical development. Osteoporosis (OP) represents a major global health burden; however, the causal plasma proteome underlying OP remains largely unexplored, limiting the discovery of effective circulating biomarkers and therapeutic agents.
OBJECTIVES
This study aimed to conduct a comprehensive proteome-wide analysis to construct a causal map of plasma proteins for OP and to identify high-confidence therapeutic targets with translational potential.
METHODS
We performed a proteome-wide Mendelian randomization (PW-MR) analysis by integrating large-scale GWAS meta-analysis data (18,008 OP cases and 928,650 controls) with cis-acting protein quantitative trait loci (pQTLs) derived from the deCODE and UKB-PPP cohorts. To ensure robustness, we employed orthogonal validation approaches, including colocalization analyses, summary data-based Mendelian randomization (SMR), and single-cell transcriptomic mapping.
RESULTS
We identified 144 plasma proteins causally associated with OP, encompassing two novel susceptibility loci (HOXC5 and HBQ1) and five previously unreported candidates (NUDT2, NUB1, TNFSF8, UNG, and MXRA8). Notably, single-cell mapping revealed that NUDT2 is specifically enriched in osteoprogenitor cells, distinct from other identified targets.
CONCLUSION
These findings delineate the first causal blueprint of the OP plasma proteome. NUDT2 is highlighted as a plausible metabolic regulator of bone formation. Collectively, this study provides a valuable resource for precision diagnostics and accelerates the development of novel therapeutics for osteoporosis.
Zhen Wang, Si-Xu Chen, Junjie Luo et al.· Journal of Advanced Research· 0 citations
Background The purpose of this study was to investigate genetic risk factors associated with ischemic heart disease (IHD) in Russian adults, to develop prognostic PRS models for IHD risk stratification, and to gain a better understanding of molecular mechanisms underlying IHD through a transcriptome analysis. Materials and methods The study analyzed data from three independent cohorts: a population sample of 69,500 individuals, a cardiac sample of 5,875 IHD patients, and a sample of 2,870 long-living adults. To identify genomic loci associated with IHD, a GWAS was performed, and its findings were used to develop a PRS model for the IHD phenotype. Additionally, a transcriptome analysis was conducted. Results The GWAS for IHD adjusted for sex, age, and the first ten principal component accounting for population structure identified 75 variants, with 67 located at 9p21.3. Based on the GWAS findings, PRS models were developed and validated for IHD. The risk of IHD adjusted for sex, age, and BMI was the lowest in the sample of long-living adults. The TWAS revealed a significant association between IHD and increased CDKN2B expression in the aorta. According to the DEG results, the CDKN1A gene, a member of the same gene family as CDKN2B, was significantly hypoexpressed in the lower limb veins of patients with IHD. Conclusion PRS models offer great benefits for IHD risk prediction, particularly in individuals at the e tremes of the heritable risk distribution. lncRNAs, such as CDKN2BAS1 and lncRNA-MAP3K4, as well as P2X2 receptors, could be potential therapeutic targets for IHD.
Veronika Daniel, Natalia Romanova, Aleksandra Mamchur et al.· Frontiers in Cardiovascular...· 0 citations
Postpartum depression (PPD) is among the most common complications of childbirth, and identifying novel treatments is vital. We aimed to identify potential drug targets for PPD by integrating the plasma proteome, transcriptome and epigenome. We designed a comprehensive analysis pipeline involving two-sample Mendelian randomisation (MR) (for proteins), colocalisation (for coding genes), and summary-based MR (SMR) (for mRNA and DNA methylation) to identify potential therapeutic targets for PPD. Genetic data on the plasma proteome were obtained from 4907 aptamers in 35,559 Icelanders and 7596 proteins in 828 FinnGen participants. The PPD genome-wide association study data were sourced from the Psychiatric Genomics Consortium (PGC) (Ncase = 17,339, Ncontrol = 53,426). A two-step MR approach was used to assess whether brain imaging-derived phenotypes (IDPs) and metabolites from blood, brain and cerebrospinal fluid mediated the observed effects. Across the two proteome datasets, the genetically predicted levels of 18 plasma proteins were nominally significantly associated with PPD, and the expression of steroid receptor RNA activator 1 (SRA1), a regulator of steroid hormone signalling, was significantly associated with PPD. SRA1, angiotensinogen (AGT, a key mediator of the renin-angiotensin and stress-response system), and glycerol-3-phosphate phosphatase (PGP, involved in lipid metabolism and cellular stress) showed increased colocalisation. The methylation of SRA1 at cg02434007 in the brain was associated with increased expression of SRA1 and a high risk of PPD, which aligns with the positive effect of SRA1 gene expression on PPD risk. Isoleucine (mediation proportion: 5.8%, p = 0.042) from blood metabolites and the IDP ICA100 edge 442 (mediation proportion: 7.6%, p = 0.044) may play mediating roles. This study reveals that SRA1 is a novel therapeutic target for PPD, which enhances the understanding of its molecular aetiology and the development of therapeutic strategies.
Ming Chen, Qinlin Wei, Hao-Wen Li et al.· npj Mental Health Research· 0 citations
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