BACKGROUND AND AIMS:LDL-C and non-HDL-C do not fully capture coronary heart disease (CHD) risk attributed to all apoB-containing lipoproteins. Use of apolipoprotein B (apoB) as a marker of total atherogenic particle number improves risk prediction, but risk may still be underestimated when triglyceride-rich lipoproteins (TRL/remnants) and lipoprotein(a) [Lp(a)] are elevated. The aim was to formulate a new metric-risk-weighted apoB (RW-apoB)-designed to capture risk from LDL, TRL/remnants, and Lp(a) in a single number. METHODS:Based on previously published estimates of the relative atherogenicity of LDL, TRL/remnant, and Lp(a) particles, RW-apoB was developed (using UK Biobank data) as an atherogenicity-weighted apoB-sum calculated as: RW-apoB = 11.65×TG(mmol/L) + 0.215×lipoprotein(a)(nmol/L) + 0.736×apoB(mg/dL). RESULTS:Assigning RW-apoB to individuals substantially reclassified their risk status. Compared with ranking by measured apoB, 52% of individuals were up- or down-ranked by ≥10 percentiles. About one-third of those in the top RW-apoB quintile-with elevated TRL and Lp(a) and a CHD event rate of 5.4%-were misclassified as lower risk by apoB. Conversely, individuals in the top measured apoB quintile but with low TRL and Lp(a) had a lower event rate (3.9%) and were correctly down-ranked. RW-apoB improved risk prediction, significantly increasing Harrell's C-index relative to apoB (P < .0001). In statin-treated subjects, RW-apoB was potentially a better index of residual risk. RW-apoB consistently outperformed apoB as a risk predictor in Cox models across the UK Biobank and three other large population cohorts. CONCLUSIONS:RW-apoB represents not only particle number but also accounts for the higher atherogenicity of TRL and Lp(a). It offers clinically meaningful improvements in CHD risk stratification.

Despite the importance of the gut microbiome to health, the role of human genetic variation in shaping its composition remains poorly understood. Here we report genome-wide association analyses of harmonized metagenomic data from 16,017 adults in four Swedish population-based studies, with replication in 12,652 people from the Norwegian HUNT study. We identified variants in the OR51E1-OR51E2 locus, encoding sensors for microbiome-derived fatty acids, associated with microbial richness. We further identified 15 study-wide significant genetic associations (P < 5.4 × 10-11) involving eight loci and 14 common bacterial species, of which 11 associations at six loci were replicated. The results confirm previously reported associations at LCT, ABO and FUT2, and provide evidence for new loci MUC12, CORO7-HMOX2, SLC5A11, FOXP1 and FUT3-FUT6, with supporting data from metabolomics and gene expression analyses. Our findings link gut microbial variation genetically to gastrointestinal functions, including enteroendocrine fatty acid sensing, bile composition and mucosal layer composition.

Atherosclerotic cardiovascular disease shows a marked male predominance(1–3), yet the biological basis for this disparity remains unclear. Mosaic loss of chromosome Y (LOY) in blood – a common, acquired and age associated mutation(4,5)- has been linked to mortality and major causes of death, including myocardial infarction(6,7). Experimental studies indicate that LOY in leukocytes is causally related to mortality(8) and promotes pathology across organs by impairing immunosurveillance of senescent cells(9), providing a mechanistic explanation for systemic effects of leukocyte Y loss. Whether LOY in blood contributes to atherosclerosis, however, is unknown. Here we show that LOY in blood is associated with subclinical and clinical atherosclerotic disease by analyzing two large, population-based cohorts: the Swedish CArdioPulmonary bioImage Study (SCAPIS) and the UK Biobank. SNP array–derived estimates of LOY mosaicism in blood leukocytes revealed dose-dependent associations with prevalence of coronary atherosclerosis, more extensive segment involvement, greater coronary stenosis and calcified plaques in SCAPIS. In UK Biobank, LOY was associated with greater carotid intima–media thickness, atherosclerosis, and myocardial infarction. Together, these findings point to a potential association between LOY in blood and a spectrum of atherosclerotic outcomes, offering one possible explanation for the higher cardiovascular risk observed in men.

Disruptions in gut microbiome are implicated in cardiometabolic disorders and other health outcomes. Antibiotics are known gut microbiome disruptors, but their long-term consequences remain underexplored. Here we combined individual-level data from the Swedish Prescribed Drug Register with fecal metagenomes of 14,979 adults to examine the association between oral antibiotic use over 8 years and gut microbiome. In multivariable confounder-adjusted regression models, antibiotic use <1 year before fecal sampling was associated with the greatest reduction in species diversity, but significant associations were also observed for use 1-4 and 4-8 years earlier. Clindamycin, fluoroquinolones and flucloxacillin accounted for most of the associations with the abundance of individual species. Use of these antibiotics 4-8 years earlier was associated with altered abundance of 10-15% of the species studied; penicillin V, extended-spectrum penicillins and nitrofurantoin were associated with only a few species. Similar results were found comparing one antibiotic course 4-8 years before sampling versus none in the past 8 years. These findings indicate that antibiotics may have long-lasting consequences for the gut microbiome.

Abstract Background Despite the high prevalence and clinical significance of emphysema, few genetic risk loci have been consistently replicated. We conducted a genome-wide association study (GWAS) of CT-based emphysema, with a particular focus on non-smoking-related genetic determinants. Methods We analyzed 25,639 individuals of European ancestry from the SCAPIS national cohort, aged 50–65 years, of which 51% were never-smokers. Emphysema was assessed through semi-quantitative visual scoring of CT scans. GWAS was performed in the whole sample and stratified on smoking status. We also examined the association of previously reported emphysema- and lung function-related variants with emphysema in our dataset. Results Emphysema criteria were fulfilled for 1,479 participants (5.6%), with higher prevalence among current ( N = 576, 18.2%) and former smokers ( N = 612, 6.5%) compared to never-smokers ( N = 263, 2.0%). We identified three independent genetic loci for emphysema in smokers and no signals in never-smokers. The strongest signal was observed in the well-established nicotinic acetylcholine receptor cluster (CHRNA5-A3-B4) locus on chromosome 15. Additionally, we discovered novel associations near the dysferlin (DYSF) gene on chromosome 2 and in an intergenic region on chromosome 3. By assessing previously lung phenotype-associated variants we also found evidence supporting association with emphysema in smokers for variants in the EFEMP1/MIR217HG/PNPT1 locus on chromosome 2, previously linked to reduced FEV 1 /FVC ratio. Conclusion This study, based on the largest unselected population sample to date, provides novel insights into the genetic architecture of emphysema. However, no signals were detected in never-smokers despite the large sample-size, likely due to the low prevalence of emphysema in that group. The proposed genetic risk loci require external replication.

OBJECTIVE:In salutogenic theory, sense of coherence (SOC) reflects an individual's capacity to mobilise appropriate resources to prevent barriers from becoming stressors. However, few studies have examined how culture defines the barriers and resources evaluated through SOC. Integrating salutogenesis with cognitive anthropology, we examine how SOC relates to cultural models of barriers to healthy eating and active living (HEAL) in socioeconomically disadvantaged neighbourhoods in Uppsala, Sweden. DESIGN:We used an iterative mixed-method approach. Qualitative analyses of interviews and observations identified barriers to HEAL. Participants then pile-sorted these barriers; shared structures were analysed using the quadratic assignment procedure and hierarchical cluster analysis. Factor analyses examined whether clusters aligned with participant difficulty ratings and Bayesian multivariate regression examined associations between extracted factors and SOC. Qualitative data were revisited to interpret relationships among SOC-associated factors. Data collection occurred between September 2023 and June 2024. RESULTS:Participants agreed on how HEAL barriers were organised into cultural subdomains. Seven subdomains yielded single-factor solutions. Four factors (How Neighbours See Me, Social Change, Self-doubt, Exercise Support) covaried negatively with SOC. Qualitative analyses indicated that these factors cohered around themes of strong kinship bonds and mistrust toward outgroup members. CONCLUSION:SOC showed selective associations within the cultural models of HEAL barriers. Thematic coherence across SOC-associated subdomains suggests a shared organising logic centred on close-tie interdependence in the setting. This pattern clarifies how SOC is implicated within a culturally organised HEAL domain and provides an exploratory basis for hypotheses about SOC in socioeconomically disadvantaged settings.

OBJECTIVE:The basis for protein synthesis is the genetic code. Many of these proteins will affect intermediary metabolites by acting as enzymes, hormones, or by other actions. The aim of the present study was to assess the relationships of a large number of proteins with endogenous metabolites. METHODS:Plasma protein levels were measured by the proximity extension assay (PEA) and metabolites by mass spectrometry. Cross-sectional relationships of 242 proteins and 790 metabolites were evaluated in the EpiHealth and POEM studies using a discovery/validation approach. Genetic instruments identified in UK Biobank for protein levels (n = 1621) and genetics for metabolite levels (n = 777) in SCAPIS and EpiHealth were employed for Mendelian randomization (MR) analysis regarding putative causal associations. RESULTS:In the observational analyses, 20% of the evaluated pairwise protein-metabolite associations were found significant in both the discovery and validation samples. We could however only find support for causal effects in the MR analysis for <0.1% of the pairwise associations, representing 326 unique proteins. The R2 for the relationship between the MR and observational estimates was only 0.05. 37 protein-metabolite relationships that were significant in a congruent fashion in both the observational and MR analyses were identified. A searchable online protein vs metabolite atlas was created for the scientific community to use these results. We also give some examples where metabolites were used to enhance protein findings in cardiovascular epidemiological research. CONCLUSION:This study provides a comprehensive assessment of a large number of protein- metabolite relationships using both observational and MR analyses, highlighting how these results could be used to enhance clinical research.

CONTEXT:Type 2 diabetes is a growing global concern with serious complications, including kidney damage and cardiovascular morbidity and mortality. Monitoring albuminuria, which is associated with these complications, is crucial in optimal diabetes management. Gut microbiota composition has been suggested to impact albuminuria, but large studies with granular data are lacking. METHODS:We investigated the relationship between 1002 gut microbial species, 1308 plasma metabolites, and albuminuria in 752 participants with type 2 diabetes from the Swedish CArdioPulmonary BioImage Study (SCAPIS). To determine the relative abundance of species, we employed deep shotgun metagenomic sequencing of fecal samples. Plasma metabolites were analyzed using mass spectrometry-based methods. RESULTS:We identified 3 species that were associated with albuminuria, including Sellimonas intestinalis, Eggerthellales sp., and Ellagibacter isourolithinifaciens. Two of these species were replicated in an independent prediabetic population (n = 3423) in SCAPIS. In total, 36 annotated metabolites were associated with the 3 albuminuria-signature species. Functional mapping of the signature species suggests a role in the regulation of the metabolites of imidazole propionate and trigonelline, which have previously been reported to play roles in the progression of albuminuria. CONCLUSION:These findings provide additional evidence of the potential impact of microbial species and contribute to our understanding of the complex relationship between the gut microbiome, plasma metabolites, and albuminuria in individuals with diabetes.

Background:While early-life dog exposure and its association with subsequent asthma is well studied, less is known about the impact of continuous or discontinued exposure on asthma outcomes in children with established asthma and allergy. Objectives:We sought to estimate the association between dog exposure and long-term asthma outcomes. Methods:A cohort study was conducted using Swedish national registers, following 99,389 children aged 3-16 years at asthma and allergy diagnosis until age 19, emigration, death, or year 2023. Dog exposure was categorized as "continuous" (parental dog ownership at diagnosis and throughout follow-up), "discontinued" (ownership ceased sometime after diagnosis), and "no exposure." Outcomes included moderate-to-severe asthma (defined by treatment steps) at 2-, 4-, and 6-year follow-up and asthma exacerbation (emergency visits and high short-acting β-2 agonist use) throughout follow-up. Results:In the cohort (median age 6.6 years; 41% female), 12.8% had continuous exposure and 1.2% had discontinued exposure. Compared to nonexposed, no association between continuous exposure and moderate-to-severe asthma was observed (adjusted odds ratio at 2-year follow-up: 1.00; 95% CI: 0.94-1.07); discontinued exposure showed similar result (adjusted odds ratio: 1.07; 95% CI: 0.93-1.23). However, both exposure groups had increased risk of exacerbations (continuous exposure: adjusted hazard ratio: 1.17; 95% CI: 1.06-1.29; and discontinued: hazard ratio: 1.52; 95% CI: 1.15-2.00), with no significant difference between the groups. Conclusion:In children with established asthma and allergy, continuous dog exposure does not seem to increase the risk of moderate-to-severe asthma, but it is associated with a modest increased risk of exacerbations. Discontinued exposure does not appear to improve asthma outcomes at the population level.

The gut microbiota is associated with human health and disease. Here we conducted a genome-wide association study of host genetic factors influencing gut microbiota composition in 12,652 individuals from the Trøndelag Health Study (HUNT), with replication in Nordic cohorts (n = 16,017-21,976). We identified 12 reproducible SNP-species associations across six genomic loci, including known (LCT, ABO) and novel (HLA-DQB1, MUC12, SLC37A2, FUT2) regions. Additionally, we detected genetic signals associated with gut microbiota functional modules at three loci (LCT, ABO, FUT2). Follow-up analyses suggest that these host-microbiota associations are linked to the pathogenesis of celiac disease and hemorrhoidal disease. Mendelian randomization analyses provided evidence supporting a causal effect of body mass index on gut microbiota composition. These findings highlight the interplay between host genetics and gut microbiota for human health and disease.

BACKGROUND:Lipidomics, the comprehensive profiling of circulating lipid species, has emerged as a powerful tool to investigate metabolic alterations underlying coronary atherosclerosis. Understanding the mechanisms driving high-risk vulnerable plaque formation and progression to myocardial infarction remains a key therapeutic priority. This study investigates associations between circulating lipid metabolites and imaging-defined features of vulnerable coronary plaque. METHODS:Following revascularization, patients with myocardial infarction underwent 3-vessel coronary artery imaging with near-infrared spectroscopy and intravascular ultrasound to assess nonflow-limiting plaques for lipid core burden index and plaque burden. Multivariable models evaluated associations between 424 lipid metabolites in plasma, quantified by mass spectrometry, pan-coronary lipid, pan-coronary plaque burden, and high-risk vulnerable plaque measures (maximum lipid core burden index within any 4-mm segment across the entire lesion ≥324.7 and/or plaque burden ≥70%) in 877 patients. Findings were validated in the SCAPIS study (Swedish Cardiopulmonary Bioimage Study) using coronary computed tomography angiography-based measures of coronary artery calcium score and segment involvement score. RESULTS:We identified 156 significant associations (P<0.05) between lipid metabolites and coronary plaque characteristics across 39 metabolic pathways. Sphingomyelins were inversely associated with all plaque metrics, and 1-palmitoyl-2-oleoyl-GPE (glycero-3-phosphoethanolamine; 16:0/18:1), a phosphatidylethanolamine, was positively associated with all plaque metrics. After correcting for multiple testing, 27 lipid species across 7 pathways remained significant (q<0.05). The majority were linked to pan-coronary lipid burden, with the strongest inverse association observed for sphingomyelin d18:1/22:1, d18:2/22:0, and d16:1/24:1. Similar inverse patterns were seen for select dihydrosphingomyelins and fatty acid dicarboxylates. In contrast, 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) remained positively associated with pan-coronary lipid. In the SCAPIS validation cohort, 19 of the 27 significant lipid associations were successfully replicated (q<0.05). CONCLUSIONS:This study is the first to demonstrate that sphingomyelins are negatively and 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) positively associated with vulnerable coronary plaque features based on multimodality intracoronary imaging in patients with myocardial infarction. Moreover, these associations were validated in a large cohort using coronary computed tomography angiography-derived measures of plaque burden. These novel results may enable the development of new diagnostic and therapeutic strategies.

Atherosclerosis develops over many years and its underlying mechanisms are still not fully understood. Plasma metabolomics across the different stages of development may help identify biomarkers that clarify disease pathways and improve early risk assessment. We performed untargeted plasma metabolomics using ultra-performance liquid chromatography-mass spectrometry in 8,146 participants without cardiovascular disease from the population-based SCAPIS cohort. Associations of 1,171 circulating metabolites with subclinical coronary atherosclerosis burden, assessed using coronary computed tomography angiography and quantified by segment involvement score, were assessed using multivariable models. Metabolites associated with coronary atherosclerosis were then evaluated in independent cohorts representing later stages of the atherosclerotic disease continuum: imminent myocardial infarction (MIMI, n=2,018), and coronary plaque burden and vulnerability in myocardial infarction survivors (PROSPECT II, n=898). Twelve metabolites, including phosphate, malate, sphingomyelins, amino acids, and one uncharacterized feature, were robustly associated with subclinical coronary atherosclerosis independent of traditional risk factors. Notably, sphingomyelins showed inverse associations with subclinical atherosclerosis, imminent myocardial infarction, and the presence of vulnerable plaques. Malate, N-acetyl-isoputreanine and an uncharacterized molecule (X-25790) were positively associated with subclinical coronary atherosclerosis and with imminent myocardial infarctions. These findings reveal a metabolomic signature across the atherosclerosis continuum, highlighting candidate biomarkers that may enhance understanding of disease mechanisms and aid risk stratification.

INTRODUCTION:Evidence for gut-kidney interactions in early kidney disease is limited, particularly in community-dwelling adults with largely preserved kidney function. Here, we quantified links between gut microbiota and estimated glomerular filtration rate (eGFR) in two population-based Swedish cohorts. METHODS:Deep shotgun metagenomics profiled fecal samples from 9788 adults in the Swedish CArdioPulmonary BioImage Study (SCAPIS) discovery cohort (mean age 58 ± 4 years; 52% women) and 2080 adults in the Malmö Offspring Study (MOS) replication cohort (mean age 40 ± 14 years; 52% women). Linear regression related the relative abundance of 494 metagenome-assembled species to the creatinine-based eGFR (by CKD-EPI equation), adjusting for demographics, albuminuria, cardiovascular risk factors and technical variables. Species passing false discovery rate under 0.05 in SCAPIS were tested in MOS for significant concordant direction. Functional enrichment linked eGFR-associated species to gut metabolic modules and plasma metabolites; partial Spearman correlations were used to assessed metabolite/species/eGFR relationships. RESULTS:The alpha diversity showed a modest inverse association with eGFR across both cohorts. We identified 44 bacterial species consistently associated with eGFR in both cohorts, collectively explaining 7% of its variance. Enrichment analysis highlighted histidine and carnitine metabolism among the top three pathways involved. Their key products, trimethylamine N-oxide and imidazole propionate, were inversely related to eGFR, and a metabolite panel accounted for 51% of eGFR variation, underscoring metabolite-mediated microbial effects. Sensitivity analyses upheld these findings. CONCLUSIONS:Gut microbial diversity and 44 reproducible species are independently linked to kidney function in community-dwelling adults. Enrichment of histidine and carnitine pathways and their circulating metabolites implicates microbial metabolism as a contributor to eGFR variability, suggesting tractable targets for early kidney protection.

In response to Campbell and Cappuccio's comments, this letter clarifies and defends the appropriate use of spot-urine sodium estimates in population-level and exploratory analyses. The critique misrepresents key aspects of the study design and overstates the limitations of spot-urine equations. While acknowledging that these methods are unsuitable for precise individual assessment, they perform adequately for ranking individuals and examining population-level associations, as supported by extensive validation studies. The reported associations with metabolic traits were internally consistent, biologically plausible, and in agreement with findings from studies using 24-hour urine collections. Dismissing such analyses as "invalid" undermines constructive scientific dialogue and disregards the exploratory value of transparent, hypothesis-generating research.

Type 2 diabetes (T2D) is etiologically heterogeneous, and process-specific polygenic scores (pPSs) only partly resolve this complexity. Here we integrate fourteen published T2D pPSs with plasma biochemistry, proteomics and NMR metabolomics in 29,425 SCAPIS participants to derive process-specific, polygenic-informed multi-molecular scores (pMMSs) that map genetic risk onto multi-omic molecular signatures. We then test the associations of these scores with subclinical coronary atherosclerosis, incident T2D, macrovascular disease, and microvascular complications in SCAPIS and 458,905 participants from UK Biobank. The novel pMMSs recapitulate the mechanistic interpretability of their underlying pPSs, yet show substantially stronger and more granular associations with molecular traits and disease risk. For example, per standard deviation, the Proinsulin pMMS indicates 4- to 5-fold increased risk of incident T2D and diabetic microvascular complications, whereas several lipid-related pMMSs highlight pleiotropic gene clusters with distinct roles in lipid metabolism and cardiometabolic disease pathogenesis. These process-specific molecular endophenotypes operationalize pleiotropy dissection for T2D risk and illustrate how polygenic risk propagates through molecular layers to shape complex cardiometabolic traits.

Abstract Background: It is thought that pets have positive effects on psychosocial factors and physical activity. However, earlier findings are inconsistent. In this study, we investigated the link between dog/cat ownership and social integration, mental and physical health and physical activity. Methods: This cross-sectional study comprised 4604 people, aged 50–64, from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Questionnaire data were used to assess dog/cat ownership. Social integration was self-reported and collected by the Interview Schedule for Social Interaction. Mental health was investigated with the SF-12 questionnaire, and physical activity was self-reported. Multiple linear regressions and ordinal regressions were used to investigate the relationships with dog/cat ownership. The analyses were adjusted for potential confounders. Results: Dog owners (n = 745) reported less social integration than non-dog owners, both regarding number of social contacts (adjusted odds ratio (aOR) 0.80, 95% confidence interval (CI) 0.69, 0.92) and availability of close relationships (aOR 0.79, CI 0.67, 0.94). No differences in mental health status regarding dog/cat ownership were detected. Dog owners reported 2 hours more weekly walking time on average (p < 0.001) and 2 hours less sitting time (p = 0.016) compared to non-dog owners. A dose-response relationship was found regarding the dog owners’ responsibility for the dogs’ exercise and the reported amount of walking (p < 0.001). Cat owners (n = 1032) walked approximately 20 minutes less per week than non-cat owners (p = 0.02). Conclusions: Dog ownership was associated with less social integration and no differences in mental health were found between dog/cat owners compared to non-owners. Dog owners were more physically active, and there was a dose-response relationship between the proportion of the engagement in the dog’s daily exercise and the time spent walking. The relationship between dog ownership and physical activity is relevant in relation to cardiovascular health.

BACKGROUND:Dihydrotestosterone (DHT), the most potent ligand to the androgen receptor, is synthesised from testosterone (T) by 5α-reductase type 1 and 2. While type 1 is expressed in several non-reproductive tissues in both sexes, men also express high levels of the high-affinity type 2 isoform in reproductive tissues; yet women have a higher circulating DHT to T (DHT/T) ratio than men. We hypothesised that the high DHT/T ratio in women is caused by high gut microbiota (GM) 5α-reductase activity or altered β-glucuronidase-induced androgen reabsorption from the gut. METHODS:We used a large cross-sectional subsample of the Swedish CArdioPulmonary bioImage Study (2897 women and 4338 men, 50-65 years of age) with GM composition and functionality determined by metagenome sequencing and circulating androgens determined by liquid chromatography-tandem mass spectrometry. FINDINGS:We confirmed that women had higher (+194%) circulating DHT/T ratio than men. The relative abundance of microbial genes for 5α-reductase type 1 (P = 3 × 10-4), but not β-glucuronidase, was positively associated with the DHT/T ratio in women. In women, the GM relative abundances of Odoribacter splanchnicus and Parabacteroides distasonis were positively associated with the relative abundance of microbial genes for 5α-reductase type 1 (P < 2 × 10-149) and the circulating DHT/T ratio (O. splanchnicus P = 3 × 10-6; P. distasonis P = 5 × 10-5). In mechanistic studies, we observed very high DHT/T ratio in intestinal content of female conventionally-raised but not germ-free mice. In female mice, the DHT/T ratio was 86.9% higher in serum from the portal vein than in inferior vena cava (P = 0.007). INTERPRETATION:These findings demonstrate that the circulating DHT/T ratio is increased by GM 5α-reductase activity in females. We propose that the GM acts as an endocrine organ influencing the androgenic status in females. FUNDING:See Acknowledgements.