Body mass index and risk of over 100 cancer forms and subtypes in 4.1 million individuals in Sweden: the Obesity and Disease Development Sweden (ODDS) pooled cohort study.

Background: Obesity, assessed by body mass index (BMI), is an established risk factor for 13 cancers. We aimed to identify further potential obesity-related cancers and to quantify their association with BMI relative to that of established obesity-related cancers. Methods: Using Cox regression models on 4,142,349 individuals in Sweden (mean age 27.1 years at weight measurement), we calculated hazard ratios (HRs) for the association between BMI and the risk of 122 cancers and cancer subtypes, grouped by topography and morphology. Cancers with a positive association (i.e., HR >1) at an α-level of 0.05 for obesity (BMI ≥30 kg/m2) vs. normal weight (BMI 18.5-24.9 kg/m2) or per 5 kg/m2 higher BMI, for which obesity is not an established risk factor, were considered potentially obesity related. Findings: After 100.2 million person-years of follow-up, 332,501 incident cancer cases were recorded. We identified 15 cancers in men and 16 in women as potentially obesity related. These were cancers of the head and neck, gastrointestinal tract, malignant melanoma, genital organs, endocrine organs, connective tissue, and haematological malignancies. Among these, there was evidence of differential associations with BMI between subtypes of gastric cancer, small intestine cancer, cervical cancer, and lymphoid neoplasms (P values for heterogeneity in HRs <0.05). The HR (95% confidence interval) per 5 kg/m2 higher BMI was 1.17 (1.15-1.20) in men and 1.13 (1.11-1.15) in women for potential obesity-related cancers (51,690 cases), and 1.24 (1.22-1.26) in men and 1.12 (1.11-1.13) in women for established obesity-related cancers (84,384 cases). Interpretation: This study suggests a large number of potential obesity-related cancers could be added to already established ones. Importantly, the magnitudes of the associations were largely comparable to those of the already established obesity-related cancers. We also provide evidence of specific cancer subtypes driving some associations with BMI. Studies accounting for cancer-specific confounders are needed to confirm these findings. Funding: Swedish Research Council, Swedish Cancer Society, Mrs. Berta Kamprad's Cancer Foundation, Crafoord Foundation, Cancer Research Foundation at the Department of Oncology, Malmö University Hospital, and China Scholarship Council.

A detailed analysis of body composition in relation to cardiopulmonary exercise test indices.

A cardiopulmonary exercise test (CPET) is a test assessing an individual's physiological response during exercise. Results may be affected by body composition, which is best evaluated through imaging techniques like magnetic resonance imaging (MRI). The aim of this study was to assess relationships between body composition and indices obtained from CPET. A total of 234 participants (112 female), all aged 50 years, underwent CPETs and whole-body MRI scans (> 1 million voxels). Voxel-wise statistical analysis of tissue volume and fat content was carried out with a method called Imiomics and related to the CPET indices peak oxygen consumption (V̇O2peak), V̇O2peak scaled by body weight (V̇O2kg) and by total lean mass (V̇O2lean), ventilatory efficiency (V̇E/V̇CO2-slope), work efficiency (ΔV̇O2/ΔWR) and peak exercise respiratory exchange ratio (RERpeak). V̇O2peak showed the highest positive correlation with volume of skeletal muscle. V̇O2kg negatively correlated with tissue volume in subcutaneous fat, particularly gluteal fat. RERpeak negatively correlated with tissue volume in skeletal muscle, subcutaneous fat, visceral fat and liver. Some associations differed between sexes: in females ΔV̇O2/ΔWR correlated positively with tissue volume of subcutaneous fat and V̇E/V̇CO2-slope with tissue volume of visceral fat, and, in males, V̇O2peak correlated positively to lung volume. In conclusion, voxel-based Imiomics provided detailed insights into how CPET indices were related to the tissue volume and fat content of different body structures.

Time trends of the association of body mass index with mortality in 3.5 million young Swedish adults.

PURPOSE: We investigated time trends of the obesity-mortality association, accounting for age, sex, and cause-specific deaths. METHODS: We analysed pooled nationwide data in Sweden for 3,472,310 individuals aged 17-39 years at baseline in 1963-2016. Cox regression and flexible parametric survival models investigated BMI-mortality associations in sub-groups of sex and baseline calendar years (men: <1975, 1975-1985, ≥1985 and women: <1985, 1985-1994, ≥1995). RESULTS: Comparing men with obesity vs. normal weight, all-cause and "other-cause" mortality associations decreased over periods; HR (95% CI) 1.92 (1.83-2.01) and 1.70 (1.58-1.82) for all-cause and 1.72 (1.58-1.87) and 1.40 (1.28-1.53) for "other-cause" mortality in <1975 and ≥1985, but increased for CVD mortality; HR 2.71 (2.51-2.94) and 3.91 (3.37-4.53). Higher age at death before 1975 coincided with more obesity-related deaths at higher ages. Furthermore, the all-cause mortality association for different ages in men showed no clear differences between periods (p-interaction=0.09), suggesting no calendar effect after accounting for attained age. Similar, but less pronounced, results were observed in women. Associations with cancer mortality showed no clear trends in men or in women. CONCLUSIONS: Accounting for differences in age and death causes between calendar periods when investigating BMI-mortality time trends may avoid misinterpreting the risks associated with obesity over time.

Cohort profile: The Obesity and Disease Development Sweden (ODDS) study, a pooled cohort.

PURPOSE: The Obesity and Disease Development Sweden (ODDS) study was designed to create a large cohort to study body mass index (BMI), waist circumference (WC) and changes in weight and WC, in relation to morbidity and mortality. PARTICIPANTS: ODDS includes 4 295 859 individuals, 2 165 048 men and 2 130 811 women, in Swedish cohorts and national registers with information on weight assessed once (2 555 098 individuals) or more (1 740 761 individuals), in total constituting 7 733 901 weight assessments at the age of 17-103 years in 1963-2020 (recalled weight as of 1911). Information on WC is available in 152 089 men and 212 658 women, out of whom 108 795 have repeated information on WC (in total 512 273 assessments). Information on morbidity and mortality was retrieved from national registers, with follow-up until the end of 2019-2021, varying between the registers. FINDINGS TO DATE: Among all weight assessments (of which 85% are objectively measured), the median year, age and BMI (IQR) is 1985 (1977-1994) in men and 2001 (1991-2010) in women, age 19 (18-40) years in men and 30 (26-36) years in women and BMI 22.9 (20.9-25.4) kg/m2 in men and 23.2 (21.2-26.1) kg/m2 in women. Normal weight (BMI 18.5-24.9 kg/m2) is present in 67% of assessments in men and 64% in women and obesity (BMI≥30 kg/m2) in 5% of assessments in men and 10% in women. The median (IQR) follow-up time from the first objectively measured or self-reported current weight assessment until emigration, death or end of follow-up is 31.4 (21.8-40.8) years in men and 19.6 (9.3-29.0) years in women. During follow-up, 283 244 men and 123 457 women died. FUTURE PLANS: The large sample size and long follow-up of the ODDS Study will provide robust results on anthropometric measures in relation to risk of common diseases and causes of deaths, and novel findings in subgroups and rarer outcomes.

Cardiopulmonary exercise testing and body composition.

Background: The cardiopulmonary exercise test (CPET) evaluates cardiopulmonary function. In light of the obesity epidemic, it is important to understand how body composition affects interpretation of CPET results. The aim of the present study was to assess the relationship between CPET measures, other than peak oxygen uptake, and body composition. Method: A total of 330 participants, aged 50 years, performed both a CPET and dual-energy X-ray absorptiometry (DXA). From the CPET, peak exercise respiratory exchange ratio (RER), ventilatory efficiency (V̇ E/V̇ CO2 slope) and work efficiency (ΔV̇ O2 /ΔWR) were recorded. Pearson's correlation was used to assess the association between CPET measures and selected body composition measures, including body mass index (BMI), waist circumference, fat mass, lean mass, body fat percentage and percentage trunk fat to fat mass. All analyses were done stratified by sex. A p-value <0.05 defined statistical significance. Results: RER was negatively correlated with body composition measures; the strongest correlation was observed with waist circumference in females (r= -0.36). V̇ E/V̇ CO2 slope had no significant correlations with any body composition measures. ΔV̇ O2 /ΔWR was positively correlated with the body composition measures; the strongest correlation was observed with BMI (r=0.24). The additive role of percentage body fat and percentage trunk fat were studied in a linear regression model using waist circumference and BMI to predict the aforementioned CPET measures and no additive role was found. Conclusion: RER and ΔV̇ O2 /ΔWR may be influenced by body composition while V̇ E/V̇ CO2 slope is not affected. Adiposity measures from DXA add no additional explanatory value to the CPET measures.

Decompression alone or decompression with fusion for lumbar spinal stenosis: five-year clinical results from a randomized clinical trial.

Aims: We compared decompression alone to decompression with fusion surgery for lumbar spinal stenosis, with or without degenerative spondylolisthesis (DS). The aim was to evaluate if five-year outcomes differed between the groups. The two-year results from the same trial revealed no differences. Methods: The Swedish Spinal Stenosis Study was a multicentre randomized controlled trial with recruitment from September 2006 to February 2012. A total of 247 patients with one- or two-level central lumbar spinal stenosis, stratified by the presence of DS, were randomized to decompression alone or decompression with fusion. The five-year Oswestry Disability Index (ODI) was the primary outcome. Secondary outcomes were the EuroQol five-dimension questionnaire (EQ-5D), visual analogue scales for back and leg pain, and patient-reported satisfaction, decreased pain, and increased walking distance. The reoperation rate was recorded. Results: Five-year follow-up was completed by 213 (95%) of the eligible patients (mean age 67 years; 155 female (67%)). After five years, ODI was similar irrespective of treatment, with a mean of 25 (SD 18) for decompression alone and 28 (SD 22) for decompression with fusion (p = 0.226). Mean EQ-5D was higher for decompression alone than for fusion (0.69 (SD 0.28) vs 0.59 (SD 0.34); p = 0.027). In the no-DS subset, fewer patients reported decreased leg pain after fusion (58%) than with decompression alone (80%) (relative risk (RR) 0.71 (95% confidence interval (CI) 0.53 to 0.97). The frequency of subsequent spinal surgery was 24% for decompression with fusion and 22% for decompression alone (RR 1.1 (95% CI 0.69 to 1.8)). Conclusion: Adding fusion to decompression in spinal stenosis surgery, with or without spondylolisthesis, does not improve the five-year ODI, which is consistent with our two-year report. Three secondary outcomes that did not differ at two years favoured decompression alone at five years. Our results support decompression alone as the preferred method for operating on spinal stenosis.

Metabolic profiling of galectin-1 and galectin-3: a cross-sectional, multi-omics, association study.

OBJECTIVES: Experimental studies indicate a role for galectin-1 and galectin-3 in metabolic disease, but clinical evidence from larger populations is limited. METHODS: We measured circulating levels of galectin-1 and galectin-3 in the Prospective investigation of Obesity, Energy and Metabolism (POEM) study, participants (n = 502, all aged 50 years) and characterized the individual association profiles with metabolic markers, including clinical measures, metabolomics, adipose tissue distribution (Imiomics) and proteomics. RESULTS: Galectin-1 and galectin-3 were associated with fatty acids, lipoproteins and triglycerides including lipid measurements in the metabolomics analysis adjusted for body mass index (BMI). Galectin-1 was associated with several measurements of adiposity, insulin secretion and insulin sensitivity, while galectin-3 was associated with triglyceride-glucose index (TyG) and fasting insulin levels. Both galectins were associated with inflammatory pathways and fatty acid binding protein (FABP)4 and -5-regulated triglyceride metabolic pathways. Galectin-1 was also associated with several proteins related to adipose tissue differentiation. CONCLUSIONS: The association profiles for galectin-1 and galectin-3 indicate overlapping metabolic effects in humans, while the distinctly different associations seen with fat mass, fat distribution, and adipose tissue differentiation markers may suggest a functional role of galectin-1 in obesity.

Meat consumption and the risk of hip fracture in women and men: two prospective Swedish cohort studies.

PURPOSE: To study the association between meat intake (predominantly red and processed meats) and the risk of hip fracture, as well as the association between meat intake and biomarkers of inflammation, oxidative stress, bone turnover, body composition, and bone mineral density (BMD). METHODS: Data from the Swedish Mammography Cohort and the Cohort of Swedish men (n = 83,603, 54% men) with repeated investigations and their respective clinical sub-cohorts was utilised. Incident hip fractures were ascertained through individual linkage to registers. Associations were investigated using multivariable Cox and linear regression analyses. RESULTS: During up to 23 years of follow-up (mean 18.2 years) and 1,538,627 person-years at risk, 7345 participants (2840 men) experienced a hip fracture. Each daily serving of meat intake conferred a hazard ratio (HR) of 1.03 (95% confidence interval [CI] 1.00; 1.06) for hip fracture. In quintile 5, compared to quintile 2, the HR was 1.11 (95% CI 1.01; 1.21) among all participants. In the sub-cohorts, meat intake was directly associated with circulating levels of interleukin-6, C-reactive protein, leptin, ferritin, parathyroid hormone, and calcium. CONCLUSION: A modest linear association was found between a higher meat intake and the risk of hip fractures. Our results from the sub-cohorts further suggest that possible mechanisms linking meat intake and hip fracture risk may be related to the regulation of bone turnover, subclinical inflammation, and oxidative stress. Although estimates are modest, limiting red and processed meat intake in a healthy diet is advisable to prevent hip fractures.

Dietary fatty acids and incident hip fractures in cohorts of women and men. A relative validation and follow-up study.

OBJECTIVES: Hip fractures are associated with a high burden of morbidity and mortality. Diet is essential for preventing fragility fractures, but the role of dietary fatty acids on the risk of hip fracture is uncertain. The aim was to investigate how intake of different dietary fatty acids relates to the risk of hip fracture. A relative validation of the long-term intake of dietary fatty acids estimated from food frequency questionnaires (FFQs) was also performed. DESIGN, SETTINGS AND PARTICIPANTS: We used data collected in two population-based cohorts, the Swedish Mammography Cohort and the Cohort of Swedish men (n = 83,603, 54% men, aged 45-82 years). Data from the repeated investigations in the cohorts and cross-sectional data from their clinical sub-cohorts were used. MEASUREMENTS: Diet data was collected in FFQs. Incident hip fractures were gathered by individual linkage to national registers. We performed Cox regression analysis to investigate associations between dietary fatty acids and hip fracture. Follow-up time was between January 1st, 1998 and December 31st, 2020. The validation was performed using correlation analyses, comparing fatty acids measured in adipose tissue with estimated fatty acid intakes from FFQs. RESULTS: During up to 23 years of follow-up (mean 18 years) and 1,538,627 person-years at risk, 7345 participants (2840 men) experienced a hip fracture. A low linoleic acid (LA) and high intakes of long-chain n-3 fatty acids were associated with higher hip fracture risk in a non-linear way. In quartile 4 compared to quartile 1 of LA, the multivariable-adjusted hazard ratio of hip fracture was 0.89 (95% Confidence Interval: 0.81, 0.97). The study confirmed the validity of FFQs to capture the intake of the specific dietary long-chain n-3 fatty acids. The estimated intake of LA, α-linolenic acid, and myristic acid were also adequately captured by the FFQs. Validity was confirmed in both women and men. CONCLUSION: A low to moderate intake of linoleic acid and a higher intake of long-chain n-3 fatty acids were associated with a higher risk of hip fractures. The results indicate that attention should be paid to dietary fatty acid composition for the optimal prevention of fragility fractures.

Declining hip fracture burden in Sweden 1998-2019 and consequences for projections through 2050.

We aimed to estimate the absolute and age-standardized number of hip fractures in Sweden during the past two decades to produce time trends and future projections. We used nationwide register data from 1998 to 2019 and a validated algorithm to calculate the annual absolute and age-standardized number of incident hip fractures over time. The total hip fracture burden was 335,399 incident events over the 22 years, with a change from 16,180 in 1998 to 13,929 in 2019, a 14% decrease. One decade after the index hip fracture event, 80% of the patients had died, and 11% had a new hip fracture. After considering the steady growth of the older population, the decline in the age-standardized number of hip fractures from 1998 through 2019 was 29.2% (95% CI 28.1-30.2%) in women and 29.3% (95% CI 27.5-30.7%) in men. With a continued similar reduction in hip fracture incidence, we can predict that 14,800 hip fractures will occur in 2034 and 12,000 in 2050 despite doubling the oldest old (≥ 80 years). Without an algorithm, a naïve estimate of the total number of hip fractures over the study period was 539,947, with a second 10-year hip fracture risk of 35%. We note an ongoing decline in the absolute and age-standardized actual number of hip fractures in Sweden, with consequences for future projections.

Plasma Protein Profiling of Incident Cardiovascular Diseases: A Multisample Evaluation.

BACKGROUND: Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs. METHODS: Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure. RESULTS: Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors. CONCLUSIONS: Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin were novel early markers of CVD. A selection of 11 proteins improved the discrimination of CVD.

Genome-Wide Association and Two-Sample Mendelian Randomization Analyses of Plasma Ghrelin and Gastrointestinal Cancer Risk.

BACKGROUND: Observational studies have suggested that the gut hormone ghrelin is an early marker of future risk of developing gastrointestinal cancer. However, whether ghrelin is a causal risk factor remains unclear. We conducted a genome-wide association study (GWAS) of plasma ghrelin and used Mendelian randomization (MR) to investigate the possible causal association between ghrelin and gastrointestinal cancer risk. METHODS: Genetic variants associated with plasma ghrelin were identified in a GWAS comprising 10,742 Swedish adults in the discovery (N = 6,259) and replication (N = 4,483) cohorts. The association between ghrelin and gastrointestinal cancer was examined through a two-sample MR analysis using the identified genetic variants as instruments and GWAS data from the UK Biobank, FinnGen, and a colorectal cancer consortium. RESULTS: GWAS found associations between multiple genetic variants within ±200 kb of the GHRL gene and plasma ghrelin. A two-sample MR analysis revealed that genetically predicted higher plasma ghrelin levels were associated with a lower risk of gastrointestinal cancer in UK Biobank and in a meta-analysis of the UK Biobank and FinnGen studies. The combined OR per approximate doubling of genetically predicted plasma ghrelin was 0.91 (95% confidence interval, 0.85-0.99; P = 0.02). Colocalization analysis revealed limited evidence of shared causal variants for plasma ghrelin and gastrointestinal cancer at the GHRL locus (posterior probability H4 = 24.5%); however, this analysis was likely underpowered. CONCLUSIONS: Our study provides evidence in support of a possible causal association between higher plasma ghrelin levels and a reduced risk of gastrointestinal cancer. IMPACT: Elevated plasma ghrelin levels might reduce the risk of gastrointestinal cancer.

Deciphering the genetic architecture of atrial fibrillation offers insights into disease prediction, pathophysiology and downstream sequelae.

Aims: The study aimed to discover novel genetic loci for atrial fibrillation (AF), explore the shared genetic etiologies between AF and other cardiovascular and cardiometabolic traits, and uncover AF pathogenesis using Mendelian randomization analysis. Methods and results: We conducted a genome-wide association study meta-analysis including 109,787 AF cases and 1,165,920 controls of European ancestry and identified 215 loci, among which 91 were novel. We performed Genomic Structural Equation Modeling analysis between AF and four cardiovascular comorbidities (coronary artery disease, ischemic stroke, heart failure, and vneous thromboembolism) and found 189 loci shared across these diseases as well as a universal genetic locus shared by atherosclerotic outcomes (i.e., rs1537373 near CDKN2B). Three genetic loci (rs10740129 near JMJD1C, rs2370982 near NRXN3, and rs9931494 near FTO) were associated with AF and cardiometabolic traits. A polygenic risk score derived from this genome-wide meta-analysis was associated with AF risk (odds ratio 2.36, 95% confidence interval 2.31-2.41 per standard deviation increase) in the UK biobank. This score, combined with age, sex, and basic clinical features, predicted AF risk (AUC 0.784, 95% CI 0.781-0.787) in Europeans. Phenome-wide association analysis of the polygenic risk score identified many AF-related comorbidities of the circulatory, endocrine, and respiratory systems. Phenome-wide and multi-omic Mendelian randomization analyses identified associations of blood lipids and pressure, diabetes, insomnia, obesity, short sleep, and smoking, 27 blood proteins, one gut microbe (genus.Catenibacterium), and 11 blood metabolites with risk to AF. Conclusions: This genome-wide association study and trans-omic Mendelian randomization analysis provides insights into disease risk prediction, pathophysiology and downstream sequelae.

Comprehensive analyses of circulating cardiometabolic proteins and objective measures of fat mass.

BACKGROUND: The underlying molecular pathways for the effect of excess fat mass on cardiometabolic diseases is not well understood. Since body mass index is a suboptimal measure of body fat content, we investigated the relationship of fat mass measured by dual-energy X-ray absorptiometry with circulating cardiometabolic proteins. METHODS: We used data from a population-based cohort of 4950 Swedish women (55-85 years), divided into discovery and replication samples; 276 proteins were assessed with three Olink Proseek Multiplex panels. We used random forest to identify the most relevant biomarker candidates related to fat mass index (FMI), multivariable linear regression to further investigate the associations between FMI characteristics and circulating proteins adjusted for potential confounders, and principal component analysis (PCA) for the detection of common covariance patterns among the proteins. RESULTS: Total FMI was associated with 66 proteins following adjustment for multiple testing in discovery and replication multivariable analyses. Five proteins not previously associated with body size were associated with either lower FMI (calsyntenin-2 (CLSTN2), kallikrein-10 (KLK10)), or higher FMI (scavenger receptor cysteine-rich domain-containing group B protein (SSC4D), trem-like transcript 2 protein (TLT-2), and interleukin-6 receptor subunit alpha (IL-6RA)). PCA provided an efficient summary of the main variation in FMI-related circulating proteins involved in glucose and lipid metabolism, appetite regulation, adipocyte differentiation, immune response and inflammation. Similar patterns were observed for regional fat mass measures. CONCLUSIONS: This is the first large study showing associations between fat mass and circulating cardiometabolic proteins. Proteins not previously linked to body size are implicated in modulation of postsynaptic signals, inflammation, and carcinogenesis.

Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases.

BACKGROUND: Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance. METHODS: We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins. RESULTS: We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F). CONCLUSION: Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.

The metabolomic profiling of total fat and fat distribution in a multi-cohort study of women and men.

Currently studies aiming for the comprehensive metabolomics profiling of measured total fat (%) as well as fat distribution in both sexes are lacking. In this work, bioimpedance analysis was applied to measure total fat (%) and fat distribution (trunk to leg ratio). Liquid chromatography-mass spectrometry-based untargeted metabolomics was employed to profile the metabolic signatures of total fat (%) and fat distribution in 3447 participants from three Swedish cohorts (EpiHealth, POEM and PIVUS) using a discovery-replication cross-sectional study design. Total fat (%) and fat distribution were associated with 387 and 120 metabolites in the replication cohort, respectively. Enriched metabolic pathways for both total fat (%) and fat distribution included protein synthesis, branched-chain amino acids biosynthesis and metabolism, glycerophospholipid metabolism and sphingolipid metabolism. Four metabolites were mainly related to fat distribution: glutarylcarnitine (C5-DC), 6-bromotryptophan, 1-stearoyl-2-oleoyl-GPI (18:0/18:1) and pseudouridine. Five metabolites showed different associations with fat distribution in men and women: quinolinate, (12Z)-9,10-dihydroxyoctadec-12-enoate (9,10-DiHOME), two sphingomyelins and metabolonic lactone sulfate. To conclude, total fat (%) and fat distribution were associated with a large number of metabolites, but only a few were exclusively associated with fat distribution and of those metabolites some were associated with sex*fat distribution. Whether these metabolites mediate the undesirable effects of obesity on health outcomes remains to be further investigated.

Urinary phosphate is associated with cardiovascular disease incidence.

INTRODUCTION: Elevated phosphate (P) in urine may reflect a high intake of inorganic P salts from food additives. Elevated P in plasma is linked to vascular dysfunction and calcification. OBJECTIVE: To explore associations between P in urine as well as in plasma and questionnaire-estimated P intake, and incidence of cardiovascular disease (CVD). METHODS: We used the Swedish Mammography Cohort-Clinical, a population-based cohort study. At baseline (2004-2009), P was measured in urine and plasma in 1625 women. Dietary P was estimated via a food-frequency questionnaire. Incident CVD was ascertained via register-linkage. Associations were assessed using Cox proportional hazards regression. RESULTS: After a median follow-up of 9.4 years, 164 composite CVD cases occurred (63 myocardial infarctions [MIs] and 101 strokes). Median P (percentiles 5-95) in urine and plasma were 2.4 (1.40-3.79) mmol/mmol creatinine and 1.13 (0.92-1.36) mmol/L, respectively, whereas dietary P intake was 1510 (1148-1918) mg/day. No correlations were observed between urinary and plasma P (r = -0.07) or dietary P (r = 0.10). Urinary P was associated with composite CVD and MI. The hazard ratio of CVD comparing extreme tertiles was 1.57 (95% confidence interval 1.05, 2.35; P trend 0.037)-independently of sodium excretion, the estimated glomerular filtration rate, both P and calcium in plasma, and diuretic use. Association with CVD for plasma P was 1.41 (0.96, 2.07; P trend 0.077). CONCLUSION: Higher level of urinary P, likely reflecting a high consumption of highly processed foods, was linked to CVD. Further investigation is needed to evaluate the potential cardiovascular toxicity associated with excessive intake of P beyond nutritional requirements.

Swedish Snuff (Snus), Cigarette Smoking, and Risk of Type 2 Diabetes.

INTRODUCTION: Cigarette smoking is a known risk factor for Type 2 diabetes, but evidence regarding former smoking and moist snuff (snus) use and Type 2 diabetes risk is inconclusive. This study investigated the relationships of cigarette smoking and Swedish snus use with the risk of Type 2 diabetes in a cohort of middle-aged and elderly participants. METHODS: Participants (N=36,742; age range=56-95 years) were followed for incident Type 2 diabetes and death between 2009 and 2017 through linkage to the Swedish National Patient, Prescribed Drug and Death Registers. Cox proportional hazards regression was used to obtain hazard ratios and 95% CIs adjusted for potential confounders, including physical activity, education, BMI, and alcohol intake. Analyses were conducted in 2021‒2022. RESULTS: Former and current smoking was associated with an increased risk of Type 2 diabetes (hazard ratios [95% CI]=1.17 [1.07, 1.29] and 1.57 [1.36, 1.81], respectively). In those who stopped smoking, Type 2 diabetes risk remained elevated up to approximately 15 years after cessation. In participants who have never smoked, snus use was linked to a higher risk of Type 2 diabetes in the model adjusted for age and sex (hazard ratio [95% CI]=1.49 [1.04, 2.15]), but this was attenuated after multivariable adjustment (hazard ratio [95% Cl]=1.29 [0.89, 1.86]). CONCLUSIONS: This study indicates that current and former smoking are associated with an increased risk of Type 2 diabetes in middle-aged and older individuals. There was less evidence of an association of snus use with the risk of Type 2 diabetes, suggesting that compounds other than nicotine may underlie the detrimental association of smoking with the risk of Type 2 diabetes.

Pre-pregnancy participation and performance in world's largest cross-country ski race as a proxy for physical exercise and fitness, and perinatal outcomes: Prospective registry-based cohort study.

OBJECTIVE: Investigate associations between pre-pregnancy participation and performance in a demanding cross-country ski race (proxy for exercise volume and fitness) and perinatal outcomes. Pre-registered protocol: osf.io/aywg2. DESIGN: Prospective cohort study. SETTING: Based on entire overlap between the Vasaloppet registry and the population-based Swedish Pregnancy Register. SAMPLE: All female Vasaloppet participants 1991-2017 with subsequent singleton delivery (skiers), and age- and county-matched non-skiers. METHODS: We calculated odds ratios (ORs) for non-skiers versus skiers (model 1) and, among skiers, by performance (model 2), in Bayesian logistic regressions adjusted for socio-demographics, lifestyle factors, and comorbidities. We repeated calculations adjusting for early pregnancy body mass index (potential mediator) and explored robustness (selection/exposure settings; multiple comparisons correction). MAIN OUTCOME MEASURES: Twenty-nine important perinatal outcomes, predefined based on existing expert consensus. RESULTS: Non-skiers (n = 194 384) versus skiers (n = 15 377) (and slower versus faster performance, not shown) consistently had higher odds of gestational diabetes mellitus (GDM) (OR 1.70, 95% highest density interval: 1.40-2.09), excessive gestational weight gain (GWG) (1.28, 1.22-1.38), psychiatric morbidity (1.60, 1.49-1.72), any caesarean section (CS) (1.34, 1.28-1.40), elective CS (1.39, 1.29-1.49), and large-for-gestational-age babies (>90th percentile, 1.11, 1.04-1.18); lower odds of inadequate GWG (0.83, 0.79-0.88); and no associations with fetal/neonatal complications (e.g. preterm birth [1.09, 0.98-1.20], small for gestational age [SGA] [1.23, 1.05-1.45]). Adjustment for body mass index attenuated associations with excessive (1.20, 1.14-1.30) and inadequate GWG (0.87, 0.83-0.92) and large for gestational age (1.07, 1.00-1.13). CONCLUSION: Non-skiers compared with skiers, and slower versus faster performance, consistently displayed higher odds of GDM, excessive GWG, psychiatric morbidity, CS and large-for-gestational-age babies; and lower odds of inadequate GWG, after adjustment for socio-demographic and lifestyle factors and comorbidities. There were no associations with fetal/neonatal complications.