Loci for insulin processing and secretion provide insight into type 2 diabetes risk.

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Major cardiovascular events and death in parents of children with type 1 diabetes: a register-based matched cohort study in Sweden.

AIMS/HYPOTHESIS: Parenting a child with type 1 diabetes has been associated with stress-related symptoms. This study aimed to elucidate the potential impact on parental risk of major cardiovascular events (MCE) and death. METHODS: In this register-based study, we included the parents of 18,871 children, born 1987-2020 and diagnosed with type 1 diabetes in Sweden at <18 years. The median parental age at the child's diagnosis was 39.0 and 41.0 years for mothers and fathers, respectively. The cohort also encompassed 714,970 population-based matched parental control participants and 12,497 parental siblings. Cox proportional hazard regression models were employed to investigate the associations between having a child with type 1 diabetes and incident MCE and all-cause death, and, as secondary outcomes, acute coronary syndrome and ischaemic heart disease (IHD). We adjusted for potential confounders including parental type 1 diabetes and country of birth. RESULTS: During follow-up (median 12 years, range 0-35), we detected no associations between parenting a child with type 1 diabetes and MCE in mothers (adjusted HR [aHR] 1.02; 95% CI 0.90, 1.15) or in fathers (aHR 1.01; 95% CI 0.94, 1.08). We noted an increased hazard of IHD in exposed mothers (aHR 1.21; 95% CI 1.05, 1.41) with no corresponding signal in fathers (aHR 0.97; 95% CI 0.89, 1.05). Parental sibling analysis did not confirm the association in exposed mothers (aHR 1.01; 95% CI 0.73, 1.41). We further observed a slightly increased hazard of all-cause death in exposed fathers (aHR 1.09; 95% CI 1.01, 1.18), with a similar but non-significant estimate noted in exposed mothers (aHR 1.07; 95% CI 0.96, 1.20). The estimates from the sibling analyses of all-cause death in fathers and mothers were 1.12 (95% CI 0.90, 1.38) and 0.73 (95% CI 0.55, 0.96), respectively. CONCLUSIONS/INTERPRETATION: Having a child diagnosed with type 1 diabetes in Sweden was not associated with MCE, but possibly with all-cause mortality. Further studies are needed to disentangle potential underlying mechanisms, and to investigate parental health outcomes across the full lifespan.

Streptococcus Species Abundance in the Gut Is Linked to Subclinical Coronary Atherosclerosis in 8973 Participants From the SCAPIS Cohort.

BACKGROUND: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis and to explore relevant clinical correlates. METHODS: We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of fecal samples, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva. RESULTS: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis (P<1×10-5). Associations were largely similar across coronary computed tomography angiography-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid ß-oxidation, and amino acid degradation were associated with coronary artery calcium score. CONCLUSIONS: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis.

Pulmonary function and atherosclerosis in the general population: causal associations and clinical implications.

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.

Sociodemographic characteristics and COVID-19 testing rates: spatiotemporal patterns and impact of test accessibility in Sweden.

BACKGROUND: Diagnostic testing is essential for disease surveillance and test-trace-isolate efforts. We aimed to investigate if residential area sociodemographic characteristics and test accessibility were associated with Coronavirus Disease 2019 (COVID-19) testing rates. METHODS: We included 426 224 patient-initiated COVID-19 polymerase chain reaction tests from Uppsala County in Sweden from 24 June 2020 to 9 February 2022. Using Poisson regression analyses, we investigated if postal code area Care Need Index (CNI; median 1.0, IQR 0.8-1.4), a composite measure of sociodemographic factors used in Sweden to allocate primary healthcare resources, was associated with COVID-19 daily testing rates after adjustments for community transmission. We assessed if the distance to testing station influenced testing, and performed a difference-in-difference-analysis of a new testing station targeting a disadvantaged neighbourhood. RESULTS: We observed that CNI, i.e. primary healthcare need, was negatively associated with COVID-19 testing rates in inhabitants 5-69 years. More pronounced differences were noted across younger age groups and in Uppsala City, with test rate ratios in children (5-14 years) ranging from 0.56 (95% CI 0.47-0.67) to 0.87 (95% CI 0.80-0.93) across three pandemic waves. Longer distance to the nearest testing station was linked to lower testing rates, e.g. every additional 10 km was associated with a 10-18% decrease in inhabitants 15-29 years in Uppsala County. The opening of the targeted testing station was associated with increased testing, including twice as high testing rates in individuals aged 70-105, supporting an intervention effect. CONCLUSIONS: Ensuring accessible testing across all residential areas constitutes a promising tool to decrease inequalities in testing.

Targeted proteomics identifies potential biomarkers of dysglycaemia, beta cell function and insulin sensitivity in Black African men and women.

AIMS/HYPOTHESIS: Using a targeted proteomics approach, we aimed to identify and validate circulating proteins associated with impaired glucose metabolism (IGM) and type 2 diabetes in a Black South African cohort. In addition, we assessed sex-specific associations between the validated proteins and pathophysiological pathways of type 2 diabetes. METHODS: This cross-sectional study included Black South African men (n=380) and women (n=375) who were part of the Middle-Aged Soweto Cohort (MASC). Dual-energy x-ray absorptiometry was used to determine fat mass and visceral adipose tissue, and fasting venous blood samples were collected for analysis of glucose, insulin and C-peptide and for targeted proteomics, measuring a total of 184 pre-selected protein biomarkers. An OGTT was performed on participants without diabetes, and peripheral insulin sensitivity (Matsuda index), HOMA-IR, basal insulin clearance, insulin secretion (C-peptide index) and beta cell function (disposition index) were estimated. Participants were classified as having normal glucose tolerance (NGT; n=546), IGM (n=116) or type 2 diabetes (n=93). Proteins associated with dysglycaemia (IGM or type 2 diabetes) in the MASC were validated in the Swedish EpiHealth cohort (NGT, n=1706; impaired fasting glucose, n=550; type 2 diabetes, n=210). RESULTS: We identified 73 proteins associated with dysglycaemia in the MASC, of which 34 were validated in the EpiHealth cohort. Among these validated proteins, 11 were associated with various measures of insulin dynamics, with the largest number of proteins being associated with HOMA-IR. In sex-specific analyses, IGF-binding protein 2 (IGFBP2) was associated with lower HOMA-IR in women (coefficient -0.35; 95% CI -0.44, -0.25) and men (coefficient -0.09; 95% CI -0.15, -0.03). Metalloproteinase inhibitor 4 (TIMP4) was associated with higher insulin secretion (coefficient 0.05; 95% CI 0.001, 0.11; p for interaction=0.025) and beta cell function (coefficient 0.06; 95% CI 0.02, 0.09; p for interaction=0.013) in women only. In contrast, a stronger positive association between IGFBP2 and insulin sensitivity determined using an OGTT (coefficient 0.38; 95% CI 0.27, 0.49) was observed in men (p for interaction=0.004). A posteriori analysis showed that the associations between TIMP4 and insulin dynamics were not mediated by adiposity. In contrast, most of the associations between IGFBP2 and insulin dynamics, except for insulin secretion, were mediated by either fat mass index or visceral adipose tissue in men and women. Fat mass index was the strongest mediator between IGFBP2 and insulin sensitivity (total effect mediated 40.7%; 95% CI 37.0, 43.6) and IGFBP2 and HOMA-IR (total effect mediated 39.1%; 95% CI 31.1, 43.5) in men. CONCLUSIONS/INTERPRETATION: We validated 34 proteins that were associated with type 2 diabetes, of which 11 were associated with measures of type 2 diabetes pathophysiology such as peripheral insulin sensitivity and beta cell function. This study highlights biomarkers that are similar between cohorts of different ancestry, with different lifestyles and sociodemographic profiles. The African-specific biomarkers identified require validation in African cohorts to identify risk markers and increase our understanding of the pathophysiology of type 2 diabetes in African populations.

Prevalence of atherosclerosis in individuals with prediabetes and diabetes compared to normoglycaemic individuals-a Swedish population-based study.

BACKGROUND: Patients with type 2 diabetes have an increased risk of death and cardiovascular events and people with diabetes or prediabetes have been found to have increased atherosclerotic burden in the coronary and carotid arteries. This study will estimate the cross-sectional prevalence of atherosclerosis in the coronary and carotid arteries in individuals with prediabetes and diabetes, compared with normoglycaemic individuals in a large population-based cohort. METHODS: The 30,154 study participants, 50-64 years, were categorized according to their fasting glycaemic status or self-reported data as normoglycaemic, prediabetes, and previously undetected or known diabetes. Prevalence of affected coronary artery segments, severity of stenosis and coronary artery calcium score (CACS) were determined by coronary computed tomography angiography. Total atherosclerotic burden was assessed in the 11 clinically most relevant segments using the Segment Involvement Score and as the presence of any coronary atherosclerosis. The presence of atherosclerotic plaque in the carotid arteries was determined by ultrasound examination. RESULTS: Study participants with prediabetes (n = 4804, 16.0%) or diabetes (n = 2282, 7.6%) had greater coronary artery plaque burden, more coronary stenosis and higher CACS than normoglycaemic participants (all, p < 0.01). Among male participants with diabetes 35.3% had CACS ≥ 100 compared to 16.1% among normoglycaemic participants. For women, the corresponding figures were 8.9% vs 6.1%. The prevalence of atherosclerosis in the coronary arteries was higher in participants with previously undetected diabetes than prediabetes, but lower than in patients with known diabetes. The prevalence of any plaque in the carotid arteries was higher in participants with prediabetes or diabetes than in normoglycaemic participants. CONCLUSIONS: In this large population-based cohort of currently asymptomatic people, the atherosclerotic burden in the coronary and carotid arteries increased with increasing degree of dysglycaemia. The finding that the atherosclerotic burden in the coronary arteries in the undetected diabetes category was midway between the prediabetes category and patients with known diabetes may have implications for screening strategies and tailored prevention interventions for people with dysglycaemia in the future.

A regression discontinuity analysis of the social distancing recommendations for older adults in Sweden during COVID-19.

BACKGROUND: This article investigates the impact of a non-mandatory and age-specific social distancing recommendation on isolation behaviours and disease outcomes in Sweden during the first wave of the coronavirus disease 2019 (COVID-19) pandemic (March to July 2020). The policy stated that people aged 70 years or older should avoid crowded places and contact with people outside the household. METHODS: We used a regression discontinuity design-in combination with self-reported isolation data from COVID Symptom Study Sweden (n = 96 053; age range: 39-79 years) and national register data (age range: 39-100+ years) on severe COVID-19 disease (hospitalization or death, n = 21 804) and confirmed cases (n = 48 984)-to estimate the effects of the policy. RESULTS: Our primary analyses showed a sharp drop in the weekly number of visits to crowded places (-13%) and severe COVID-19 cases (-16%) at the 70-year threshold. These results imply that the age-specific recommendations prevented approximately 1800-2700 severe COVID-19 cases, depending on model specification. CONCLUSIONS: It seems that the non-mandatory, age-specific recommendations helped control COVID-19 disease during the first wave of the pandemic in Sweden, as opposed to not implementing a social distancing policy aimed at older adults. Our study provides empirical data on how populations may react to non-mandatory, age-specific social distancing policies in the face of a novel virus.

Fasting glucose, bone area and bone mineral density: a Mendelian randomisation study.

AIMS/HYPOTHESIS: Observational studies indicate that type 2 diabetes mellitus and fasting glucose levels are associated with a greater risk for hip fracture, smaller bone area and higher bone mineral density (BMD). However, these findings may be biased by residual confounding and reverse causation. Mendelian randomisation (MR) utilises genetic variants as instruments for exposures in an attempt to address these biases. Thus, we implemented MR to determine whether fasting glucose levels in individuals without diabetes are causally associated with bone area and BMD at the total hip. METHODS: We selected 35 SNPs strongly associated with fasting glucose (p < 5 × 10-8) in a non-diabetic European-descent population from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 133,010). MR was used to assess the associations of genetically predicted fasting glucose concentrations with total hip bone area and BMD in 4966 men and women without diabetes from the Swedish Mammography Cohort, Prospective Investigation of Vasculature in Uppsala Seniors and Uppsala Longitudinal Study of Adult Men. RESULTS: In a meta-analysis of the three cohorts, a genetically predicted 1 mmol/l increment of fasting glucose was associated with a 2% smaller total hip bone area (-0.67 cm2 [95% CI -1.30, -0.03; p = 0.039]), yet was also associated, albeit without reaching statistical significance, with a 4% higher total hip BMD (0.040 g/cm2 [95% CI -0.00, 0.07; p = 0.060]). CONCLUSIONS/INTERPRETATION: Fasting glucose may be a causal risk factor for smaller bone area at the hip, yet possibly for greater BMD. Further MR studies with larger sample sizes are required to corroborate these findings.

Cancer and Risk of COVID-19 Through a General Community Survey.

Individuals with cancer may be at high risk for coronavirus disease 2019 (COVID-19) and adverse outcomes. However, evidence from large population-based studies examining whether cancer and cancer-related therapy exacerbates the risk of COVID-19 infection is still limited. Data were collected from the COVID Symptom Study smartphone application since March 29 through May 8, 2020. Among 23,266 participants with cancer and 1,784,293 without cancer, we documented 10,404 reports of a positive COVID-19 test. Compared with participants without cancer, those living with cancer had a 60% increased risk of a positive COVID-19 test. Among patients with cancer, current treatment with chemotherapy or immunotherapy was associated with a 2.2-fold increased risk of a positive test. The association between cancer and COVID-19 infection was stronger among participants >65 years and males. Future studies are needed to identify subgroups by tumor types and treatment regimens who are particularly at risk for COVID-19 infection and adverse outcomes.

Sleep duration is associated with protein biomarkers for cardiometabolic health: A large-scale population study.

Sleep problems and short sleep duration have been linked to adverse health effects, such as cardiovascular disease and diabetes, but the mechanisms are not fully understood. Finding biomarkers could explain mechanistic pathways and help in understanding relationships between sleep and cardiometabolic health. The aim was to assess if sleep duration and sleep quality affect the cardiometabolic-related protein profile. In total, 242 proteins related to cardiometabolic health were measured in 2,430 plasma samples (male:female ratio 1:1, aged 45-75 years) from the population-based EpiHealth cohort, using a proximity extension assay. The association of self-reported sleep duration and sleep quality with each of the 242 proteins (primary outcome) was assessed with linear regression modelling, adjusting for confounders, and corrected for multiple testing using the false discovery rate (5%). Potential effect modification of age and sex was also tested using an interaction term. We identified U-shaped associations between sleep duration and the plasma levels of the proteins follistatin (more prominent in younger individuals), matrix metallopeptidase 9 (men only), urokinase receptor, adrenomedullin and kidney injury molecule, all previously known to be related to cardiovascular risk. There was no relationship between sleep quality and any of the proteins, after adjustment for confounders. These results give new leads to investigate the potential mechanistic pathways between sleep and cardiometabolic health.

Global Plasma Metabolomics to Identify Potential Biomarkers of Blood Pressure Progression.

OBJECTIVE: The pathophysiology of hypertension remains incompletely understood. We investigated associations of circulating metabolites with longitudinal blood pressure (BP) changes in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort and validated the findings in the Uppsala Longitudinal Study of Adult Men cohort. Approach and Results: Circulating metabolite levels were assessed with liquid- and gas-chromatography coupled to mass spectrometry among persons without BP-lowering medication at baseline. We studied associations of baseline levels of metabolites with changes in BP levels and the clinical BP stage between baseline and a follow-up examination 5 years later. In the discovery cohort, we investigated 504 individuals that contributed with 757 observations of paired BP measurements. The mean baseline systolic and diastolic BPs were 144 (19.7)/76 (9.7) mm Hg, and change in systolic and diastolic BPs were 3.7 (15.8)/-0.5 (8.6) mm Hg over 5 years. The metabolites associated with diastolic BP change were ceramide, triacylglycerol, total glycerolipids, oleic acid, and cholesterylester. No associations with longitudinal changes in systolic BP or BP stage were observed. Metabolites with similar structures to the 5 top findings in the discovery cohort were investigated in the validation cohort. Diacylglycerol (36:2) and monoacylglycerol (18:0), 2 glycerolipids, were associated with diastolic BP change in the validation cohort. CONCLUSIONS: Circulating baseline levels of ceramide, triacylglycerol, total glycerolipids, and oleic acid were positively associated with longitudinal diastolic BP change, whereas cholesterylester levels were inversely associated with longitudinal diastolic BP change. Two glycerolipids were validated in an independent cohort. These metabolites may point towards pathophysiological pathways of hypertension.

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology.

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Blood pressure phenotypes based on ambulatory monitoring in a general middle-aged population.

BACKGROUND: Ambulatory blood pressure monitoring (ABPM) is increasingly recommended for clinical use, but more knowledge about the prevalence and variability in ABPM-derived phenotypes in the general population is needed. We describe these parameters in the community-based Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort. METHODS: We examined 5881 men and women aged 50-64 with 24-hour ABPM recordings using validated monitors. ABPM phenotypes were defined according to European guidelines. White coat hypertension was defined as elevated office BP (≥140/90 mmHg) with normal mean ambulatory BP (<135/85 mmHg in day-time, <120/70 mmHg in night-time, <130/80 mmHg over 24-h); and masked hypertension as normal office BP (<140/90 mmHg) with elevated mean ambulatory BP (≥135/85 mmHg in day-time, ≥120/70 mmHg in night-time, ≥130/80 mmHg over 24-h). Blood pressure variability was assessed using the coefficient of variation (CV), standard deviation (SD), and average real variability. RESULTS: Based on the ABPM recordings, 36.9% of participants had 24-h hypertension, 40.7% had day-time hypertension, and 37.6% nocturnal hypertension. Among participants treated with anti-hypertensive drugs, one in three had elevated office blood pressures, and more than half had elevated 24-h, day-time or nocturnal blood pressures. Among participants without anti-hypertensive drugs, only one in six had elevated office blood pressures, but one in three had elevated 24-h, day-time or nocturnal blood pressures. Men had higher 24-h blood pressures, more masked hypertension, but less white-coat hypertension than women. The prevalence of white-coat hypertension increased with age, but not the prevalence of masked hypertension. A positive association between blood pressure level and variability was observed, and within-person and between-person SD and CV were of similar magnitude. The variance in ABPM on repeated measurements was substantial. CONCLUSIONS: In the middle-aged general population, masked hypertension is an underappreciated problem on the population level.

Season of birth, childhood asthma and allergy in a nationwide cohort-Mediation through lower respiratory infections.

BACKGROUND: Previous studies have suggested an association between season of birth and risk of childhood asthma and allergic disease. The association may be modified by birth year and region, or mediated by respiratory tract infections. OBJECTIVE: We aimed to estimate the association between season of birth and risk of childhood asthma/wheeze or allergic rhinoconjunctivitis in a population-based setting, and the mediating effect of lower respiratory infections. METHODS: Two population-based cohorts were identified from the nationwide Swedish Medical Birth, Patient and Prescribed Drug Registers. The association between birth month/season and asthma/wheeze incidence was analysed using Cox proportional regression in the younger cohort born 2005-2010 (n = 582 494) and asthma/allergic rhinoconjunctivitis prevalence during the 7th year of life using log-binomial models in the older cohort born 2001-2004 (n = 367 583). Interactions were formally tested. Mediation analyses to address the effect of lower respiratory infections were performed in the older cohort using the R package "medflex." RESULTS: Children born during fall and winter had an increased risk of asthma/wheeze after 2 years of age in the younger cohort: hazard ratio 1.24 (95% confidence interval, CI 1.17, 1.33) for winter and risk of prevalent asthma during their 7th year of life in the older cohort; prevalence ratio (PR) 1.12 (95% CI 1.08, 1.16) for winter. These estimates were partly mediated by lower respiratory infections; the indirect effect for winter compared with summer was PR 1.03 (95% CI 1.03, 1.04). The association was similar for allergic rhinoconjunctivitis in the 7th year of life, but not mediated by respiratory infections. CONCLUSION: We found that the association between season of birth and risk of childhood asthma/wheeze, but not allergic rhinoconjunctivitis, is partly mediated through lower respiratory infections. CLINICAL RELEVANCE: This has important implications for patient care, such as asthma management programmes to notify timing of seasonality for viral respiratory tract infections.

Correction: Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study.

[This corrects the article DOI: 10.1371/journal.pgen.1006379.].

A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke.

BACKGROUND AND PURPOSE: To search for novel pathophysiological pathways related to ischemic stroke using a metabolomics approach. METHODS: We identified 204 metabolites in plasma by liquid chromatography mass spectrometry in 3 independent population-based samples (TwinGene, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) and Uppsala Longitudinal Study of Adult Men). TwinGene was used for discovery and the other 2 samples were meta-analyzed as replication. In PIVUS, traditional cardiovascular (CV) risk factors, multiple markers of subclinical CV disease, markers of coagulation/fibrinolysis were measured and analyzed in relation to top metabolites. RESULTS: In TwinGene (177 incident cases, median follow-up 4.3 years), levels of 28 metabolites were associated with incident ischemic stroke at a false discover rate (FDR) of 5%. In the replication (together 194 incident cases, follow-up 10 and 12 years, respectively), only sphingomyelin (32:1) was significantly associated (HR .69 per SD change, 95% CI .57-0.83, P value = .00014; FDR <5%) when adjusted for systolic blood pressure, diabetes, smoking, low density lipoportein (LDL)- and high density lipoprotein (HDL), body mass index (BMI) and atrial fibrillation. In PIVUS, sphingomyelin (32:1) levels were significantly related to both LDL- and HDL-cholesterol in a positive fashion, and to serum triglycerides, BMI and diabetes in a negative fashion. Furthermore, sphingomyelin (32:1) levels were related to vasodilation in the forearm resistance vessels, and inversely to leukocyte count (P < .0069 and .0026, respectively). CONCLUSIONS: An inverse relationship between sphingomyelin (32:1) and incident ischemic stroke was identified, replicated, and characterized. A possible protective role for sphingomyelins in stroke development has to be further investigated in additional experimental and clinical studies.

In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study.

AIMS/HYPOTHESIS: The pathogenesis of type 2 diabetes is not fully understood. We investigated whether circulating levels of preselected proteins were associated with the outcome 'diabetes' and whether these associations were causal. METHODS: In 2467 individuals of the population-based, cross-sectional EpiHealth study (45-75 years, 50% women), 249 plasma proteins were analysed by the proximity extension assay technique. DNA was genotyped using the Illumina HumanCoreExome-12 v1.0 BeadChip. Diabetes was defined as taking glucose-lowering treatment or having a fasting plasma glucose of ≥7.0 mmol/l. The associations between proteins and diabetes were assessed using logistic regression. To investigate causal relationships between proteins and diabetes, a bidirectional two-sample Mendelian randomisation was performed based on large, genome-wide association studies belonging to the DIAGRAM and MAGIC consortia, and a genome-wide association study in the EpiHealth study. RESULTS: Twenty-six proteins were positively associated with diabetes, including cathepsin D, retinal dehydrogenase 1, α-L-iduronidase, hydroxyacid oxidase 1 and galectin-4 (top five findings). Three proteins, lipoprotein lipase, IGF-binding protein 2 and paraoxonase 3 (PON-3), were inversely associated with diabetes. Fourteen of the proteins are novel discoveries. The Mendelian randomisation study did not disclose any significant causal effects between the proteins and diabetes in either direction that were consistent with the relationships found between the protein levels and diabetes. CONCLUSIONS/INTERPRETATION: The 29 proteins associated with diabetes are involved in several physiological pathways, but given the power of the study no causal link was identified for those proteins tested in Mendelian randomisation. Therefore, the identified proteins are likely to be biomarkers for type 2 diabetes, rather than representing causal pathways.