Erik Melén

BackgroundThere is limited evidence from multi-exposure models on the environmental impact on type 2 diabetes (T2D), considering complex interrelations between the exposures. We aimed to identify air pollution, temperature and greenness features associated with T2D prevalence in a large pan-European study, specifically predicting the impact of exposure change under different scenarios.MethodsWe included 10 European population-based cohorts within the EXPANSE project. Information on environmental exposures, covariates and T2D diagnosis at recruitment were obtained for 87,044 individuals, including 5,662 T2D cases. Data on air pollution, greenness, and temperature at residential addresses originated from uniform pan-European models. T2D identification was based on questionnaires, registers or biomarker measurements. Adjusted cross-sectional associations between exposures and T2D were assessed, and all exposure two-way interactions and square terms were a priori included in elastic net regression models to identify the most influential environmental factors and combinations. Results were contextualized within different environmental scenarios.ResultsPM10 and temperature annual mean and variability, as well as their interaction term, were consistently associated with T2D prevalence across strata of sex, body mass index, and urbanicity. Associations with greenness, PM2.5 and PM2.5-average temperature interaction were also observed but less consistently across strata. In the scenario analysis, reducing air pollution was related to lower T2D prevalence, while a beneficial association with increasing greenness was most consistently observed in the highly urbanized subgroup.ConclusionsOur findings support a role of particulate air pollution in T2D development and suggest that beneficial effects of increased greenness primarily occur in highly urbanized areas.

Background: Lung function (LF) development from adolescence to adulthood varies widely. Two related but distinct phenomena are relevant: pronounced growth (large positive change in FEV ₁ z-score) and classical catch-up (crossing the lower limit of normal). We aimed to quantify both. Methods: We used data from 2169 participants in the HUNT Study with spirometry measured between 13 and 42 years. Change in FEV ₁ z-score between baseline and follow-up was categorized into five FEV ₁ change groups: pronounced increase, moderate increase, unchanged, moderate decline and pronounced decline. A catch-up group (z≤−1.645 to >−1.645) was also identified. Results: Of 82 individuals (3.8%) with pronounced LF increase from adolescence to adulthood, only 39 (48%) met the classical catch-up definition. Conversely, 48 of 87 (55%) individuals classified as catch-up did not show pronounced increase. Both groups shared a similar phenotype (female-predominant, low baseline BMI, and favorable adult metabolic profiles), but differed in adult LF: pronounced increase reached above-average FEV ₁ (z=+0.65), while classical catch-up reached only partial normalization (z=−0.55). In contrast, the pronounced decline group had the highest BMI, C-reactive protein (CRP), and burden of chronic symptoms. Baseline characteristics differed between change groups, though individual distributions overlapped substantially. Conclusion: Pronounced LF growth and classical catch-up identify overlapping but distinct individuals with similar phenotypes yet different degrees of adult lung-function normalization. A substantial proportion of the most favorable lung-function gains originate from apparently normal baselines and are not detected by a binary catch-up definition.

Background: The long‐term prognosis of childhood asthma remains uncertain. We aimed to (1) assess the prevalence of asthma remission from childhood to young adulthood, (2) identify associated factors, and (3) evaluate whether symptom‐based remission was related to objective markers of inflammation and lung function. Materials and Methods: We analyzed data from 2698 participants in the Swedish population‐based BAMSE birth cohort, followed up to age 24 years with questionnaires and clinical examinations. Symptom‐based remission was defined as absence of asthma symptoms and medication in the preceding year. Clinical remission also required no hospital visits and optimization of lung function (postbronchodilator forced expiratory volume in 1 s ≥ 80%). Complete remission required normal eosinophil counts (< 0.3 × 10 ⁹ /L) and fractional exhaled nitric oxide levels (< 40 ppb). Results: Among 257 participants with asthma at age 8 years, 39% achieved symptom‐based remission, 29% clinical remission, and 18% complete remission at age 24 years. Male sex increased the likelihood of symptom‐based remission (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.3–4.5), whereas food sensitization (OR 0.3, 95% CI 0.3–0.6) and overweight/obesity (OR 0.4, 95% CI 0.2–0.9) decreased it. Among individuals in symptom‐based remission, 27% displayed abnormal results in at least one objective marker. Conclusions: Four of 10 participants with asthma in childhood achieved symptom‐based remission by young adulthood, but rates declined when stricter, objective definitions were applied. A substantial subset of individuals with symptom‐based remission still showed signs of type two inflammation or reduced lung function, indicating that absence of symptoms does not necessarily reflect complete disease resolution.

Background: In birth-cohort studies, response rates generally decline over time. We aimed to evaluate representativeness and identify predictors of retention up to young adulthood in a population-based birth cohort originally focused on asthma and allergies. Methods: The Barn/Child, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) birth cohort was established in 1994–6 in Stockholm, Sweden. We utilized data from questionnaires and Swedish registers to compare the characteristics of participants at age 24 years (n = 3064) with those of the original cohort (n = 4089) and the general population born in 1994–6 in Stockholm county (n = 68 378) and Sweden (n = 310 976). Logistic regression was used to identify predictors of retention at age 24 years. Results: The response rate declined over time and was higher in females than in males in adolescence and young adulthood (80.0% versus 70.0% at age 24 years). Compared with the original cohort, participants at age 24 years more often had dispensed asthma medications (6.6% versus 5.8%) and university education (52.6% versus 47.8%), but had less often a mother who smoked during pregnancy (9.6% versus 10.8%). Similar patterns were observed in comparisons with the general population. Female sex [odds ratio (OR) 1.75, 95% confidence interval (CI) 1.49–2.05] and high parental education (OR 1.33, 95% CI 1.12–1.59) were the predominant predictors of retention in the cohort. Conclusion: Female sex, higher socio-economic status, and asthma were predictive factors of retention in the cohort after 24 years. This may have influenced the observed prevalence rates of asthma and allergies, and associations between potential risk factors and outcomes associated with retention.

Background: Cytotoxic type 2 T cells (Tc2) are increasingly recognized as contributors to type 2 inflammation, including asthma, yet the metabolic programs that support their function remain poorly defined. We aimed to define the metabolic requirements of Tc2 cells, identify pathways that regulate their effector function, and assess whether serotonin‐modifying therapies are associated with altered Tc2 responses and allergic sensitization in humans. Methods: Tc2 cells from human peripheral blood and lung tissue were analyzed using Seahorse metabolic assays, Mitotracker staining, flow cytometry, and RNA sequencing. Effector functions were evaluated following inhibition of glycolysis, fatty acid metabolism, and monoamine oxidase A (MAOA) inhibition. In parallel, anti‐depressant prescription data were analyzed in the population‐based BAMSE cohort to assess associations with allergic sensitization. Peripheral blood mononuclear cells from individuals prescribed selective serotonin reuptake inhibitors (SSRIs) and matched controls were stimulated ex vivo to assess cytokine production. Results: Tc2 cells exhibited a distinct metabolic profile characterized by increased mitochondrial respiration, glycolytic activity, and elevated expression of GLUT1 and CD36. Type 2 cytokine production (IL‐4, IL‐5, IL‐13) was enhanced by alarmins and significantly reduced following inhibition of glycolysis, fatty acid metabolism, or PPARγ activity. RNA sequencing identified high MAOA expression in Tc2 cells, and pharmacological inhibition of MAOA selectively reduced type 2 cytokine production without affecting IFN‐γ. In the BAMSE cohort, dispensing of prescribed anti‐depressive drugs was associated with reduced IgE sensitization. Consistent with these findings, individuals prescribed SSRIs exhibited reduced IL‐5 ⁺ and IL‐13 ⁺ expressing Tc2 cells and increased IFN‐γ–producing Tc2 cells following ex vivo stimulation. Conclusion: Tc2 cells rely on coordinated lipid metabolism and serotonin catabolism to sustain type 2 cytokine production. Serotonin‐modifying therapies were associated with reduced allergic sensitization and altered Tc2 function in humans, consistent with a link between serotonin signaling and type 2 immunity.

Proteomic research enhances our understanding of health- and disease-related biological processes. Protein profiling during healthy childhood provides important insights into normal physiological development. We longitudinally measured 5416 plasma proteins at four follow-ups during childhood (4-, 8-, 16 years) and early adulthood (24 years) in 100 randomly selected subjects participating in a population-based Swedish cohort, using Olink Explore HT. In total, 3509 proteins were included in the analysis. 54% of the proteins were found to be associated with age, and we observed several protein trajectories from childhood to adulthood based on clustering. In addition to proteins involved in bone, teeth and cartilage formation, we identified differences in proteins involved in neural function, drug metabolism, and hormonal control. There were pronounced sex-related differences in protein levels, particularly at follow-ups 16 and 24, characterized by, for example, growth, response to stimuli and regulation of catabolic processes. We demonstrate dynamic age- and sex-related changes in protein levels during the first two decades of life. Our study results may serve as an important resource in understanding human physiological development, disease etiology, and for future protein biomarker research.

Background: As preterm birth is a risk factor for developing chronic lung disease later in life and has been associated with asthma-like symptoms, we hypothesised that preterm-born adults with and without a history of bronchopulmonary dysplasia (BPD) resemble patients with asthma with respect to altered mucin expression in the airways. Methods: Bronchial biopsies were retrieved from 39 adults born very-to-extremely preterm (of which 22 had a history of BPD), 18 adults with mild allergic asthma and 24 healthy controls. Mucin (MUC) 5AC and MUC5B protein expressions were determined by immunohistochemistry and immunoelectron microscopy. Additionally, the percentage of goblet cells was estimated. Results: MUC5AC expression and the percentage of goblet cells were lower in preterm-born adults than in asthma patients but did not markedly differ from those of healthy controls. In the preterm-born adults, MUC5AC expression correlated negatively with forced expiratory volume in 1 s to forced vital capacity ratio (FEV ₁ /FVC) and positively with St George's Respiratory Questionnaire scores. Preterm-born adults with high MUC5AC expression had more bronchial hyperreactivity than those with low expression. MUC5B expression was lower in preterm-born adults with bronchial hyperreactivity and higher in those who reported having phlegm compared with those who did not have these signs. Conclusions: Unlike patients with asthma, preterm-born adults with or without BPD do not exhibit increased MUC5AC expression compared with healthy controls. However, the associations of MUC5AC and MUC5B expression with lung function, symptoms and quality-of-life indices suggest a potential clinical role for these mucins in this population.

Population-based studies of circulating blood proteins have provided profound insights into human biology. However, short-lived changes often remained undetected. To address this, we performed a comprehensive longitudinal dried blood spot (DBS) self-sampling study in 808 young adults of the BAMSE cohort during 2020-2022. We profiled serological, autoimmune, and proteomic phenotypes in relation to SARS-CoV-2 exposures (infection, vaccination), physiological traits, genetic variation, and blood counts. Data-driven seroclustering revealed dynamic immune response to both exposures, while analysis of anti-interferon autoantibodies (AAbs) uncovered associations of pre-existing stable AAbs with prolonged COVID-19 symptoms. Genome-wide mapping determined 664 pQTLs, with cis-pQTLs associated showing increased longitudinal stability. We also identified relationships between blood cell counts and DBS proteins beyond the hematocrit effects. Paired pre- and post-exposure highlighted transient alterations for infection (e.g. LAP3) and vaccinations (e.g. TIMP3). Multi-molecular phenotyping in self-sampling can capture dynamic immune trajectories, informing precision medicine efforts with clinically valuable insights on short-term variability in health phenotypes.