Fatigue persists as a dominant and debilitating phenomenon in long-COVID, yet its underlying biological mechanisms remain unclear. While inflammatory variables tend to normalize within months post-inf Show more
Fatigue persists as a dominant and debilitating phenomenon in long-COVID, yet its underlying biological mechanisms remain unclear. While inflammatory variables tend to normalize within months post-infection, fatigue continues to significantly impact quality of life. Understanding whether specific biomarkers associate with long-COVID fatigue could shed light on pathophysiological mechanisms and potential therapeutic targets. In this single-center, cross-sectional controlled study, we enrolled 48 individuals with long-COVID (according to NICE criteria) and 48 age- and sex-matched recovered controls with prior SARS-CoV-2 infection but no persistent symptoms. We carefully excluded all subjects with other diseases or conditions that could influence fatigue levels. Fatigue severity was assessed using three validated instruments: Fatigue Visual Analog Scale (fVAS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and SF-36 vitality subscale. Blood samples were analyzed for pro-inflammatory markers (CRP, TNF-α, IL-6, IL-1β) and biomarkers associated with cellular stress responses and neuroprotection (HSP90α, APOA4, Serpin F1/PEDF, Hemopexin). Anti-nuclear antibodies (ANA) were tested to assess potential autoimmune mechanisms. Depression was assessed using the Hospital Anxiety and Depression Scale, Depression Subscale (HADS-D). Long-COVID patients demonstrated significantly higher fatigue severity across all instruments compared to recovered controls: fVAS median scores 63 versus 5 (p < 0.001), FACIT-F scores 21.5 versus 49 (p < 0.001), and SF-36 vitality scores 25 versus 72.5 (p < 0.001). Depression scores were also significantly elevated in long-COVID cases. However, none of the measured biomarkers differed significantly between groups: HSP90α, Serpin F1, Hemopexin, APOA4, and CRP showed no differences, while TNF-α and IL-6 showed only tendencies toward higher levels in long-COVID (p = 0.07 and p = 0.07, respectively). IL-1β concentrations were in most cases below the lower limit of detection and were excluded from further analysis. ANA positivity was 10.4% in cases versus 4.2% in controls (p = 0.38) and did not influence fatigue levels. Multivariable regression analysis revealed no significant associations between biomarkers and fatigue severity. Fatigue in long-COVID represents severe, persistent disability comparable to observations in chronic inflammatory diseases and chronic fatigue syndrome but is not associated with traditional inflammatory biomarkers or cellular stress response proteins measured in peripheral blood. The absence of biomarker associations suggests that long-COVID fatigue may involve more complex mechanisms, potentially including persistent neuro-immune dysregulation, epigenetic changes, or pathophysiological processes not reflected in systemic biomarker concentrations including neurobiological mechanisms such as altered predictive processing and central nervous system-confined neuroinflammation. These findings highlight the need for alternative approaches to understanding and treating long-COVID fatigue beyond conventional inflammatory paradigms. Show less
The complexity of obesity and onset and susceptibility of cardio-metabolic disorders are still poorly understood and is addressed here through studies of genetic influence on weight gain and increased Show more
The complexity of obesity and onset and susceptibility of cardio-metabolic disorders are still poorly understood and is addressed here through studies of genetic influence on weight gain and increased metabolic risk longitudinally. Twenty seven previously identified obesity, eating disorder or metabolic risk susceptibility SNPs were tested for association with weight or metabolically related traits longitudinally in 3999 adults participating both in the HUNT2 (1995-97) and HUNT3 (2006-08) surveys. Regression analyses were performed with changes from normal weight to overweight/obesity or from metabolically healthy to adverse developments with regards to blood pressure, glucose, HDL cholesterol, triglycerides or metabolic syndrome as outcomes. Additionally, a sub-sample of 1380 adolescents was included for testing association of nine SNPs with longitudinal weight gain into young adulthood. The most substantial effect on BMI-based weight gain from normal to overweight/obesity in adults was observed for the DRD2 variant (rs6277)(OR: 0.79, 95% CI: 0.69-0.90, P = 3.9x10(-4), adj. P = 0.015). DRD2 was not associated with BMI on a cross-sectional level. In the adolescent sample, FTO (rs1121980) was associated with change to overweight at adulthood in the combined male-female sample (OR: 1.27, 95% CI: 1.09-1.49, P = 3.0x10(-3), adj. P = 0.019) and in females (OR: 1.53, 95% CI: 1.23-1.91, P = 1.8x10(-4), adj. P = 0.003). When testing for association to longitudinal adverse developments with regard to blood pressure, blood lipids and glucose, only rs964184 (ZNF259/APOA5) was significantly associated to unfavourable triglyceride changes (OR: 1.66, 95% CI: 1.36-2.03, P = 5.7x10(-7), adj. P = 0.001). Pleiotropic effects on metabolic traits, however, were observed for several genetic loci cross-sectionally, ZNF259/APOA5, LPL and GRB14 being the most important. DRD2 exhibits effects on weight gain from normal weight to overweight/obesity in adults, while, FTO is associated to weight gain from adolescence to young adulthood. Unhealthy longitudinal triglyceride development is strongly affected by ZNF259/APOA. Our main finding, linking the DRD2 variant directly to the longitudinal weight gain observed, has not previously been identified. It suggests a genetic pre-disposition involving the dopaminergic signalling pathways known to play a role in food reward and satiety linked mechanisms. Show less
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between bod Show more
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation. Show less