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- Klaric, Lucija, et al.
(author)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Other publication (other academic/artistic)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 2. |
- Ekblom Bak, Elin, 1981-, et al.
(author)
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Accelerometer derived physical activity and subclinical coronary and carotid atherosclerosis : cross-sectional analyses in 22 703 middle-aged men and women in the SCAPIS study
- 2023
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In: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 13:11
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Journal article (peer-reviewed)abstract
- OBJECTIVES: The aim included investigation of the associations between sedentary (SED), low-intensity physical activity (LIPA), moderate-to-vigorous intensity PA (MVPA) and the prevalence of subclinical atherosclerosis in both coronaries and carotids and the estimated difference in prevalence by theoretical reallocation of time in different PA behaviours.DESIGN: Cross-sectional.SETTING: Multisite study at university hospitals.PARTICIPANTS: A total of 22 670 participants without cardiovascular disease (51% women, 57.4 years, SD 4.3) from the population-based Swedish CArdioPulmonary bioImage study were included. SED, LIPA and MVPA were assessed by hip-worn accelerometer.PRIMARY AND SECONDARY OUTCOMES: Any and significant subclinical coronary atherosclerosis (CA), Coronary Artery Calcium Score (CACS) and carotid atherosclerosis (CarA) were derived from imaging data from coronary CT angiography and carotid ultrasound.RESULTS: High daily SED (>70% ≈10.5 hours/day) associated with a higher OR 1.44 (95% CI 1.09 to 1.91), for significant CA, and with lower OR 0.77 (95% CI 0.63 to 0.95), for significant CarA. High LIPA (>55% ≈8 hours/day) associated with lower OR for significant CA 0.70 (95% CI 0.51 to 0.96), and CACS, 0.71 (95% CI 0.51 to 0.97), but with higher OR for CarA 1.41 (95% CI 1.12 to 1.76). MVPA above reference level, >2% ≈20 min/day, associated with lower OR for significant CA (OR range 0.61-0.67), CACS (OR range 0.71-0.75) and CarA (OR range 0.72-0.79). Theoretical replacement of 30 min of SED into an equal amount of MVPA associated with lower OR for significant CA, especially in participants with high SED 0.84 (95% CI 0.76 to 0.96) or low MVPA 0.51 (0.36 to 0.73).CONCLUSIONS: MVPA was associated with a lower risk for significant atherosclerosis in both coronaries and carotids, while the association varied in strength and direction for SED and LIPA, respectively. If causal, clinical implications include avoiding high levels of daily SED and low levels of MVPA to reduce the risk of developing significant subclinical atherosclerosis.
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