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- Klaric, Lucija, et al.
(författare)
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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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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)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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- Sundström, Johan, Professor, 1971-, et al.
(författare)
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Risk factors for subarachnoid haemorrhage : a nationwide cohort of 950 000 adults
- 2019
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 48:6, s. 2018-2025
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium.METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries.RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH.CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.
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- Abelson, Anna-Karin, et al.
(författare)
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STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
- 2009
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 68:11, s. 1746-1753
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.
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- Abrahamsson, Niclas, 1976-, et al.
(författare)
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Gastric bypass reduces symptoms and hormonal responses to hypoglycemia
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:9, s. 2667-2675
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Tidskriftsartikel (refereegranskat)abstract
- Gastric bypass (GBP) surgery, one of the most common bariatric procedures, induces weight loss and metabolic effects. The mechanisms are not fully understood, but reduced food intake and effects on gastrointestinal hormones are thought to contribute. We recently observed that GBP patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes. Here, we subjected patients before and after undergoing GBP surgery to hypoglycemia and examined symptoms and hormonal and autonomic nerve responses. Twelve obese patients without diabetes (8 women, mean age 43.1 years [SD 10.8] and BMI 40.6 kg/m(2) [SD 3.1]) were examined before and 23 weeks (range 19-25) after GBP surgery with hyperinsulinemic-hypoglycemic clamp (stepwise to plasma glucose 2.7 mmol/L). The mean change in Edinburgh Hypoglycemia Score during clamp was attenuated from 10.7 (6.4) before surgery to 5.2 (4.9) after surgery. There were also marked postsurgery reductions in levels of glucagon, cortisol, and catecholamine and the sympathetic nerve responses to hypoglycemia. In addition, growth hormone displayed a delayed response but to a higher peak level. Levels of glucagon-like peptide 1 and gastric inhibitory polypeptide rose during hypoglycemia but rose less postsurgery compared with presurgery. Thus, GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia. Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery.
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- Abrahamsson, Niclas, 1976-
(författare)
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On the Impact of Bariatric Surgery on Glucose Homeostasis
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity has grown to epidemic proportions, and in lack of efficient life-style and medical treatments, the bariatric surgeries are performed in rising numbers. The most common surgery is the Gastric Bypass (GBP) surgery, with the Biliopancreatic diversion with duodenal switch (DS) as an option for the most extreme cases with a BMI>50 kg/m2.In paper I 20 GBP-patients were examined during the first post-operative year regarding the natriuretic peptide, NT-ProBNP, which is secreted from the cardiac ventricles. Levels of NT-ProBNP quickly increased during the first post-surgery week, and later established itself on a higher level than pre-surgery.In paper II we report of 5 patient-cases after GBP-surgery with severe problems with postprandial hypoglycaemia that were successfully treated with GLP-1-analogs. The effect of treatment could be observed both symptomatically and in some cases using continuous glucose measuring systems (CGMS).In paper III three groups of subjects; 15 post-GBP patients, 15 post-DS, and 15 obese controls were examined for three days using CGMS during everyday life. The post-GBP group had high glucose variability as measured by MAGE and CONGA, whereas the post-DS group had low variability. Both post-operative groups exhibited significant time in hypoglycaemia, about 40 and 80 minutes per day <3.3mmol/l and 20 and 40 minutes < 2.8mmol/l, respectively, longer time for DS-group. Remarkably, only about 20% of these hypoglycaemic episodes were accompanied with symptoms.In Paper IV the hypoglycaemia counter regulatory system was investigated; 12 patients were examined before and after GBP-surgery with a stepped hypoglycaemic hyperinsulinemic clamp. The results show a downregulation of symptoms, counter regulatory hormones (glucagon, cortisol, epinephrine, norepinephrine, growth hormone), incretin hormones (GLP-1 and GIP), and sympathetic nervous response.In conclusion patients post bariatric surgery exhibit a downregulated counter regulatory response to hypoglycaemia, accompanied by frequent asymptomatic hypoglycaemic episodes in everyday life. Patients suffering from severe hypoglycaemic episodes can often be treated successfully with GLP-1-analogues.
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