| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
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| 4. |
- Butler-Laporte, G, et al.
(författare)
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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
- 2022
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 18:11, s. e1010367-
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Tidskriftsartikel (refereegranskat)abstract
- Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
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| 5. |
- Cruz, Raquel, et al.
(författare)
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Novel genes and sex differences in COVID-19 severity
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
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Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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| 7. |
- Frithiof, R, et al.
(författare)
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Hypothalamic paraventricular nucleus mediates sodium-induced changes in cardiovascular and renal function in conscious sheep
- 2009
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Ingår i: American journal of physiology. Regulatory, integrative and comparative physiology. - : American Physiological Society. - 1522-1490 .- 0363-6119. ; 297:1, s. R185-R193
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of the paraventricular nucleus of the hypothalamus (PVN) in mediating cardiovascular, renal, hormonal, and sympathetic nerve responses to increased cerebrospinal fluid (CSF) [Na+] was investigated in conscious sheep. Intracerebroventricular hypertonic NaCl (0.5 mol/l, 20 μl/min for 60 min) increased arterial blood pressure [AP; +13.4 (sd 2.0) mmHg, P < 0.001] and central venous pressure [CVP; +2.8 (sd 1.3) mmHg, P < 0.001], but did not significantly change heart rate or cardiac output ( n = 6). Elevated CSF [Na+] also lowered plasma ANG II levels [−3.3 (sd 1.6) pmol/l, P = 0.004] and increased creatinine clearance [+31.5 (sd 32.7) ml/min, P = 0.03] and renal sodium excretion [+9.2 (sd 9.2) mmol/h, P = 0.003]. Lidocaine injection (1 μl, 2%) into the PVN prior to the ICV infusion had no apparent effect per se, but it abolished the AP, CVP, creatinine clearance, and ANG II responses to hypertonic NaCl, as well as reducing the increase in renal sodium excretion ( n = 6). Subsequent studies were performed in conscious sheep with chronically implanted electrodes for measurement of renal sympathetic nerve activity (RSNA). The effects of ICV hypertonic NaCl on AP and RSNA were measured before and after PVN-injection of glycine (250 nmol in 500 nl artificial CSF). ICV NaCl increased AP and decreased RSNA ( P < 0.001). These effects were significantly reduced by glycine ( P = 0.02–0.001, n = 5). Saline injected into the PVN ( n = 5) or lidocaine injected outside the PVN ( n = 6) had no effect on the response to ICV hypertonic NaCl. These results indicate that the PVN is an important mediator of cerebrally induced homeostatic responses to elevated sodium concentration/hyperosmolality.
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| 8. |
- Nakanishi, T, et al.
(författare)
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Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundThere is considerable variability in COVID-19 outcomes amongst younger adults—and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium.MethodThe major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors.FindingsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2–1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3–1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors.InterpretationThe major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality—and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management.FundingFunding was obtained by each of the participating cohorts individually.
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