Abstract:Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 11… Show more
“…29 Because of this, for our main exposure, we were limited to using the well understood rs2228145 SNP, which has been widely used for MR in European ancestry populations. 8,12,30 Although in-vitro work has confirmed this variant reduces cell surface expression of IL6R, 16 and large scale transcriptome studies in healthy patients 31 and those with infection 32 have shown this is a splicing variant, the use of a single variant reduces the statistical power of the study. This is compounded by the low minor allele frequency (~10%) in African ancestry populations, reducing the power to identify small associations further.…”
Introduction: Severe malaria remains a deadly disease for many young children in low – and middle–income countries. Levels of Interleukin–6 (IL–6) have been shown to identify cases of severe malaria and associate with severity, but it is unknown if this association is causal, or whether manipulation of IL–6 might alter outcomes in severe malaria. Methods: A single nucleotide polymorphism (SNP, rs2228145) in the IL–6 receptor (IL6R) was chosen as a genetic variant that is known to alter IL–6 signalling. We measured the association between the minor allele of this SNP (C) and C–reactive protein (CRP) levels, a marker of IL–6 signalling in the non–European ancestry population recruited to UK Biobank. We then took this forward as an instrument to perform Mendelian randomisation (MR) in MalariaGEN, a large cohort study of patients with severe malaria at eleven worldwide sites. As a secondary approach, we identified cis protein quantitative trait loci (cis–pQTL) for IL6R itself and other markers of IL–6 signalling in a recently published GWAS of the plasma proteome performed in African Americans. We then performed MR using these instruments in the African MalariaGEN sites (9/11). Analyses were performed at each site, and meta–analysed using inverse variance weighting. Additional analyses were performed for specific sub–phenotypes of severe malaria: cerebral malaria and severe malarial anaemia. Results: The minor allele (C) of rs2228145 was associated with decreased CRP across all tested continental ancestries in UK Biobank. There was no evidence of heterogeneity of effect and a large overall effect (beta -0.11 per standard deviation of normalised CRP per C allele, p = 7.55 x 10-255) In Mendelian randomisation studies using this SNP, we did not identify an effect of decreased IL–6 signalling on severe malaria case status (Odds ratio 1.14, 95% CI 0.56 – 2.34, p = 0.713). Estimates of the association with any severe malaria sub–phenotype were similarly null although there was significant imprecision in all estimates. Using an alternative instrument (cis–pQTLs for IL6R), which included 3 SNPS (including rs2228145), we identified the same null effect, but with greater precision (Odds ratio 1.02, 95% CI 0.95 1.10), and no effect on any severe malaria subtypes. Conclusions: Mendelian randomisation analyses using a SNP in the IL–6 receptor known to alter IL–6 signalling do not support a causal role for IL–6 signalling in the development of severe malaria, or any severe malaria sub–phenotype. This result suggests IL–6 may not be causal for severe outcomes in malaria, and that therapeutic manipulation of IL–6 may not be a suitable treatment for severe malaria.
“…29 Because of this, for our main exposure, we were limited to using the well understood rs2228145 SNP, which has been widely used for MR in European ancestry populations. 8,12,30 Although in-vitro work has confirmed this variant reduces cell surface expression of IL6R, 16 and large scale transcriptome studies in healthy patients 31 and those with infection 32 have shown this is a splicing variant, the use of a single variant reduces the statistical power of the study. This is compounded by the low minor allele frequency (~10%) in African ancestry populations, reducing the power to identify small associations further.…”
Introduction: Severe malaria remains a deadly disease for many young children in low – and middle–income countries. Levels of Interleukin–6 (IL–6) have been shown to identify cases of severe malaria and associate with severity, but it is unknown if this association is causal, or whether manipulation of IL–6 might alter outcomes in severe malaria. Methods: A single nucleotide polymorphism (SNP, rs2228145) in the IL–6 receptor (IL6R) was chosen as a genetic variant that is known to alter IL–6 signalling. We measured the association between the minor allele of this SNP (C) and C–reactive protein (CRP) levels, a marker of IL–6 signalling in the non–European ancestry population recruited to UK Biobank. We then took this forward as an instrument to perform Mendelian randomisation (MR) in MalariaGEN, a large cohort study of patients with severe malaria at eleven worldwide sites. As a secondary approach, we identified cis protein quantitative trait loci (cis–pQTL) for IL6R itself and other markers of IL–6 signalling in a recently published GWAS of the plasma proteome performed in African Americans. We then performed MR using these instruments in the African MalariaGEN sites (9/11). Analyses were performed at each site, and meta–analysed using inverse variance weighting. Additional analyses were performed for specific sub–phenotypes of severe malaria: cerebral malaria and severe malarial anaemia. Results: The minor allele (C) of rs2228145 was associated with decreased CRP across all tested continental ancestries in UK Biobank. There was no evidence of heterogeneity of effect and a large overall effect (beta -0.11 per standard deviation of normalised CRP per C allele, p = 7.55 x 10-255) In Mendelian randomisation studies using this SNP, we did not identify an effect of decreased IL–6 signalling on severe malaria case status (Odds ratio 1.14, 95% CI 0.56 – 2.34, p = 0.713). Estimates of the association with any severe malaria sub–phenotype were similarly null although there was significant imprecision in all estimates. Using an alternative instrument (cis–pQTLs for IL6R), which included 3 SNPS (including rs2228145), we identified the same null effect, but with greater precision (Odds ratio 1.02, 95% CI 0.95 1.10), and no effect on any severe malaria subtypes. Conclusions: Mendelian randomisation analyses using a SNP in the IL–6 receptor known to alter IL–6 signalling do not support a causal role for IL–6 signalling in the development of severe malaria, or any severe malaria sub–phenotype. This result suggests IL–6 may not be causal for severe outcomes in malaria, and that therapeutic manipulation of IL–6 may not be a suitable treatment for severe malaria.
“…Because of this, for our main exposure, we were limited to using the well-understood rs2228145 SNP, which has been widely used for MR in European ancestry populations [11 , 15 , 34] . Although in vitro work has confirmed that this variant reduces cell surface expression of IL6R [14] and large-scale transcriptome studies in healthy patients [35] and those with infection [36] have shown this is a splicing variant, the use of a single variant reduces the statistical power of the study. This is compounded by the low minor allele frequency (∼10%) in AFR populations, reducing the power to identify small associations further.…”
“…Next, we integrated our scRNA-seq data with polygenic signals from the largest COVID-19 GWAS 2 using a single-cell disease-relevance score (scDRS) 4 to evaluate the contribution of genome-wide host genetics to risk of COVID-19 and identify subpopulations of disease-associated PBMCs. Finally, to understand how transcriptional dynamics are regulated by COVID-19-associated variants, we examined single-cell expression quantitative trait loci (eQTL) effects of the COVID-19 risk variants that were replicated in a GWAS of a Japanese population 3 , 5 . Fig.…”
Section: The Discoverymentioning
confidence: 99%
“…In early 2020, the Japan COVID-19 Task Force was established as a nationwide multi-center consortium and conducted a COVID-19 GWAS and eQTL analysis in the Japanese population 3 , 5 . In parallel, we conducted PBMC scRNA-seq analysis of Japanese patients with COVID-19 and healthy controls, supported by the Team Osaka University Research Project and the Nippon Foundation.…”
Single-cell RNA-sequencing analysis combined with host genetic data for a Japanese population reveals the dysfunction of innate immune cells, particularly non-classical monocytes, in individuals with severe COVID-19, as well as enrichment of host genetic risk factors for severe COVID-19 in monocytes and dendritic cells.
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