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Shared genetic influences between blood analyte levels and risk of severe COVID-19.

ABSTRACT: Genome-wide association studies (GWASs) show that genetic factors contribute to the risk of severe coronavirus disease 2019 (COVID-19) and blood analyte levels. Here, we utilize GWAS summary statistics to study the shared genetic influences (pleiotropy) between severe COVID-19 and 344 blood analytes at the genome, gene, and single-nucleotide polymorphism (SNP) levels. Our pleiotropy analyses genetically link blood levels of 71 analytes to severe COVID-19 in at least one of the three levels of investigation-suggesting shared biological mechanisms or causal relationships. Six analytes (alanine aminotransferase, alkaline phosphatase, apolipoprotein B, C-reactive protein, triglycerides, and urate) display evidence of pleiotropy with severe COVID-19 at all three levels. Causality analyses indicate that higher triglycerides levels causally increase the risk of severe COVID-19, thereby providing important support for the use of lipid-lowering drugs such as statins and fibrates to prevent severe COVID-19.

SUBMITTER: Tanha HM

PROVIDER: S-EPMC9637519 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Shared genetic influences between blood analyte levels and risk of severe COVID-19.

Tanha Hamzeh M HM Sathyanarayanan Anita A Mehta Divya D Nyholt Dale R DR

Cell reports 20221107 8

Genome-wide association studies (GWASs) show that genetic factors contribute to the risk of severe coronavirus disease 2019 (COVID-19) and blood analyte levels. Here, we utilize GWAS summary statistics to study the shared genetic influences (pleiotropy) between severe COVID-19 and 344 blood analytes at the genome, gene, and single-nucleotide polymorphism (SNP) levels. Our pleiotropy analyses genetically link blood levels of 71 analytes to severe COVID-19 in at least one of the three levels of in ...[more]

PMID: 36400032

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity.MethodsThe genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10-8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls).FindingsWe detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04-0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92-1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06-1·38], P = 4·24 × 10-3). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73-1·00], P = 2·99 × 10-2) .InterpretationThe strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors.FundingNovo Nordisk Foundation and Oak Foundation.

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Shared genetic influences between blood analyte levels and risk of severe COVID-19.

Publications

Shared genetic influences between blood analyte levels and risk of severe COVID-19.

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