Preprint Article Version 2 Preserved in Portico This version is not peer-reviewed

The Frequency of Combined IFITM3 Haplotype Involving the Reference Alleles of Both rs12252 and rs34481144 is in Line with COVID-19 Standardized Mortality Ratio of Ethnic Groups in England

Version 1 : Received: 15 May 2020 / Approved: 16 May 2020 / Online: 16 May 2020 (17:38:28 CEST)
Version 2 : Received: 14 August 2020 / Approved: 20 August 2020 / Online: 20 August 2020 (04:29:43 CEST)

A peer-reviewed article of this Preprint also exists.

Journal reference: PeerJ 2020
DOI: 10.7717/peerj.10402


Evidence was brought forward in England and the USA that Black, Asian, Latino and Minority Ethnic people exhibit higher mortality risk from COVID-19 than White people. While socioeconomic factors were suggested to contribute to this trend, they arguably do not explain the range of the differences observed, allowing for possible genetic implications. Almost concurrently, the analysis of a cohort in Chinese COVID-19 patients proposed an association between the severity of the disease and the presence of the minor allele of rs12252 of the Interferon-induced transmembrane protein 3 (IFITM3) gene. This SNP, together with rs34481144, are the two most studied polymorphisms of IFITM3 and have been associated in the past with increased severity in Influenza, Dengue, Ebola, and HIV viruses. IFITM3 is an immune effector protein that is pivotal for the restriction of viral replication, but also for the regulation of cytokine production. Following up to these two developments in the ongoing SARS-CoV-2 pandemic, the present study investigates a possible association between the differences in mortality of ethnic groups in England and the combined haplotypes of rs12252 and rs34481144. The respective allele frequencies were collected for 26 populations from 1000 Genomes Project and subgroups were pooled wherever possible to create correspondences with ethnic groups in England. A significant correlation (r=0.9687, p= 0.0003) was observed between the reported Standardized Mortality Ratios and the frequency of the combined haplotype of both reference alleles, suggesting that the combination of reference alleles of the specific SNPs may be implicated in more severe outcomes of COVID-19. This study calls for further focus on the role of IFITM3 variants in the mechanism of cellular invasion of SARS-CoV-2, their impact in COVID-19 severity and their possible implications in vaccination efficacy.

Supplementary and Associated Material The '1000 Genomes Project' haplotype frequencies per ethnic population were extracted from LDhap tool.


COVID-19; SARS-CoV-2; pandemic; IFITM3; rs12252; rs34481144; ethnic groups; bame; cytokine storm


LIFE SCIENCES, Molecular Biology

Comments (1)

Comment 1
Received: 20 August 2020
Commenter: Dimitris Nikoloudis
Commenter's Conflict of Interests: Author
Comment: Made many changes in the content and form of the manuscript, (a) to include all the newly published pieces of related research in our discussion, and (b) to address feedback received by peers. The main conclusions remain unchanged, but they are now more clear and better supported by recent findings. 

This study leverages genetic data from various ethnic groups from 1000 Genomes Project in order to suggest a potentially crucial role of IFITM3 protein variants in COVID-19 severity. 
Our sole incentive is to help improve the existing and future treatment protocols for severe COVID-19 patients, and in no case to provide anyone with DNA-based arguments that may be used to mask existing social inequalities or racism.
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