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

Abstract

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 on 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 the 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) and a striking agreement was observed between the reported Standardized Mortality Ratios and the frequency of the combined haplotype of both reference alleles, suggesting that the combination of the 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.

Human genetic basis of coronavirus disease 2019

“… 144 Rs34481144 A-allele (38–56% in Europeans, 2–14% in Africans, and 1–2% in Chinese) might increase COVID-19 susceptibility by triggering methylation of the IFITM3 promoter to decrease IFITM3 mRNA expression in CD8 + T cells and depressing surrounding gene transcription. 145 , 146 …”

Lessons in self-defence: inhibition of virus entry by intrinsic immunity

“…Among those that are endowed with antiviral activity, IFITM3 is the best characterized because it exhibits the most potent restriction of important viral pathogens such as IAV and ZIKV 26 , 33 , 47 . Furthermore, single-nucleotide polymorphisms in human IFITM3 have been associated with severe outcomes following infection by IAV 48 , 49 and SARS-CoV-2 (refs 50 , 51 ). Mice encode IFITM proteins as well, and in addition to the five found in humans, they also possess IFITM6 and IFITM7.…”

The Interferon-Induced Transmembrane Protein 3 -rs12252 Allele May Predict COVID-19 Severity Among Ethnic Minorities

“…Another allele of the IFITM3 rs34481144 has been associated with severity of influenza. A significant correlation was observed between the mortality rate with COVID-19 for ethnic groups in Britain and the combined frequency of IFITM3 alleles rs12252 and rs34481144 in these ethnic groups, suggesting that these alleles may be associated with more severe outcomes (Nikoloudis et al, 2020 ). The IFITM3-rs12252 variant was also associated with hospitalization and mortality in a study of 880 patients from Saudi Arabia, and they had a lower level of Interferon Gamma (Alghamdi et al, 2021 ).…”