key: cord-0867070-onvutowm authors: Panda, Aditya K.; Padhi, Archana; Prusty, B. Anjan Kumar title: CCR5 Δ32 minorallele is associated with susceptibility to SARS-CoV-2 infection and death: An epidemiological investigation date: 2020-07-10 journal: Clin Chim Acta DOI: 10.1016/j.cca.2020.07.012 sha: 20566d87a38faecb36be05390d579a85d7142013 doc_id: 867070 cord_uid: onvutowm nan To the Editor, The coronavirus disease , which has created the recent pandemic, caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread over to 227 countries globally. This virus has taken a heavy toll on human beings, as on date (3 rd July, 2020), an estimated 11.03 million people are infected and about 0.52 million have died from COVID-19. The infection and mortality rate in different countries are seemingly different. The genetic makeup of the subject might be playing a role in susceptibility to COVID-19 disease or poor prognosis. Recently, Delanghe et al. [1] highlighted the association of angiotensin-converting enzyme 1 (ACE-1) genetic variant with susceptibility to SARS-CoV-2 infection and related mortality in some of the European countries. Thus, the role of biochemical receptors in inducing susceptibility to SARS-CoV-2 infection and death cannot be ruled out. C-C chemokine receptor 5 (CCR5) is an essential member of the G proteincoupled receptor family abundantly present on the surface of monocytes, T cell, and macrophages. CCR5 is known to be responsible for the induction of inflammation to a wide range of infectious diseases and recruit leukocytes towards inflammation sites [2] . The critical role of CCR5 has been elegantly described in a wide range of viral infections: Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) and Hepatitis B Virus (HBV), West Nile Virus (WNV), Tick-Borne Encephalitis Virus (TBEV) [2] . Differential surface expression of CCR5has been linked with susceptibility/resistance against viral diseases. CCR5 gene is located at the short arm (p.21) of chromosome 3. A common 32bp deletion variant at the coding region leads to the creation of a premature stop codon and produce 215 amino acids length instead of a full length of 352 amino acids. CCR5 Δ32 variant produces truncated protein and significantly diminished surface expression of the receptor [3] . The polymorphism has been reported worldwide (https://www.ncbi.nlm.nih.gov/snp/rs333#frequency_tab, accessed on 29 th June 2020). As the CCR5 plays an essential role in the pathogenesis of various viral infections and the Δ32 variants regulate the surface expression, we attempted to address a preliminary question, i.e. "Is the differential infection and mortality rate with COVID-19 worldwide correlated with the distribution of CCR5 Δ32 mutant?". Accordingly, data of COVID-19 disease and mortality rate per million of inhabitants were obtained from the website (Figure-1) . Further, correlation analysis of CCR5 Δ32 minor allele frequency with COVID-19 mortality rate in African population revealed a positive correlation (Spearman r=0.6210, p=0.0045) . These data and findings are indicative of an association of CCR5 Δ32 with susceptibility to SARS-CoV-2 infection and mortality. However, the mechanism of CCR5 Δ32 allele offering predisposition to SARS-CoV-2 infection susceptibility and death of the patient is not known. An earlier investigation in CCR5 deficient mice demonstrated the suppression of Th1 immune response and susceptibility to viral and bacterial infections [5, 6] . Higher incidence of HCV [7] and WNV [8] have been associated with the deletion allele of the CCR5 gene, further corroborating our observations. On the contrary, 32bp deletion allele of the CCR5 gene is known to offer protection against HIV infection by hindering the entry of viruses inside the immune cells [9] . Earlier reports have demonstrated significant correlation of ACE-1 (D allele: Spearman r=-0.510 and p=0.01) [1] and C3 (S allele:r2=0.480, p<0.001) [10] with mortality due to SARS-CoV-2 infection. However, in the present study we observed a positive correlation on 55% of included population, projecting CCR5 delta 32 allele as an important genetic marker of SARS-CoV-2 related death. Although the present report highlighted a significant association of CCR5 Δ32 variant with susceptibility and mortality from SARS-CoV-2 infection, it has set the stage for in-depth analysis by factoring in various other aspects. Inclusion of other genetic polymorphisms of the CCR5 gene can further highlight the role of CCR5 in COVID-19 pathogenesis. Additionally, other parameters such as testing capacity, inter-country movement frequency, health policy of the regional government, the density of the population, demographic age profile of the infected cases, various co-morbidities phenotypes [11] can place crucial role in enhancing the understanding and strengthening the present analysis. In conclusion, COVID-19 infection and mortality are associated with CCR5 Δ32 allele, and population-based genetic association studies in different cohorts are required to validate our findings. infection cases/million and the number of patients death due to COVID-19/million worldwide. Prevalence of CCR-5 Δ32 mutant allele in healthy controls was searched from earlier published reports and correlated with COVID-19 infection (A) and death rate (B) per million throughout the globe. Each dot represented a country. A positive correlation was observed in the distribution of CCR-5 Δ32 minor allele with the number of cases (Spearman r=0.4628, p<0.0001, n=107) and death (Spearman r=0.5517, p<0.0001, n=107) from COVID-19. A total of one hundred seven countries were considered for the analysis based on availability of data. The list of countries are follows "Afghanistan, Albania, Algeria, ACE Ins/Del genetic polymorphism and epidemiological findings in COVID-19 A Moving Target: The Multiple Roles of CCR5 in Infectious Diseases The human CC chemokine receptor 5 (CCR5) gene. Multiple transcripts with 5'-end heterogeneity, dual promoter usage, and evidence for polymorphisms within the regulatory regions and noncoding exons Frequencies of gene variant CCR5-Delta32 in 87 countries based on next-generation sequencing of 1.3 million individuals sampled from 3 national DKMS donor centers The role of CC chemokine receptor 5 in antiviral immunity Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus CC-chemokine receptor 5 (CCR5) in hepatitis C--at the crossroads of the antiviral immune response? CCR5 deficiency increases risk of symptomatic West Nile virus infection Host genes and HIV: the role of the chemokine receptor gene CCR5 and its allele C3 and ACE1 polymorphisms are more important confounders in the spread and outcome of COVID-19 in comparison with ABO polymorphism COVID-19 infections are also affected by human ACE1 D/I polymorphism The authors declared no potential conflicts of interest concerning the research, authorship and/or publication of this article.