Common drugs, vitamins, nutritional supplements and COVID-19 mortality.

The FDA has approved only one drug, remdesivir, for the treatment of COVID-19. The FDA has granted an emergency use authorization for the rheumatoid arthritis treatment drug, baricitinib (Olumiant), for the treatment of COVID-19 in some cases. For this reason, investigators have paid considerable attention to the association between commonly used drugs and the outcome of patients with COVID-19. Aspirin and ibuprofen have been reported to reduce the mortality rate. Omeprazole can increase mortality. In addition, some studies have demonstrated that famotidine diminishes mortality, while others have indicated that famotidine leads to a poorer prognosis. The present study used UK Biobank (UKB) data to assess the association of commonly used drugs with COVID-19 mortality. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6. The UK Biobank Data Parser (ukbb_parser) was used, a python-based package that allows easy interfacing with the large UK Biobank dataset. The results revealed that aspirin and omeprazole were associated with an elevated mortality rate. Ibuprofen-related mortality was lower than laxative-related mortality. Aspirin users were also significantly older than other subjects. The association with mortality of cholesterol-lowering medications, blood pressure-lowering medications, hormone replacement and oral contraceptives in 134 female subjects revealed insignificant variability. The association of nutritional supplements in 238 subjects with mortality indicated that variability was insignificant. The lower mortality linked to the supplementation of vitamin D and vitamin B, presumably B complex, has been previously observed. On the whole, the present study demonstrates that although some of the associations described among drugs and COVID-19 are not novel, the utility of a new source, UKB, may prove to be useful in further examining these associations.

ABO blood groups, COVID-19 infection and mortality.

BACKGROUND: A recent study showed that the ABO gene, chr 9q34.2, which determines blood type, may affect COVID-19 disease severity, although this result has not been reproducible. A UK study of 2200 COVID-19 patients found no relationship of ABO blood type to disease severity. A Danish study identified ABO blood group as a risk factor for SARS-CoV-2 infection but not for hospitalization or death from COVID-19. AIM: In the current study, we wished to analyze the relationship of ABO blood group and the ABO genetic locus to COVID-19 test positivity and mortality in subjects from the UK Biobank (UKB). METHODS: ABO blood type is from UKB data field 23165. Blood type was imputed for genotyped UK Biobank participants using three SNPs (rs505922, rs8176719, and rs8176746) in the ABO gene on chromosome 9q34.2. We analyzed the chromosome 9 snp rs657152 to assess the relationship of the ABO locus to COVID-19 test positivity and mortality. RESULTS: COVID-19 test results (negative or positive) were not related to blood group in males (p = 0.977, two tailed Fisher exact test) or females (p = 0.548). COVID-19 outcomes (alive or died) were not related to blood group in males (p = 0.102, two tailed Fisher exact test) or females (p = 0.226). We found no significant relationship of rs657152 to COVID-19 test positivity or mortality. CONCLUSION: We were not able to confirm that ABO blood group influences risk of COVID-19 infection or outcome.

Homozygosity for rs17775810 Minor Allele Associated With Reduced Mortality of COVID-19 in the UK Biobank Cohort.

BACKGROUND/AIM: Adult outpatients with symptomatic COVID-19 treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. Fluvoxamine strongly binds to the sigma-1 receptor (S1R) that regulates inflammation by inhibiting the production of cytokines, believed to be responsible for severe COVID-19. We evaluated the S1R locus on chr 9p13.3 in subjects tested positive for SARS-CoV-2. We focused on SNP rs17775810 that has been previously identified by examining loss-of-function mutations in the S1R gene associated with distal hereditary motor neuropathy. PATIENTS AND METHODS: We utilized UK Biobank (UKB) data. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. RESULTS: The effect of rs17775810 genotype on survival was significant (p=0.036, 2 tailed Fisher exact test). The minor allele homozygotes (TT) had the lowest death rate (0%), whereas the non-TT genotypes (i.e. CT and CC) had the highest death rate (16.2%). CONCLUSION: The rs17775810 analysis corroborates the favorable effect of fluvoxamine on COVID-19 survival.

BIN1 rs744373 SNP and COVID-19 mortality.

Apolipoprotein E (APOE) e4 genotype, which increases the risk of Alzheimer's disease (AD), predicted severe COVID-19 infection in one UK Biobank (UKB) cohort. Single nucleotide polymorphisms (SNPs) in the bridging integrator 1 (BIN1) gene indicate the second highest odds-ratios for sporadic AD, exceeded only by APOE variants. The objective of the present study was to evaluate the effects of BIN1 and the SNP rs744373 on COVID-19-relaetd survival using UKB-derived data. In addition, the interaction and alignment of BIN1 and SARS-Cov-2 were evaluated. For this purpose, the major (non-Alzheimer's) BIN1 allele was designated as BIN and the SNP rs744373 minor (Alzheimer's) allele as RS7. To evaluate the interaction and alignment of BIN1 and SARS-Cov-2, Protein Data Bank (pdb) entries were searched on the RCSB Protein Data Bank. The results revealed that the BIN RS7 heterozygote was associated with the lowest mortality rate (11.7%), followed by the BIN BIN homozygote (17.2%). The RS7 RS7 homozygote was associated with the highest mortality rate (28.1%). Logistic regression analysis was also performed using survival or mortality as the dependent variable, and sex, age, genotype, AD and coronary heart disease (CHD) as independent variables. The effects of sex, age and genotype were significant at the 95% level. The male sex and older-aged subjects were more likely to succumb to test-confirmed COVID-19 than females and younger subjects. The effects of AD and CHD were insignificant. Protein molecule alignment analyses suggested that the BIN allele may interfere with the replication of the SARs-Cov2 virus. The findings of the present study demonstrate that the risks for COVID-19 mortality are not simply related to an advanced chronological age or the comorbidities commonly observed in aged subjects, such as CHD and AD, but also with AD genes.

Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2.

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One drug that has attracted interest is the antiparasitic compound ivermectin, a macrocyclic lactone derived from the bacterium Streptomyces avermitilis. We carried out a docking study to determine if ivermectin might be able to attach to the SARS-CoV-2 spike receptor-binding domain bound with ACE2. MATERIALS AND METHODS: We used the program AutoDock Vina Extended to perform the docking study. RESULTS: Ivermectin docked in the region of leucine 91 of the spike and histidine 378 of the ACE2 receptor. The binding energy of ivermectin to the spike-ACE2 complex was -18 kcal/mol and binding constant was 5.8 e-08. CONCLUSION: The ivermectin docking we identified may interfere with the attachment of the spike to the human cell membrane. Clinical trials now underway should determine whether ivermectin is an effective treatment for SARS-Cov2 infection.

Human Gene Sequences in SARS-CoV-2 and Other Viruses.

In a previous study, we identified a 117 base severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequence in the human genome with 94.6% identity. The sequence was in chromosome 1p within an intronic region of the netrin G1 (NTNG1) gene. The sequence matched a sequence in the SARS-CoV-2 Orf1b gene in non-structural protein 14 (NSP14), which is an exonuclease and NSP15, an endoribonuclease. In the current study we compared the human genome with other viral genomes to determine some of the characteristics of human sequences found in the latter. Most of the viruses had human sequences, but they were short. Hepatitis A and St Louis encephalitis had human sequences that were longer than the 117 base SARS-Cov-2 sequence, but they were in non-coding regions of the human genome. The SARS-Cov-2 sequence was the only long sequence found in a human gene (NTNG1). The related coronaviruses SARS-Cov had a 41 BP human sequence on chromosome 3 that was not part of a human gene, and MERS had no human sequence. The 117 base SARS-CoV-2 human sequence is relatively close to the viral spike sequence, separated only by NSP16, a 904 base sequence. The mechanism for SARS-CoV-2 infection is the binding of the virus spike protein to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. We have no explanation for the NSP14 and NSP15 SARS-Cov-2 sequences we observed here or how they might relate to infectiousness. Further studies are warranted.

SARS-CoV-2 orf1b Gene Sequence in the NTNG1 Gene on Human Chromosome 1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus. It is contagious in humans and is the cause of the coronavirus disease 2019 (COVID-19) pandemic. In the current analysis, we searched for SARS-CoV-2 sequences within the human genome. To compare the SARS-CoV-2 genome to the human genome, we used the blast-like alignment tool (BLAT) of the University of California, Santa Cruz Genome Browser. BLAT can align a user sequence of 25 bases or more to the genome. BLAT search results revealed a 117-base pair SARS-CoV-2 sequence in the human genome with 94.6% identity. The sequence was in chromosome 1p within an intronic region of the netrin G1 (NTNG1) gene. The sequence matched a sequence in the SARS-CoV-2 orf1b (open reading frames) gene. The SARS-CoV-2 human sequence lies within non-structural proteins 14 and 15 (NSP14 and NSP15), and is quite close to the viral spike sequence, separated only by NSP16, a 904-base pair sequence. The mechanism for SARS-CoV-2 infection is the binding of the virus spike protein to the membrane-bound form of angiotensin-converting enzyme 2 and internalization of the complex by the host cell. It is probably no accident that a sequence from the SARS-CoV-2 orf1b gene is found in the human NTNG1 gene, implicated in schizophrenia, and that haloperidol, used to treat schizophrenia, may also be a treatment for COVID-19. We suggest, therefore, that it is important to investigate other haloperidol analogs. Among them are benperidol, bromperidol, bromperidol decanoate, droperidol, seperidol hydrochloride, and trifluperidol. These analogs might be valuable in the treatment of COVID-19 and other coronavirus infections.