Hydroxychloroquine: An Introduction

Hydroxychloroquine is a derivative of chloroquine that has both anti-inflammatory and antimalarial activities. It is also used as an antirheumatic agent (used to treat joint pain) in systemic lupus erythematosus and rheumatoid arthritis.

The exact mechanism of hydroxychloroquine action is unknown. It has been documented that its activity hampers the parasite’s ability to break down hemoglobin, preventing its normal growth and replication.

Studies have also shown that it inhibits the stimulation of toll-like receptor (TLR) 9 family that induces inflammatory responses by activating the innate immune system.

Several in vitro studies have confirmed the effectiveness of hydroxychloroquine on severe acute respiratory syndrome (SARS) virus. Multiple clinical trials are currently being conducted to identify the effect of hydroxychloroquine on COVID-19.

Genetics and Hydroxychloroquine Response

The IL-10 Gene and Hydroxychloroquine Response

The IL-10 gene contains instructions for the production of a cytokine protein, which plays an anti-inflammatory and immunomodulatory role in lymphocytes. A study in mice documented that the cytokine functions as an essential immunoregulatory in the intestinal tract. Genetic variations in this gene may alter the production of IL-10 and influence the susceptibility to autoimmune diseases.

rs1800896 and Hydroxychloroquine Response
The rs1800896 is a single nucleotide polymorphism or an SNP in the IL-10 gene associated with the regulation of IL­10 production.

Studies have shown that rs1800896 is associated with susceptibility to asthma, inflammatory bowel disease, and other chronic infections.

In a case-control study on patients with SLE (Systemic Lupus Erythematosus), people with TT genotype responded better to hydroxychloroquine.

Summary

  1. Hydroxychloroquine is a drug used to treat acute attacks of malaria, systemic lupus erythematosus (a chronic inflammatory condition of the body), and rheumatoid arthritis.
  2. Hydroxychloroquine works by killing the organisms that cause malaria; however, the exact mechanism of action is unknown.
  3. Several studies have confirmed the effectiveness of hydroxychloroquine on severe acute respiratory syndrome (SARS) virus.
  4. Studies have shown that a person's genetic makeup can influence the response to hydroxychloroquine.
  5. IL-10 gene contains the production of a type of cytokine protein with anti-inflammatory effects.
  6. People with certain variants of this gene gave a better response to hydroxychloroquine than others.

Drug Response And COVID-19

Various existing drugs are being explored in clinical trials for their potential against COVID-19, including Hydroxychloroquine, Lopinavir/ Ritonavir, and VPM1002 (recombinant BCG vaccine).
So far, a newly developed antiviral called Remdesivir is the only drug approved worldwide to treat COVID-19 patients.
Certain genetic variations can affect the metabolism, efficacy, and side effects of drugs. Identifying such variants will help healthcare professionals prescribe the right medication to achieve the best possible beneficial outcomes while avoiding adverse effects.

Response to BCG Vaccine

The BCG (Bacille Calmette-Guerin) is a vaccine that uses a live attenuated strain derived from an isolate of Mycobacterium Bovis, which has been used worldwide against tuberculosis. It is known to provide only partial and inconsistent immunity. The discrepancy in immunity levels between individuals may be due to different BCG vaccine strains, prior exposure to environmental mycobacteria, and host genetics.

It is considered a biologic response modifier, a type of immunotherapy that, when administered, increases immunity to build up the body’s resistance against the disease.

A recent study published in The Journal Of Clinical Investigation analyzed the blood of 6,000 healthcare workers in the Cedars-Sinai Health System for evidence of antibodies against SARS-CoV-2 with their medical history. They documented that workers who had received BCG vaccinations in the past (nearly 30% of of the study population) were significantly less likely to test positive for SARS-CoV-2 antibodies in their blood or to report having had infections with coronavirus or coronavirus-associated symptoms over the prior six months than those who had not received BCG. The authors speculated that the BCG-vaccinated individuals might have been less sick and produced fewer antibodies or mounted a more efficient cellular immune response against the virus.

Genetics and BCG Vaccine

Studies have shown the correlation of certain genetic variants in innate immunity genes and BCG-induced immune responses after vaccination.

The TLR1 and Response to BCG Vaccine

The TLR1 gene encodes a protein that belongs to the Toll-like receptor (TLR) family. It plays an essential role in pathogen recognition and activation of innate immunity. They recognize small molecular motifs (pathogen-associated molecular patterns) expressed on infectious agents and mediate the production of cytokines necessary for the development of effective immunity.
Studies have documented that genetic variants in the TLR pathway that regulate cellular function are associated with susceptibility to some infections, including TB.

rs3923647 and BCG Vaccine Response
The rs3923647 is an SNP in the TLR1 gene. The T allele has been associated with a better immune response upon BCG vaccine administration.

Summary

  1. BCG, or bacilli Calmette-Guerin, is a vaccine for tuberculosis (TB) disease. It is used in countries with a high prevalence of TB to prevent childhood tuberculous meningitis.
  2. BCG has been noted to reduce the incidence of respiratory tract infections in children and adults and have antiviral effects
  3. Based on this, research has proposed that BCG vaccination may induce (partial) protection against the susceptibility to and/or severity of SARS-CoV-2 infection.
  4. Studies have shown that a person's genetic makeup can influence the immune response induced by the BCG vaccine.
  5. People carrying certain variants of the TLR1 or Toll-like receptor 1 gene have better immune responses upon BCG vaccination compared to others.

Dexamethasone: An Introduction

Dexamethasone is a corticosteroid medication used for rheumatic disease, skin infections, hypersensitivity reactions, eye infections, ulcerative colitis, and chronic obstructive pulmonary disorder. Dexamethasone is a glucocorticoid. Glucocorticoids act as an anti-inflammatory drug.

The National Health Service in the UK and the National Institutes of Health (NIH) in the US recommend dexamethasone for patients with COVID-19 who need either mechanical ventilation or supplemental oxygen (without ventilation).

In a clinical trial conducted in the UK, treatment with dexamethasone was shown to reduce mortality rates by a third among COVID-19 patients on ventilators.

Genetics and Dexamethasone Response

The F2RL1 and Dexamethasone Response

The F2RL1 (also known as protease-activated receptor 2) gene contains instructions for the production of a receptor that belongs to the G-protein coupled receptor 1 family of proteins. When activated, they stimulate vascular smooth muscle relaxation, dilate blood vessels, increase blood flow, and lower blood pressure. It is also essential for the inflammatory response, as well as innate and adaptive immunity.

rs2243057 and Dexamethasone response
The rs2243057 is a single nucleotide polymorphism or an SNP in the F2RL1 gene. According to a study, dexamethasone-treated patients with A allele carriers were associated with adverse pleiotropic effects, including osteonecrosis and thrombosis as compared to G allele carriers.

Summary

  1. Dexamethasone belongs to a class of drugs known as corticosteroids, used to treat conditions such as arthritis, allergies, immune system disorders, and certain types of cancer.
  2. Dexamethasone has anti-inflammatory and immunosuppressant effects.
  3. Clinical trials reveal that treatment with dexamethasone reduces mortality rates by a third among COVID-19 patients on ventilators.
  4. Studies have shown that a person's genetic makeup can influence the response to dexamethasone.
  5. The F2RL1 gene, also known as protease-activated receptor 2 regulates the inflammatory response, as well as innate and adaptive immunity.
  6. People with certain variants of this gene are at an increased risk for bone death ad thrombosis when administered this drug.

Coronavirus disease 2019 (COVID-19) is a highly contagious, potentially fatal respiratory illness caused by a coronavirus (SARS-CoV). It was first identified in Wuhan, China, in December 2019, and later it rapidly spread across the world. On March 11, 2020, the World Health Organization (WHO) declared COVID-19 as a pandemic disease.

How is COVID-19 Transmitted?

COVID-19 is likely to transmit through:
1. Respiratory droplets when an infected person coughs or sneezes
2. By touching surfaces contaminated by the virus and then touching the eyes, nose, or mouth.
3. From close contact with an infected person.

Signs and Symptoms

The symptoms of COVID-19 can vary in severity - from very mild to severe illness.
In about 80% of affected people, it causes only mild symptoms.
Some common symptoms include:
1. Shortness of breath or breathing difficulties
2. Fever or chills
3. Cough
4. Fatigue
5. Muscle or body aches
6. Headaches
7. Sore throat
8. Loss of taste or smell
9. Congestion or runny nose
10. Nausea or vomiting

These symptoms may appear between two and fourteen days after exposure to the virus. Children have similar but usually milder symptoms than adults. Older adults and people who have severe underlying medical conditions like heart or lung disease or diabetes are at higher risk of more serious complications from COVID-19.

According to the Chinese Center for Disease Control (CCDC), COVID-19 death cases were already suffering from 10.5% cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer.

Role of Genetics in COVID-19

Genes can determine an individual’s susceptibility to infectious diseases such as COVID-19. They also influence the chances of developing complications from these infections.
Some individuals who get infected remain asymptomatic. Some may develop mild symptoms, while others experience severe symptoms that require hospitalization. These inter-individual differences might be influenced by both genetic and non-genetic factors (environmental/lifestyle).

Research studies have documented that the SARS-CoV-2 virus enters the body by interacting with the ACE2 protein present on the outer surface of certain cells. Certain variants of the ACE2 gene may prevent the SARS-CoV-2 virus from entering cells, thus decreasing a person’s vulnerability to the virus. Variants in LZTFL1, ABO, ACE2, HLA, DPP9, OAS3, IFNAR2, TYK2, and other genes have also been correlated with COVID-19 severity.

A recent genome-wide association study of COVID-19 has shown a significant association of COVID-19 severity with a multigene locus at 3p21.31 and the ABO blood group locus at 9q34.2.

The LZTFL1 Gene

The LZTFL1 gene contains instructions to produce a protein that is widely expressed in the cytoplasm (the fluid that fills the cells) and cilia (hair-like projection found on the surface of the cells). It is involved in protein trafficking (transport) to the ciliary membrane. It functions as a tumor suppressor by interacting with E-cadherin and the actin cytoskeleton, thereby regulating the transition of epithelial cells to mesenchymal cells [ECM].

rs11385942 and COVID-19 Severity
The rs11385942 is an indel (insertion-deletion) variation located in the intronic region of the LZTFL1 gene. Studies have shown that the frequency of minor risk allele (A) was higher among patients receiving mechanical ventilation than those receiving supplemental oxygen only. This finding indicates that this risk allele confers a predisposition to the most severe forms of COVID-19.

The ABO Gene

The ABO gene contains instructions to produce an enzyme called glycosyltransferase that transfers specific sugar residues to H substance and is responsible for the formation of antigens in blood group A and B. Certain variants in the ABO gene are associated with an increased risk for certain cancers and cardio-cerebrovascular disease.

Furthermore, recent studies have documented that blood groups may play a key role in determining the susceptibility and severity of COVID-19. According to a study, people with A blood group are associated with an increased risk of acquiring COVID-19, whereas people with O blood group are associated with a lower risk.

rs657152 and COVID-19 Severity
The rs657152 is a C>A polymorphism in the ABO gene, which may influence several biological molecules, including LDL cholesterol, liver-derived alkaline phosphatase, and interleukin-6, thus contributing to the occurrence and development of the disease.

Based on a GWAS that studied COVID-19 severity, the rs657152 risk allele (A) was significantly associated with a higher risk of a severe COVID infection.

rs657152 and COVID-19 Severity
The rs657152 is a C>A polymorphism located in the intronic region of the ABO gene, which may influence several biological molecules, including LDL cholesterol, liver-derived alkaline phosphatase, and interleukin-6, thus contributing to the occurrence and development of the disease.

Based on a GWAS that studied COVID-19 severity, the rs657152 risk allele (A) was significantly associated with a higher risk of a severe COVID infection.

Summary

  1. Coronavirus disease 2019 (COVID-19) is defined as an illness caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  2. COVID-19 can be transmitted through respiratory droplets, touching contaminated surfaces and touching your mouth, and from close contact with the affected person.
  3. Some signs and symptoms of COVID-19 are cough, fatigue, fever, shortness of breath, and loss of smell and taste.
  4. A person's genetic makeup can influence, to an extent, influences the risk of catching COVID-19, as well as the severity of the disease.
  5. The virus enters the body by interacting with the ACE2 protein produced by the ACE2 gene.
  6. In some individuals, the ACE2 gene produces a higher number of ACE2 proteins and increases both the risk and severity of COVID-19.
  7. Other genes like ABO, LZTFL1, and HLA have also been correlated with COVID-19 severity.

Gut Microbium: An Introduction

The human body’s largest microorganism population resides in the intestine and is collectively called the gut microbiota/microbiome. Every individual’s microbiome is unique and is influenced by genetic, environmental, or lifestyle factors.

The gut microbiome contains a complex community of microbes that live within the gastrointestinal (GI) tract, and many of these microbes are found to be beneficial to health. Some of them, however, can be harmful and promote infections and diseases. It plays an essential role in human health and influences the development of chronic diseases ranging from metabolic disease to colorectal cancer. There is extensive research investigating the biological functions of the gut microbiota in influencing lung disorders that include asthma, chronic obstructive pulmonary disease, chronic bronchitis, lung cancer, pleural effusion, and viral infection. It is also recognized that viral infections in the respiratory tract cause a disturbance in the gut microbiome.

Importance of Bifidobacterium

Some Bifidobacterium strains are considered essential probiotics and are used in the food industry. Different strains of bifidobacteria may exert a range of beneficial health effects, including the regulation of intestinal microbial homeostasis, inhibition of pathogens and harmful bacteria that colonize in the gut mucosa, and regulation of immune responses. It also improves the gut mucosal barrier and lowers levels of endotoxin in the intestine.

Genetics and Bifidobacterium Growth

The MCM6 Gene and Bifidobacterium Growth

The MCM6 gene contains instructions for the production of the protein minichromosome maintenance complex component (MCM). They are essential for the initiation of eukaryotic genome replication. It contains two of the regulatory regions for the LCT gene. This gene produces the lactase enzymes that are required for the digestion of lactose in milk.

Variants in these genes are often associated with lactose intolerance in adult life. The variants result in a decreased ability of the epithelial cells in the small intestine to digest lactose due to the decline in the lactase enzyme.

Research studies have shown the association between _LCT/MCM6_ variants and the abundance of bifidobacterium in the gastrointestinal tract.

rs4988235 and Tendency of Bifidobacterium growth
The rs4988235 is a single nucleotide polymorphism or an SNP in the MCM6 gene. Individuals carrying the homozygous CC variation have been found to be lactose intolerant/ lactose non-persistent, compared to those with the TT or TC variant, which have been correlated with lactase persistence.

Multiple studies have found that rs4988235 has been associated with Bifidobacterium abundance in the gut. As bifidobacterium assimilates lactose as a preferred carbon source for growth, it is reasonable that subjects with the CC genotype have a higher Bifidobacterium abundance in their gut.

The rs4988235 SNP is mainly documented as an essential locus related to lactase activity in the European population.

Summary

  1. Gut microbiota is the microorganisms, including bacteria, archaea, and fungi, in the digestive tracts of humans and other animals, including insects.
  2. The microbiome makeup of each individual is influenced by various factors like genetics, environment, and lifestyle.
  3. Gut microbiota plays an essential role in human health and influences the risk of various chronic diseases.
  4. Viral infections in the respiratory tract cause a disturbance in the gut microbiome.
  5. MCM6 and LCT are two genes that have been studied to influence the abundance of bifidobacterium in the gastrointestinal tract.
  6. People with certain variants in these genes have more bifidobacterium and hence, increases protection against various lung disorders.

Lopinavir and Ritonavir: An Introduction

Lopinavir and Ritonavir are a combination of antiviral medicines used to treat human immunodeficiency virus (HIV) infection. They belong to a class of medications called protease inhibitors, which functions by decreasing the amount of HIV in the blood. When taken together, ritonavir also helps increase the amount of lopinavir in the body. The lopinavir blocks the protease action and results in the formation of defective viruses that cannot infect the body’s cells. As a result, the number of viruses in the body decreases. Nevertheless, it does not prevent the transmission of HIV among individuals, and it does not cure HIV infections.

Preliminary in-vitro studies have shown that the lopinavir/ritonavir combination may inhibit the replication of the Novel Coronavirus. Certain case reports published by scientists from China, Thailand, and Japan have described the effectiveness of this combination in COVID-19. Several clinical trials are currently being conducted to identify the effectiveness, with some showing no benefit and others, some promise.

Genetics and Lopinavir - Ritonavir Response

The CYP3A4 and Lopinavir - Ritonavir Response

The CYP3A4 gene contains instructions for the production of a protein that belongs to the cytochrome P450 superfamily of enzymes. Its expression is induced by glucocorticoids and some pharmacological agents. It catalyzes many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids.

rs28371759 and Lopinavir - Ritonavir Response
The rs28371759 is a single nucleotide polymorphism or an SNP in the CYP3A4 gene. Studies have shown that the minor allele - C is associated with increased enzyme activity, thus facilitating the metabolism of drugs like lopinavir. The minor allele carriers may need to increase the dosage of these drugs compared to wild-type carriers.

Summary

  1. The combination of lopinavir and ritonavir is used with other medications to treat human immunodeficiency virus (HIV) infection.
  2. They belong to a class of medications called protease inhibitors. They work by decreasing the amount of HIV in the blood.
  3. Lopinavir is also an inhibitor of the severe acute respiratory syndrome coronavirus (SARS-CoV)
  4. Studies have shown that a person's genetic makeup can influence the response to lopinavir and ritonavir.
  5. The CYP3A4 gene contains instructions for the production of a protein that belongs to the cytochrome P450 superfamily of enzymes.
  6. CYP450 enzymes are the most prevalent drug-metabolizing enzyme
  7. People with certain variants of the CYP3A4 gene require an increased dosage of lopinavir and ritonavir to achieve the desired effects.
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