Genetic Basis Of Polymorphism Research Articles

Effects of Efavirenz for the Treatment of HIV Section on the Basis of Genetic Polymorphisms

Introduction: CYP2B6 is a liver enzyme that is involved in the metabolism of several drugs including Efavirenz, which is one of the mainstay treatments for Acquired Immunodeficiency Syndrome (AIDS) caused by the Human Immunodeficiency Virus (HIV). Polymorphisms in the CYP2B6 gene determine the rate of enzyme activity. One such polymorphism, rs3745274, where there is a change from G to T at codon 516 results in an amino acid change from glutamine to histidine at position 172. The Food and Drug Administration (FDA) USA has recommended this molecular marker as a companion diagnostic test for Efavirenz. Aim: To evaluate the effect of Efavirenz in the treatment of HIV on the basis of genetic polymorphisms. To determine the CYP2B6 genotype of healthy individuals and those with HIV before starting the antiretroviral therapy. To review the reported cases of genetic polymorphisms and document drug toxicity in the selected population. Materials and Methods: A prospective clinical observational study was done at Kamineni Hospital, Hyderabad, Telangana, India, from September 2017 to August 2020 with an inclusion criterion of participants above the age of 18 years who are HIV positive diagnosed by Enzyme Linked Immunosorbent Assay (ELISA) test, reporting to the Outpatient Department (OPD) or getting admitted for treatment with Efavirenz with a sample size of 369 based on the prevalence of CYP2B6 polymorphism in Southern India. Results: Out of the study population, 276 HIV patients and 93 controls were genotyped by Polymerase Chain Reaction (PCR) and subjected to Restriction Fragment Length Polymorphism (RFLP) technique to establish CYP2B6 - 516 G>T polymorphism. About 69% is of GT genotype, 18% is of TT genotype and 13% is of GG genotype. Patients with GT genotype are intermediate metabolisers of the drug, those with TT genotype are poor metabolisers of the drug, and GG genotype is an extensive metaboliser of the drug. Individuals with the 516T allele have low enzyme activity and are poor metabolisers of the drug, causing delayed clearance leading to Adverse Drug Reactions (ADR) causing neurological deficits and cardiac complications. Conclusion: This observation helps the clinician adjust the dose of Efavirenz by studying the genetic polymorphism of the patient. Based on this study, we recommend that all HIV diagnosed patients undergo CYP2B6 genotyping before starting an Efavirenz based regimen to decrease the adverse drug reactions and promote effective Highly Active Antiretroviral Therapy (HAART) therapy.

Polymorphism of Beta2-Adrenoceptor and Regular Use of Formoterol in Asthma: Preliminary Results

Polymorphism at codon 16 of the beta2-adrenoceptor (beta2-AR) affects the responsiveness to salmeterol in asthmatics. Data concerning formoterol are more controversial in the literature. The aim of this study was to verify whether homozygous for arginine-16 (ArgArg16) and homozygous for glycine-16 (GlyGly16) genotypes differently influence the long-term responsiveness to formoterol. Twenty-nine patients with mild-to-moderate asthma, in stable clinical conditions, underwent genotyping at codon 16 of the beta2-AR by RFLP-PCR assay. The effects of a 4-week monotherapy with formoterol (12 μg BID) were tested on the peak expiratory flow (PEF) variability and the forced expiratory volume in 1 sec (FEV1) slope of the dose-response curve to salbutamol. Variability in PEF significantly increased during the 4-week treatment period in 14 patients with GlyGly16, but not in 15 patients with ArgArg16 and ArgGly16(P=0.032). The FEV1 slope of the dose-response curve to salbutamol decreased after the 4-week treatment period in GlyGly16, but not in pooled ArgArg16 and ArgGly16 patients. This study provides preliminary evidence that tolerance to formoterol develops more frequently in asthmatics with GlyGly16 genotype. If confirmed in a larger population, this finding might be useful in choosing the bronchodilator therapy on the basis of genetic polymorphism of the beta2-AR.

Pharmacoepigenetics: Its Role in Interindividual Differences in Drug Response

Pharmacoepigenetics potentially offers another level of explanation for interindividual variations in drug response that cannot be accounted for on the basis of genetic polymorphism. Many genes encoding enzymes, drug transporters, transcription factors, drug targets, and nuclear receptors are under epigenetic control. In addition, microRNAs (miRNAs) that govern the expression of these genes have recently been identified. This finding has implications, for example, in the context of drug resistance during cancer treatment. In this overview, we summarize the field, which is still in its infancy. Clinical Pharmacology & Therapeutics (2009); 85, 4, 426–430 doi:10.1038/clpt.2009.2

Possible genetic basis of pederin polymorphism in rove beetles (Paederus riparius).

In Paederus riparius, (+) females able to biosynthesize the unique hemolymph toxin pederin and (-) females lacking this ability co-occur in natural populations. Larvae descended from both types of females were reared in the laboratory and the imagoes were crossed in order to get information about a possible genetic basis of this polymorphism. The daughters of (+) mothers become (+) females or (-) females, while the progeny of (-) mothers comprises only (-) females. This suggests a matrilineal trait because pederin biosynthesis cannot be inherited from the father. The rather stable proportion of nearly 90% (+) females in collected females is not maintained, however, when the beetles are reared in the laboratory. This observation is discussed with regard to artificial rearing conditions, where individuals are kept separate and cannot prey on conspecifics.

Analysis of Epstein-Barr Virus Gene Polymorphisms in Normal Donors and in Virus-Associated Tumors From Different Geographic Locations

While Epstein-Barr virus (EBV) infection is associated with the development of certain lymphoid and epithelial tumors, the role of the virus in the pathogenesis of these malignancies remains unknown. It has been suggested that EBV strain variation may contribute to tumor development. Two major strains of EBV, type 1 and type 2, have been identified on the basis of genetic polymorphisms and other minor genetic variations give rise to distinct EBV isolates. We analyzed EBV strain variation in healthy individuals and compared them with EBV isolates present in lymphoid and epithelial neoplasms from the same geographic regions. In particular, the incidence of the 30-bp latent membrane protein (LMP1) gene deletion, recently implicated in the development of more aggressive forms of virus-positive lymphomas and Hodgkin's disease [HD], was examined in the normal population. While a preferential association of the LMP1 deletion with the type 2 strain of EBV was observed, there was no increased incidence of virus isolates carrying this deletion in HD, Burkitt's lymphoma, or virus-associated carcinomas compared with the appropriate normal population. A polymorphism in the BamHI F region of the EBV genome, previously identified in Chinese populations, was found at increased incidence in European HD biopsies. Overall, we found that most of the EBV gene polymorphisms detected in EBV isolates from healthy virus carriers occurred with similar frequency in virus-associated tumors from the same geographical region.

Evidence suggesting that the odortypes of pregnant women are a compound of maternal and fetal odortypes.

Odortypes--namely, body odors that distinguish one individual from another on the basis of genetic polymorphism at the major histocompatibility complex and other loci--are a fundamental element in the social life and reproductive behavior of the mouse, including familial imprinting, mate choice, and control of early pregnancy. Odortypes are strongly represented in urine. During mouse pregnancy, an outcrossed mother's urine acquires fetal major histocompatibility complex odortypes of paternal origin, an observation that we took as the focus of a search for odortypes in humans, using a fully automated computer-programmed olfactometer in which trained rats are known to distinguish precisely the odortypes of another species. Five women provided urine samples before and after birth, which in each case appropriately trained rats were found to distinguish in the olfactometer. Whether this olfactory distinction of mothers' urine before and after birth reflects in part the odortype and hence genotype of the fetus, and not just the state of pregnancy per se, was tested in a second study in which each mother's postpartum urine was mixed either with urine from her own infant or with urine of a different, same-aged infant. Responses of trained rats were more positive with respect to the former (congruous) mixtures than to the latter (incongruous) mixtures, implying that, as in the mouse, human fetal odortypes of paternal genomic origin are represented in the odortype of the mother, doubtless by circulatory transfer of the pertinent odorants.

Genetic basis of polymorphism in the color vision of platyrrhine monkeys

It was earlier proposed that the polymorphism of color vision observed in some neotropical monkeys could be accounted for by assuming that these animals have only a single photopigment gene locus on the X-chromosome. Three kinds of evidence have been added to existing data sets in an effort to evaluate the adequacy of the single locus model: (1) photopigment complements of squirrel monkeys ( Saimiri sciureus) have been determined using electroretinogram flicker photometry; (2) photopigment pedigrees have been established for several families of squirrel monkey; (3) X-chromosome pigment genes obtained from six dichromatic monkeys (three squirrel monkeys; three tamarins— Saguinus fuscicollis) have been examined to search for sequence polymorphisms at those gene loci believed crucial for spectral tuning. All of these results are in accord with the idea that some species of platyrrhine primate have only a single type of photopigment gene on the X-chromosome.

Indentification of Pyrus Species by Peroxidase Isozyme Phenotypes of Flower Buds.

Forty-one Pyrus species and cultivars were analyzed for peroxidase isozyme phenotypes by polyacrylamide gel electrophoresis. Five peroxidase isozyme phenotypes were specified for flower buds in Pyrus plants, and were consistent and repeatable. Intercultivar and interspecific polymorphism was not sufficient to permit reliable identification of every Pyrus plants examined. Bud sport could not be distinguished from the original cultivar. The genetic basis of polymorphism was unknown, being unable to compare the peroxidase isozyme genotype observed in a hybrid with that predicted on the basis of parental peroxidase isozyme genotype. Some of the local (Kanto Province) cultivars were specified by their peroxidase isozyme phenotypes.

Multiple forms of octopine dehydrogenase in Strombus luhuanus (mollusca, gastropoda, strombidae): genetic basis of polymorphism, properties of the enzymes, and relationship between the octopine dehydrogenase phenotype and the accumulation of anaerobic end products during exercise.

Octopine dehydrogenase (ODH) is electrophoretically polymorphic in the gastropod mollusk Strombus luhuanus. The frequencies of the six electrophoretic phenotypes in the Heron Island population, together with the molecular weight values of 38,000 obtained for each of the three forms of the enzyme, demonstrate that the monomeric enzyme is encoded by three codominant alleles at a single locus. The purified allozymes are indistinguishable in terms of Km values for substrates, product inhibition by octopine and NAD, pH optima, and substrate inhibition by pyruvate. No statistically significant correlations were found between the ODH phenotype and the maximum activities of ODH or alanopine dehydrogenase, the capacity for anaerobic muscle work, or the accumulation of octopine or strombine/alanopine during exercise. It would appear that the ODH allozymes may be functionally equivalent both in vitro and in vivo.