Applied Pharmacogenomics And Molecular Medicine

Describe the Applied Pharmacogenomics and Molecular Medicine. 

Clinical Features of ADR and HLA Allele B*5701

Clinical features of ADR and HLA allele B*5701 include the following signs and symptoms that present as manifestations of the pathologic diseases. Drugs like Abacavir and Flucloxacillin have been indicated to present ADRS through HLA associations of this particular variant. Abacavir is a nucleoside reverse transcriptase inhibitor that is normally used in combination with other antiretroviral drugs for treatment of HIV might lead to hypersensitivity by exhibiting symptoms including fever, rash, malaise alongside constitutional symptoms, respiratory symptoms and gastrointestinal tract symptoms in conjunctional with organ involvement that are most prominent during the initial  2 to 6 weeks of treatment. Prolonged usage might aggravate the symptoms and pose severe threat to patient in case the patient is re-challenged following discontinuation. Further, for Flucloxacillin that is considered as a narrow spectrum anti-Staphylococcal semi-synthetic penicillin may induce hepatotoxicity. Common symptoms include cholestatic hepatitis that might manifest within 1-45 days post conduct of treatment (1).

Genetic background concerning the HLA allele influence encompasses several factors. Drug hypersensitivity reactions has been attributed to certain genetic basis that is further represented by the HLA alleles located in the MHC on the short arm of chromosome 6. This extremely polymorphic region of the genome has been found to be associated with both infectious as well as autoimmune diseases. Genetic variants, T-cell clonotypes and expression of organ homing receptors in conjunction with HLA allele contribute towards affecting the organ systems. Moreover, ethnic background and ADR to therapeutically and structurally unrelated compounds causing similar sort of organ injury also underpins the genetic influence in HLA allele. Research ahs elucidated the differential pattern of drug-HLA-tissue injury interactions that cannot be stated enough for predicting the susceptibility of the individuals who possess increased threat of inflicting the specific disorder. Antigen presentation, DHRs against NSAIDs are also found to be influenced by HLA (2).

The underlying mechanism between ADR and HLA allele B*5701 are found to be exhibited by virtue of multiple genetic as well as non-genetic factors that has the potential of modifying the action of  a drug that culminate in generating differential responses for particular drug across different individuals. Immune response to drug also causes hypersensitivity reactions. In this regard, HLA molecules exerts integral role in the immune system through presentation of both exogenous and endogenous peptide antigens to T cells for initiating antigen specific immune responses. For this, CD4⁺ and CD8⁺ T cells are recruited by HLA class I and class II alleles. Apart from the normal immune mediating role, these cells are well efficient to bid peptides within the peptide-binding groove. Hence, plausible differences are observed based on presentation of the antigens and recruitment of T cells. Association of the HLA-B*5701 allele with drug hypersensitivity accounts for slow progression of the HIV1 infection in susceptible individuals rather than conferring protection against the disease(3).

Knowledge advances for ADR and HLA-B*5701 has paved the way for improvising strategies in clinical practice. HLA-B*5701 has been found to correlate with both abacavir drug induced skin injury as well as flucloxacillin drug induced liver injury. In this connection phamacogenetic screening for HLA-B*5701 prior to abcavir therapy has been found to harbor beneficial outcomes by means of mitigation of the incidence of abcavir hypersensitivity syndrome specific to clinical practice (4). Further knowledge pertaining to the pathogenesis of the T-cell mediated drug hypersensitivity reactions in conjunction with definite understanding of risk factors and the underlying mechanisms that lead to the generation of such hypersensitive reactions further contribute to the improvisation of strategies for pre screening phases that will ultimately result in development of safer and more economical drug design. Early screening of the chemical entities prior to drug development will help in recognizing the novel drug actions in course of early stage of drug development (5).

Genetic Background Concerning the HLA Allele Influence

The ethnic influence of certain HLA drugs may be further illustrated through the drug named Carbamazepine. Carabamazepine is considered as an aromatic amine anticonvulsant that may be applied in the treatment of bipolar disorder, trigeminal neuralgia and epilepsy. People having South Asian descent have been reported of having increased proximity to develop certain disorders upon initiation of the drug as part of the treatment therapy. The variant of HLA-B*1502 has been found to occur and present increased association with the Stevens-Johnson syndrome and toxic epidermal necrolysis. Furthermore, the drug induced hypersensitivity syndrome in addition to drug reaction with eosinophilia and systemic symptoms, maculoppapular eruptions are also found to be present in persons belonging to Thai, Chinese, Malaysian and Indian origin. These hypersensitive reactions are found to be mediated specifically by the T-cells and thereby exert their potential influence upon the cells of various body systems with the alleles being located on HLA genes (6).

Clinical features in association with the ADR and the thiopurine S-methyltransferase (TPMT) gene has been presented through innumerable research. Inflammatory bowel disease has been found to result because of deficiency of TPMT gene that cause alteration and faulty metabolism of the azathioprine metabolism. Thiopurine therapy might result in presenting one of the most threatening ADR through exhibition of leucopenia. Variants in the gene encoding TPMT are held responsible for altering the enzymatic activity that leads to leucopenia through accumulation of the heightened levels of thiopurine metabolites (7). Deficiency in the TPMT gene culminates in the accumulation of 6-mercaptopurine in addition to the wide conversion of 6-mercaptopurine to cytotoxic 6-thioguanine nucleotides analogues that might lead to the causation of bone marrow toxicity and myelosuppression. These effects are particularly visible in patients with irritable bowel disease as well as those patients who are likely to undergo organ transplantation and hence require immunosuppressant drugs (8).

Genetic polymorphism in the 6-mercaptopurine enzymes has been found to play a central role in the generation of ADRs that might have potential repercussions in the metabolic pathways. Thiopurine induced ADRs in the form of hepatotoxicity or pancreatits are found not to be the resultant effect of the TPMT polymorphism in many of the cases. Situations specific to acute lymphoblastic leukemia, irritable bowel disease and other types of autoimmune disorders are compliant with these findings. TPMT deficient genotypes in conjunction with heterozygous individuals are likely to face the negative outcomes relevant to thiopurine induced severe hematotoxicity. On the other hand, the factors relevant to modulation of the risk of myelosuppression are found to be affected by factors related to disease progression and introduction of co-medications. The wild type TPMT alleles are found to express more severe symptoms that might further affect the metabolism of the individuals who are deficient in TPMT gene in contrast to those who possess the TPMT variants. Research has shown that TPMT gene variant allele require significantly lower median cumulative dosage as well as cumulative median daily dose of mercaptopurine in contrast to those possessing the wild type alleles (9).

Role of HLA Molecules in Immune System

The underlying mechanism that link ADR with TPMT has been studied across various researches. The inter-individual variability in relation to the TPMT activity has been found to be significantly affected by several factors that include the levels of the enzymatic activity of the functional gene. Thiopurine therapy has been opined to exert detrimental effects leading to the causation of certain diseases (10). Both genetic and non-genetic biomarkers are found to exert their influences in the emanation of adverse drug reaction through modulation nd alteration of the TPMT gene. Those individuals who express the mutant TPMT genes have been reported of presenting more severe form of leucopenia in comparison to those who possess the TPMT wild type variants. The TPMT polymorphism genotyping are found to showcase such results through following of proper protocols and relevant procedures (12).

Advancements of knowledge of ADR for TPMT have undergone significant changes in the recent years. The most significant and empowering achievement of all has been the introduction of personalized medicine that corroborates to the application of the discipline concerning pharmacogenomics into effective clinical practice. The clinical outcomes of the genotype-phenotype interactions following a specific drug application have been addressed in certain cases whereby pharmacokinetics has profound influence. The phenoconversion phenomenon because of drug interactions present challenges by mimicking the genetically determined enzyme deficiency that is intimately associated with  understanding the ADR and TPMT gene relationship. In order to avert the potential negative outcomes of the TPMT gene, laboratory tests of both genotypic and phenotypic nature may be considered for screening of the vulnerable individuals and gaining information about the TPMT status. Further in cases of toxicity of myelosuppression type, TPMT testing has been suggested as per the studies that account for adjusting the mercaptopurine dose as well as for the sake of administering the normal dose of other myelosuppressive chemotherapy for the purpose of carrying out treatment. The allelic pattern specific to a patient may be determined by means of genotypic testing. On the other hand, phenotypic testing caters to the detection of the thiopurine nucleotides or further determination of TPMT activity in erythrocytes. More precaution and care must be taken while conducting phenotypic testing as the coadministered drugs might affect the measurement of TPMT activity in blood.  Further recent blood transfusions might misrepresent the actual TPMT activity. Hence, the clinical practices to mitigate ADR associated with TPMT gene must be handled deftly (12).    

References

Pirmohamed M, Ostrov DA, Park BK. New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity. Journal of Allergy and Clinical Immunology. 2015 Aug 31;136(2):236-44.

A Cornejo-Garcia J, Oussalah A, Blanca M, Gueant-Rodriguez RM, Mayorga C, Waton J, Barbaud A, Gaeta F, Romano A, Gueant JL. Genetic predictors of drug hypersensitivity. Current pharmaceutical design. 2016 Dec 1;22(45):6725-33.

Ho SS, McLachlan AJ, Chen TF, Hibbs DE, Fois RA. Relationships Between Pharmacovigilance, Molecular, Structural, and Pathway Data: Revealing Mechanisms for Immune?Mediated Drug?Induced Liver Injury. CPT: pharmacometrics & systems pharmacology. 2015 Jul 1;4(7):426-41.

Yip VL, Alfirevic A, Pirmohamed M. Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review. Clinical reviews in allergy & immunology. 2015 Jun 1;48(2-3):165-75.

Pavlos R, Mallal S, Ostrov D, Buus S, Metushi I, Peters B, Phillips E. T Cell–Mediated hypersensitivity reactions to drugs. Annual review of medicine. 2015 Jan 14;66:439-54.

Grover S, Kukreti R. HLA alleles and hypersensitivity to carbamazepine: an updated systematic review with meta-analysis. Pharmacogenetics and genomics. 2014 Feb 1;24(2):94-112.

Coenen MJ, de Jong DJ, van Marrewijk CJ, Derijks LJ, Vermeulen SH, Wong DR, Klungel OH, Verbeek AL, Hooymans PM, Peters WH, te Morsche RH. Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology. 2015 Oct 31;149(4):907-17.

Abaji R, Krajinovic M. Thiopurine S-methyltransferase polymorphisms in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders: influence on treatment response. Pharmacogenomics and personalized medicine. 2017;10:143.

Farfan MJ, Salas C, Canales C, Silva F, Villarroel M, Kopp K, Torres JP, Santolaya ME, Morales J. Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia. BMC cancer. 2014 Apr 28;14(1):299.

Tan Y, Hu Y, Liu X, Yin Z, Chen XW, Liu M. Improving drug safety: From adverse drug reaction knowledge discovery to clinical implementation. Methods. 2016 Nov 1;110:14-25.

Tamm R.In-depth analysis of factors affecting variability in thiopurine methyltransferase activity (Doctoral dissertation).

Lennard L. Implementation of TPMT testing. British journal of clinical pharmacology. 2014 Apr 1;77(4):704-14.