Studies On Genetic Polymorphism Of Drug Metabolizing Enzymes And Other Relevant Genes In Type 2 Diabetes Mellitus - Essay Example

Genetic polymorphism is now considered the major cause of Type 2 diabetes mellitus development due to association studies in major populations including Caucasians, Africans and Asians. Understanding of genetic polymorphism is facilitated by considering the differences of genetic pools among various ethnic groups in the world. Although Arabs are usually identified as Caucasians, modern Arab populations, especially in Egypt, Palestine, Jordan and Lebanon, are the result of a long history of blending with different human races (Der Kalustian et al.,1980). Arabs, Africans, Europeans, and other Asian people intermarried during wars, mass migrations, trade and religious practices (pilgrimage). Overall, this kind of "out breeding" rendered Arab populations more susceptible to genetic disorders when it comes to consanguinity. This may be explained by the fact that the out-breeding introduced a variety of deleterious recessive alleles common among other populations apart from the alleles already common among Arabs. Therefore, data obtained from other ethnic groups cannot be applied to the Arab population. There is no previous report available on the genetic polymorphism of CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, CYP11B1, CYP11B2, Haptoglobin, ACE, PPARG2, TCF7L2, Haptoglobin and IL-1RA and their association with T2DM in the Arab population. Hence, the present research project has been undertaken with the aim to establish the genetic polymorphism of these genes in the Arab population and to carry out the Association study of genetic variants of these genes with T2DM. Relevance The proposed study will facilitate improvement of the drug therapy and diagnosis of T2DM in the Arab population residing in the UAE. The study may find new genetic risk factors of T2DM in Arabs which can be utilized as targets for early diagnosis of T2DM, screening and more personalized medical therapy and potential development of new antidiabetic drugs. The primary objective of this project falls within the Abu Dhabi Vision 2030. This study will lead to substantial improvements in quality of life for affected individuals and a reduction of healthcare costs. Objectives and Goals We propose to initiate a seed project in the United Arab Emirates (UAE) and particularly in Abu Dhabi with the aim of studying the Genetic Polymorphism Of Drug Metabolizing Enzymes and Other Relevant Genes In Type 2 Diabetes Mellitus and related Complications in Arabs Residing in the UAE. Our long term goals are to utilize the outcome of the study in individualization of drug therapy and molecular diagnosis of T2DM in the Arab population residing in the UAE, to develop new techniques for molecular diagnosis of T2DM, to find new genetic risk factors of T2DM in Arabs which will be utilized as markers of early diagnosis of T2DM as well as targets for development of new antidiabetic drugs, to find the prevalence of genetic polymorphism of the above mentioned genes in the Saudi Arab population and to work towards the individualization of drug therapy for T2DM based on the genetic profile of patients. Our immediate goals are to study allele and genotype frequencies of CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, CYP11B1, CYP11B2, Haptoglobin, ACE, PPARG2, TCF7L2, and IL-1RA in the Saudi Arabian population, to carry out the association study of genetic variants in these genes with Type 2 Diabetes Mellitus and related hypertension and nephropathy, as well as to compare the allele and genotype frequencies found in Arabs with those in other ethnic groups. Project Description Background DRUG METABOLISM AND CYTOCHROME P450 (CYP) Cytochromes P450 (CYPs) represent a super family of heme-containing proteins, found primarily in the liver. Eighteen gene families, consisting of 43 subfamilies, 57 active and 58 pseudogenes, exist in the human (Nelson et al, 2004). The members of the first 3 families (CYP1, 2 and3) are involved in the metabolism of drugs. Hence, these CYPs play an important role in the pharmacokinetics of drugs. It is now well documented that large inter-individual variation in drug response observed in various ethnic groups results from genetic polymorphism in CYPs. CYP1 family has 2 subfamilies, CYP1A and 1B. CYP1A has two genes, namely CYP1A1 and CYP1A2. Both members of CYP1A perform an important role in biotransformation of xenobiotics in food and environmental pollutants. Also, some commonly prescribed drugs are substrates of CYP1A2. These include antipsychotics, namely clozapine and olanzapine. CYP2 is the largest among CYP families and consists of 13 subfamilies, namely CYP2A to 2H, 2J, 2S, 2T, 2U, and 2W. CYP2A has 3 active genes CYP2A6, CYP2A7 and CYP2A13, and 3 pseudo-genes. CYP2A6 metabolizes several xenobiotics, including coumarin, butadiene and nicotine. CYP2C has four genes, namely CYP2C8, 2C9, 2C18 and 2C19. CYP2C8 metabolizes at least 5 % drugs including paclitaxel, all-trans retinoic acid, cerivastatin, rosiglitazone and amodiaquine. CYP2C19 metabolizes antidepressants, benzodiazepines and proton pump inhibitors (PPIs). CYP2D has a single gene, namely CYP2D6, and two pseudo genes. CYP2D6 metabolizes more than 80 drugs including antidepressants, antianginals, analgesics, neuroleptics, antiarrhythmics, antiinflammatory agents, antitussives, and b-blockers. CYP3 plays an important role in the metabolism of a large number of chemotherapeutic drugs. CYP3 has one subfamily of. CYP3A, which consists of four genes, namely CYP3A4, 3A5, 3A7, 3A43, and two pseudo-genes CYP3A5P1 and CYP3A5P2. CYP3A members are most abundant CYPs and account for approximately 30 % of total CYP content in the human liver. CYP3A forms the most versatile biotransformation systems that facilitate the elimination of xenobiotics and endobiotics from the body. It is generally accepted that CYP3A members play a greater role in the metabolic elimination of numerous drugs than any other biotransformation enzyme. Genetic polymorphism of CYPs: Genetic polymorphism is the occurrence of a variant allele of gene with a frequency of 0.01 or greater in a population (Nebert, 2000). CYPs are highly polymorphic genes. Genetic polymorphism of many CYPs has been established, including CYP1A1, CYP1A2, CYP2A6, CYP2C8, CYP2C19, CYP2D6 and CYP3A. Various allelic forms of these CYPs have been reported in a range of ethnic groups like Caucasians, Africans, and Asians. A large inter-individual variation in drug response has been observed in these ethnic groups because of variations in the CYPs genes. The role of CYP polymorphism in etiology of diabetes has also been examined in one recent study (Weise et al, 2010) Type 2 diabetes mellitus (T2DM) is a common disease characterized by insulin resistance and reduced insulin secretion. It has become a health problem world-wide, yet the underlying molecular mechanisms involved in the development of diabetes remain poorly understood. Linkage and candidate gene studies have been highly successful in identifying genes for monogenic and syndromic forms of diabetes. However, this approach has yielded limited results in mapping the genes for T2DM. The latest success of the genome-wide association (GWA) studies using high density SNPs across the genome and complex genetic analyses have identified several genes with previously unknown functions (Waters et al, 2010; Tan et al, 2010). In this investigation, we will examine the role of genetic polymorphism of nine most significant genes with T2DM in a diabetic case-control cohort of Arabs residing in the UAE. These genes were previously reported to be polymorphic. However, no report is available for the Arab population of the UAE. Our study will be focused on the Cytochrome P450 3A4 (CYP3A4), CYP3A5, CYP11B1, CYP11B2, Haptoglobin, angiotensin converting enzyme (ACE), peroxisome proliferator-activated receptor gamma 2 (PPARG2; Pro12 Ala;rs1801282), Transcription factor 7 like2 (TCF7L2), and Interleukin-1 receptor antagonist (IL-1RA). CYP3A4 and 3A5 are xenobiotic metabolizing enzymes found in the liver. The role of these CYPs has been hypothesized in the progression of T2DM on the basis of their involvement in the metabolism of cortisol to its active metabolite 6 beta-OH-Cortisol. These genes are highly polymorphic, and their genetic variants have been reported in various ethnic groups. CYP11B2 encodes the enzyme aldosterone synthase which catalyzes 3 terminal steps 11b-hydroxylation, 18-hydroxylation, and 18-oxidation of the precursor, as well as 11- deoxycorticosterone in aldosterone synthesis. In the zona fasciculata, cortisol is synthesized by a similar pathway, but the final stage is an 11b-hydroxylation of 11- deoxycortisol (S) by the highly homologous enzyme 11b-hydroxylase. The CYP11B1gene, which is controlled by the adrenocorticotropic hormone (corticotrophin [ACTH]), encodes 11b-hydroxylase. ACE catalyzes the synthesis of angitensin II which regulates the synthesis of aldosterone by regulating CYP11B2 genes. Haptoglobin (Hp) is a plasma a2-glycoprotein which binds free haemoglobin, thus preventing oxidative damage. The essential role of Hp in removing free haemoglobin from the circulation and the existence of several Hp types of differing molecular masses suggests the possibility of associations between Hp types and the disease (Costacou et al, 2008). Angiotensin converting enzyme (ACE) is involved in synthesis of angiotensin II, an active component of RAS system which regulates the blood pressure. Angiotensin can directly act on kidney tubules as well as increas the secretion of aldosterone, the hormone required for Na+ and water retention in the body. Hence, polymorphism in ACE gene may affect the blood pressure and renal function in diabetics. Peroxisome proliferator-activated receptor (PPAR) ? is a nuclear hormone Receptor that binds to the PPAR response element (PPRE), a direct repeat of AGGTCA spaced by a nucleotide on DNA as a heterodimer with retinoid X receptor (RXR). and transactivated by its ligands including 15-deoxy-?12,14-prostaglandin J2 (15dPGJ2), and insulin-sensitizing thiazolidinediones (TZDs). The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR-g2 was found to associate with reduced risk for type 2 diabetes (Sanghera et al, 2008). Transcription factor 7-like 2 (TCF7L2) gene spans a 215,863 bases region on chromosome 10q25.3, and its product is a high-mobility box-containing transcription factor that has a role in activating many genes downstream of the Wnt signaling pathway and in T2DM. An association has recently been established between type 2 diabetes and a variation in the transcription factor TCF7L2 gene (Tong et al, 2009; Ng et al, 2008; Rees et al, 2008). Several case-control studies have now replicated these findings (Lin et al, 2010). Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring inhibitor of IL-1a and -b. Although devoid of biological activity, IL-1RA competes with IL-1 for binding to IL-1 receptors. The gene coding for IL-1RA is polymorphic. A region within the second intron contains a variable number of 86-bp tandem repeats. This polymorphism in the IL-1RA gene has been associated with many clinical conditions, including altered metabolic conditions, type 2 diabetes and related complications. Innovation An extensive review of the literature using PubMed and Science Direct revealed a scarcity of published studies on the genetic polymorphism of drug metabolizing enzymes and other relevant gene in Type 2 Diabetes Mellitus among Arabs and no studies conducted among the UAE population. Therefore, the proposed study will be the first pharmacogenetic study focusing on the identification of the genes involved in the drug metabolizing enzymes related to T2D among the UAE population. Thus, the completion of this important project will help to diagnose the T2DM and adjust the dose of the drugs to T2DM patients. Broader Impact The proposed work described here will systematically catalogue samples and clinical data of the populations in the UAE (and possibly other representatives of the Arab world). It will be an invaluable resource for basic research focused on identifying genetic polymorphism of drug metabolizing enzymes and other relevant genes in Type 2 Diabetes Mellitus that afflict the local population of the UAE. The study will result in great benefits gained from the identification of genes that contribute to the disease since it will help to adjust the medication dose. The understanding of the etiology of the drug metabolism for T2DM disease will improve prognosis and assist in the development of cures and intervention studies. These measures will improve the quality of life of the citizens of the UAE through the provision of better health care services and a reduction of healthcare costs. Internal Benefits The Molecular laboratory in the Department of Biomedical Science at Khalifa University will provide the following benefits to the collaborators: Training opportunities for medical graduates, Medical doctors, and students. Typically, staff transfer will be encouraged and experts from other institutions could be placed at Khalifa University. Double badge opportunities for students with reputable universities will be explored and adjunct positions for staff will be established. Two interns will be hired in the project with undergraduate or postgraduate qualification. These interns will be given hands-on training of genotyping techniques to be used in the project. Regional Benefits The borders currently separating nations of the Arab world are political boundaries. These do not account for the distribution of the Arabs who can be found scattered throughout the Middle East and the rest of the world. The benefits from the discoveries made through this project will extend to all nations across this region. Despite the unique nature of the project initiative which focuses on Arabs, the concept of the pharmacogenetic study is not novel. Hence, other research groups in the region will predictably contemplate the establishment of similar initiatives. So the essential mandate of this project will be to promote cooperative research throughout the region. Consequently, successful implementation of this plan will result in this inaugural Arab-based epidemiological resource based in the UAE. Read More