Javad Jamshidi Fasa University of Medical Sciences, December 2014 Session 8 Medical Genetics Pharmaco genetics

The sensitivity to drugs is different among people Individual differences in response to drugs in humans are, often genetically determined study of genetically determined variations that are revealed solely by the effects of drugs Pharmacogenetics is now used to describe the influence of genes on the efficacy and side effects of drugs 2

3

4

5 The metabolism of isoniazid shows two: rapid and slow inactivators. To avoid side effects and also efficient treatment dose should be controlled Slow inactivators are homozygous for an AR allele of the liver enzyme N-acetyltransferase, with lower activity levels Metabolize several other drugs include hydralazine which is an antihypertensive, and sulfasalazine,used to treat Crohn

6 N-acetyltransferase activity varies in different populations. There are three genes for N -acetyltransferase in Humans: NATP: pseudogene, is not expressed NAT1: No differences in activity between individuals NAT2 : Responsible for the inherited polymorphic variation

7 Some people are sensitive to primaquine Defective X-linked, glucose 6-phosphate dehydrogenase (G6PD). Sensitive to many other compounds, including phenacetin, and certain sulfonamides The first recognized Pharmacogenetic disorder, having been described by Pythagoras around 500 Be.

8 Coumarin anticoagulant drugs, such as warfarin, are used to prevent the blood from clotting Warfarin is metabolized by the cytochrome P450 enzyme encoded by the CYP2C9 gene (CYP2C9*2 and CYP2C9*3) result in decreased metabolism Require a lower warfarin dose to maintain their target INR range and may be at increased risk of bleeding

9 There is a bimodal distribution in the response to the drug in the general population. Approximately 5% to 10% of persons of European origin are poor metabolizers One of the P450 family of genes on chromosome 22, known as CYP2D6. This enzyme is involved in the metabolism of more than 20% of prescribed drugs including: β -blockers metoprolol and carvedilol The antidepressants fluoxetine and imipramine The painkiller codeine The anti-cancer drug tamoxifen

10 Personalized or individualized medicine, where the treatment is dependent on the individual's genotype Pharmacogenomics is the study of the interaction of an individual's genetic makeup and response to a drug. Inherited variation at the DNA level play an essential role in determining the variability in responses to a drug

11 The objective is to identify a genetic profile that characterizes patients who are more likely to suffer an adverse event. The best example is abacavir, used to treat HIV. About 5% of patients show fatal hypersensitivity to abacavir and this limited its use A strong association with the HLA allele B*5701 was proven in Today testing for B*5701 is routine practice before abacavir is prescribed.

12 Drug should be prescribed only to those patients likely to respond to them. Herceptin is an antibody that targets overexpression of HER2/neu protein observed in approximately one-third of patients with breast cancer. Patients are prescribed herceptin only if their tumor has been shown to overexpress HER2/neu.

Javad Jamshidi Fasa University of Medical Sciences, December 2014 Cancer Genetics

Uncontrolled growth of cells Not all tumors are cancerous Six characteristics of cancer cells: Self-sufficiency in growth signaling Insensitivity to anti-growth signals Evasion of apoptosis Enabling of a limitless replicative potential Induction and sustainment of angiogenesis Metastasis and invasion of tissue

Carcinoma Originate in epithelial origin, Most common,80-90 percent of all cancer Sarcoma Originates in supportive and connective tissues Myeloma Originates in the plasma cells of bone marrow Leukemia Cancers of the bone marrow (the site of blood cell production) Lymphoma Originate in glands or nodes of the lymphatic system

Small proportion is predisposed by inherited germline mutations behaving as mendelian traits For many cancers, environmental factors are etiologically more important than heredity Cancer is a genetic disease of somatic cells End result of an accumulation of both inherited and somatic mutations in cell growth related genes

Germline mutations in at least 70 genes, and somatic mutations in at least 350 genes In the majority of cancers, there is no clear-cut mode of inheritance, nor any clearly defined environmental cause Evidence to help differentiate environmental and genetic factors comes from epidemiological, family and twin studies, disease associations, biochemical factors

Breast cancer Women who have borne children have a lower risk The younger the age has her first pregnancy, the lower risk The later the age at menarche, the lower breast cancer risk Varies greatly between different populations Gastric cancer People from lower socioeconomic groups have an increased risk Salts and preservatives, nitrates, are possible carcinogens Shows variations in incidence in different populations Helicobacter pylori infection, increases the risk by five to six fold

The frequency with which other family members develop the same cancer can provide evidence for a genetic contribution. For a woman who has a first-degree relative with breast cancer, the risk is between 1.5 and 3 times the risk for the general population. In gastric cancer, first degree relatives have a 2-3 fold increased risk compared with the general population

Concordance rates for breast cancer in both monozygotic (MZ) and dizygotic (DZ) twins are low Only slightly greater in MZ female twins, at 17%, than the 13% found in DZ female twins. This suggests, overall, that environmental factors are more important than genetic factors.

Association of a particular blood group with a disease suggests a possible genetic contribution to the etiology. It is estimated that those with blood group A have a 20% increased risk of developing gastric cancer Blood group A  pernicious anemia  gastric cancer

Biochemical factors can determine the susceptibility to environmental carcinogens Association between slow-acetylator status and bladder cancer glutathione S-transferase activity, influences the risk of developing lung cancer in smokers

Certain viruses are tumor-forming or oncogenic in humans A limited number of DNA viruses, whereas a variety of RNA viruses, or retroviruses Epstein-Barr (EBV)  Burkitt lymphoma HepatitisB (HBV)  Hepatocellular carcinom