Pharmacogenetics and pharmacogenomics: moving towards personalized medicine

Genetic polymorphisms are well recognized as one of the main cause of variations in personal drug response. Pharmacogenetics investigates the role of polymorphisms in the individual response to pharmacological treatments in order to design specific genetic tests, which can be performed before drug administration to optimize drug response and reduce adverse events.

by Dr Francesca Marini and Professor Maria Luisa Brandi

Personalized medicine based on genetics
The complete sequencing of the human genome in 2001, by the Human Genome Project, has opened the new era of personalized medicine based on genetics. Polymorphic variations are suspected to cover at least 20% of the entire human genome. An average of about 6 million single nucleotide polymorphisms (SNPs) and other sequence variations (i.e. copy number variations, CNVs) are estimated to exist between any two randomly selected human individuals. Advancements in understanding of variations in the human genome and rapid improvements in high-throughput genotyping technology have made it feasible to study most of the human genetic diversity in relation to phenotypes. Today, the challenge for genomic medicine is contextualizing the myriad of genomic variations in terms of their functional consequences for disease predisposition and for different responses to medications.

The ability to predict the outcome of drug therapies, by a simple analysis of common variants in the genotype, is today one of the main challenges for individualised medicine. Pharmacogenetics and its whole-genome application, pharmacogenomics, are the utilization of individual genetic data to predict the individual response to drug treatment with respect to both beneficial and adverse effects.

They, currently, represent one of the disciplines most pursued by basic and clinical research. Pharmacogenetics examines the single gene and/or single polymorphism influences in drug response in terms of drug absorption and disposition (pharmacokinetics) or drug action (pharmacodynamics), including polymorphic variations in genes encoding drug-metabolizing enzymes, drug transporters, drug receptors and drug biological targets. Pharmacogenomics studies alterations in gene and protein expression that may be correlated with pharmacological function and therapeutic response, encompassing factors beyond those that are inherited, such as epigenetics (pharmacoepigenomics).

One of the main goals of pharmacogenetics and pharmacogenomics is the identification of genetic biomarkers that lead to the recognition, in advance, of patients who will not respond to a therapy, or who will be at risk of developing adverse reactions, in order to design specific pre-prescription genetic tests. A biomarker is most commonly a genetic variant, but can also include functional deficiencies, expression changes, chromosomal abnormalities, epigenetic variants, etc. A necessary step, for the application of pharmacogenetic results into clinical practice is the validation of biomarkers, a process that requires several stages: 1) the correct design of prospective association studies and setting of all experimental conditions to increase sensitivity, reliability and specificity of the assay; 2) replication of results in different, independent studies; 3) biomarker characterization, through evaluation of variability of a particular biomarker in different human populations to determine ethnical differences, relevant interactions and potential confounders; and 4) expression and functional studies, to establish the possibility of a casual relationship between a candidate biomarker and the response to a drug.

Pharmacogenetic data on more than 110 commonly used drugs and over 35 genes are currently depicted in the Food and Drug Administration (FDA)-approved “Table of Pharmacogenomic Biomarkers in Drug Labels” (, and, for many of them, the list includes specific clinical actions to be taken based on genetic information. These specific tests are currently used in clinical practice, mostly in oncology, psychiatry, neurology and cardiovascular disease. The first clinical application of a pharmacogenetic test was approved by the FDA in January 2005: the AmpliChip CYP450 test that includes genetic variants of CYP2C19 and CYP2D6 genes (two drug–metabolising P450 cytochromes, responsible of the most frequent variation in phase I metabolism of approximately 80% of all prescribed drugs today). In June 2007, the FDA released an online “Guidance on pharmacogenetic tests and genetic tests for heritable markers” (available at, which presents general guidelines for the rapid transfer of experimental results to the clinical practice and for the correct performing and data handling of pharmacogenetics screenings. The application of rapid, simple and non-invasive pharmacogenetic tests, that can be easily performed on a blood sample and do not need to be repeated during the patient’s lifetime, would help clinicians in tailoring the best therapy for each patient, reducing adverse events and maximizing positive effects. Results from pharmacogenetic tests would allow clinicians to adjust dosages, choose between similar drugs or offer an alternative therapy, if available, before the administration of each treatment. Data obtained from pharmacogenetic tests should become part of the patient medical records, with access protected by medical privacy laws, and available, before drug administration, to clinicians granted the official permission of the patient.

The accuracy of pharmacogenetic testing and the correct management and interpretation of the results will become crucial factors in determining the benefits and/or risks for patients. Also, all the new technologies, including the development of pharmacogenetic diagnostic tools, will require a high level of expertise to be appropriately applied. Several studies have documented the lack of knowledge and confidence of primary care physicians in the field of genetic tests, with only 4% of general practitioners in the US and only 21% in the UK feeling confident and sufficiently prepared for counselling patients regarding genetic tests [1, 2]. Specific training programmes about pharmacogenetic testing for medical geneticists and health care professionals are strongly recommended and they should encompass clinical genetics, genetic counselling, knowledge of inherited and ancillary genetic data management and legal protection.

Pharmacogenetics and osteoporosis: state of the art and translation into clinical practice
Osteoporosis is the most common metabolic bone disorder of the elderly, affecting both sexes (with a higher prevalence in women) and all ethnicities, and is characterized by a low bone mass and bone microarchitectural deterioration, with a consequent increase in bone fragility and susceptibility to spontaneous fracture. Today it is well known that, despite the fact that osteoporosis is a multifactorial complex disorder, genetic factors exert a key role in the acquisition of personal bone mass peak, in the determination of microarchitectural bone structure, and in the regulation of bone metabolism. Numerous and effective anti-fracture treatments, acting on bone cells to restore a normal bone turnover, are today available: hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), bisphosphonates, calcitonin, parathyroid hormone (PTH), Teriparatide, Strontium Ranelate, and anti-RANK monoclonal antibody (Denusomab), administered alone or in combination with supplements of vitamin D and calcium. Response to all of these drugs is variable among treated patients both in terms of efficacy [evaluated as bone mineral density (BMD) gain, reduction of bone turnover, reduction of fracture risk] and of adverse reactions. In the last two decades, some pharmacogenetic studies on anti-osteoporotic drugs have been performed, but their number is still very limited and no conclusive results are available yet.

The main characteristics and results of these studies have been summarized in some recent reviews [3–5]. Results, replicated in at least two different unrelated studies, seem to indicate that:

  1. The PvuII polymorphism of estrogen receptor alpha (ERα) gene is associated with the response to HRT. The P allele appeared to have a more positive effect on BMD maintenance and gain and on reduction of fracture risk.
  2. The BsmI polymorphism of vitamin D receptor (VDR) gene is associated with the response to various anti-osteoporotic therapies (raloxifene and bisphosphonates – the latter alone or in combination with raloxifene or HRT). The BB genotype seemed to be related to a higher BMD increase after drug treatment.
  3. Sp1 polymorphism of the gene encoding the alpha1 chain of collagene type 1 (COL1A1) is associated with the response to HRT and bisphosphonates. SS genotype was found to be associated to higher increase of BMD.
  4. The rs2297480 polymorphisms of the farnesyl pyrophosphate synthase (FDPS) gene is associated to the response to bisphosphonates. A allele and AA genotype seemed to present a better response in terms of reduction of bone turnover markers or increase of BMD values.

These preliminary data appear to be promising, but they surely need to be implemented and validated before any application to clinical practice. Association studies on pharmacogenetics of osteoporosis need to be confirmed in larger cohorts, different ethnical populations and multicentre studies, preferentially from prospective controlled clinical trials, including analysis of genetic variations in genes encoding for drug transporters, drug receptors, drug metabolizing enzymes and drug molecular targets. Moreover, the single gene-approach should be integrated with multi-candidate gene and genome-wide association studies on large cohorts to individuate also unsuspected candidate genes and polymorphisms. Subsequently, data obtained from genetic studies should be implemented and validated using gene expression and proteomic analyses and by performing specific functional in vitro and in vivo studies. Also, the effects of epigenetic mechanisms (i.e. histone modifications, cytosine methylation in gene promoters and microRNAs), on the regulation of expression of genes encoding drug metabolic enzymes, transporters receptors and targets, should be taken into account and investigated.

1. Burke W, Emery J. Nat Rev Genet 2002; 3(7): 561–566.
2. Suchard MA, Yudkin P, Sinsheimer JS, Fowler GH. Br J Gen Pract 1999; 49(438): 45–46.
3. Marini F, Brandi ML. Expert Rev Endocrinol Metab 2010; 5(6): 905–910.
4. Marini F, Brandi ML. Curr Osteoporos Rep 2012; 10(3): 221–227.
5. Marini F, Brandi ML. J Pharmacogenom Pharmacoproteomics 2012; 3(3): 109.

The authors
Francesca Marini PhD and Maria Luisa Brandi MD, PhD
Metabolic Bone Unit, Department of Internal Medicine, University of Florence, Florence, 50139, Italy.