Department of Medical Sciences

Clinical pharmacogenetics and osteoporosis

Genetic and environmental factors play important roles for the development of osteoporosis and other diseases, but also for how individuals respond to drug treatment. Starting with the question why the incidence of osteoporosis is so very high in Sweden, we are investigating genetic - and environmental risk factors for this disease. In our pharmacogentic research programs, we look for genetic differences between individual that can explain variable responses to pharmaceutical drug treatments, with the goal to enable personalized drug dosage.

Each year some 18 000 Swedes suffer from hip fracture, the most serious consequence of osteoporosis. Through epidemiological studies we have shown that a high intake of Vitamin A correlates with an increased risk of osteoporosis. We are now trying to identify additional risk factors, and are studying the molecular mechanisms responsible for the bone toxicity of Vitamin A.

The optimal dose of a drug is a balance between efficacy and side effects, and may vary significantly among individuals due to genetic differences. One such drug is warfarin, used worldwide to prevent blood thrombi, that causes excess bleeding in subgroups of patients. Through pharmacogenetic studies we have identified two genes that affect what is the optimal dose, and thereby facilitated a personalized adjustment of warfarin treatment. In similar studies we work with drugs used to treat e.g. Alzheimer's disease and schizophrenia towards the goal to identify genetic markers which can be employed to optimize the dosage for individual patients.

Projects

Clinical Pharmacogenetics and Osteoporosis

Håkan Melhus, Mia Wadelius, Pär Hallberg and Gabriella Scordo

Genetic, dietary and environmental risk factors for osteoporosis

Thomas Lind, Annica Rasmusson, Håkan Melhus

We aim to identify and study genetic and environmental risk factors that can help us explain why Sweden and Norway have the world’s highest incidence of osteoporotic fractures, and to develop new treatments for osteoporosis. We have primarily studied genetic and dietary factors, especially vitamin A and D.

In a collaboration project with Assoc. Prof. M Lind financed by Formas we also investigate if developmental low-dose exposure to bisphenol A disturbs the balance between bone and adipose tissue.

Mechanistic studies on Vitamin A-induced bone toxicity

Thomas Lind, Annica Rasmusson, Håkan Melhus

Vitamin A is the only known substance that can induce spontaneous fractures in laboratory animals. We have previously shown that excessive doses lead to a reduced diameter of the long bones without affecting the bone mineral density in rodents, i. e. a new type of bone fragility. We try to clarify the molecular mechanisms behind this vitamin A-induced bone toxicity by both in vitro and in vivo studies.

Warfarin pharmacogenetics and pharmacometrics

Niclas Eriksson, Anna-Karin Hamberg, Hugo Kohnke, Mia Wadelius

There have been significant advances in the pharmacogenetics of warfarin, but also controversies. In 2015, we further explored reasons for discordant results in randomised clinical trials. We published a tool for pharmacometric modelling and simulation of warfarin dose. We presented a novel gene regulatory variant associated with warfarin dose at the American Society of Human Genetics (ASHG) meeting in October 2015.

Genetics of serious adverse drug reactions

Pär Hallberg, Håkan Melhus, Mia Wadelius

SWEDEGENE (www.swedegene.se) is a national study of genetic susceptibility to adverse drug reactions led by our group. We currently have clinical data and DNA from over 2300 cases and access to genome-wide data plus diagnoses and withdrawn prescriptions from 5000 Swedish controls. We lead the European Drug-induced Agranulocytosis Consortium, and presented these results at the American Society of Human Genetics (ASHG) meeting in October 2015. We are partners of the EU FP7 funded study PREDICTION-ADR. Genome-wide genotyping or exome sequencing is performed at the Uppsala SciLife SNP&SEQ platform.

Improving the Quality and Safety of Drug Use in Hospitalized Elderly

Ulrika Gillespie, Håkan Melhus

Elderly people admitted to hospital are at high risk for rehospitalisation and medication errors. In a previous randomized controlled trial (RCT) we could show that a clinical pharmacist intervention reduces the

number of revisits to hospital for patients 80 years or older acutely admitted to hospital. Starting in 2017, we will perform a multicentre, cluster-randomized, crossover trial studying the effects of hospital-initiated comprehensive medication reviews, including active follow-up on elderly patients’ healthcare utilization compared to solely hospital based reviews and usual care.

Bisphosphonate-Associated Atypical Fractures and osteoporosis

Pär Hallberg, Mohammad Kharazmi

We aim to increase the knowledge about the adverse effects of bisphosphonates, manifesting as atypical fractures in the skeleton and osteonecrosis of the jaw. Specifically, we have studied the relative risks of atypical fractures associated with different bisphosphonates, whether gender is a risk factor, described the characteristics of prodromal symptoms, and published case reports of bisphosphonate-related osteonecrosis of the jaw. We are currently investigating whether or not atypical fractures are associated with an increased mortality compared with ordinary low-trauma fractures of the femoral shaft. These studies are partly based on data from SWEDEGENE.

Pharmacogenetics and therapeutic outcome

Gabriella Scordo

Gabriella Scordo

We investigate, by an integrated pharmacokinetic-pharmacodynamic approach, the contribution of allelic variability in genes coding for proteins involved in drug metabolism, transport and effects to the clinical outcome of the drugs used in neuropsychiatry (with focus on the therapy of schizophrenia, depression and Alzheimer’s disease) and cardiology. The aim is to identify genetic markers of treatment outcome, quantify their predictive value, and evaluate how this information can be used to design genotype-based dosing schedules for improved pharmacotherapy. Furthermore we evaluate the frequencies of these polymorphisms in different ethnic groups, in order to identify differences in the distribution patterns underlying the need for different dose recommendations in different populations.

Clinical consequences of polymorphisms in xenobiotics metabolising enzymes

Gabriella Scordo

Gabriella Scordo

We collaborate in an international, multicenter project that aims to identify and clarify the role of the genetic polymorphism in the enzymes that metabolize xenobiotics in the susceptibility to develop Multiple Chemical Sensitivity (MCS), a multi-systemic syndrome characterized by intolerance to environmental chemicals.