Pharmacogenetic Epidemiology of Statins in an Ageing Population

__Abstract__ Cardiovascular disease (CVD) is an important cause of morbidity and mortality worldwide. The increasing incidence and prevalence of CVD constitutes a considerable disease burden and major health challenge for prevention and treatment. CVD frequently co-exists with other diseases such as type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver diseases (NAFLD), which are both strongly related to the metabolic syndrome. The 3- hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors or statins are cholesterol-lowering drugs that are beneficial in the primary and secondary prevention of CVD. With an approximately 20-25% reduction of the risk of major cardiovascular endpoints, these drugs have definitely entered daily clinical practice, and their use is expected to increase even more with a widening of therapeutic indications. However, current pharmacotherapy may not be optimal for all patients, and some individuals may not respond adequately to statins. This inadequate response may consist of a lack of therapeutic effect or the occurrence of adverse drug reactions (ADRs), and can have several underlying reasons. Insight into why people do not respond adequately to statins might improve clinical practice, can partly avoid these events, and may finally lead to tailored drug therapy. Moreover, in 2013, the American guidelines on primary prevention of CVD lowered the threshold for the indication for statin treatment, and thereby widened the target population for these already frequently prescribed drugs. This might have implications for current clinical practice, since prescribers should not ignore the potential risk of overtreatment or unintended effects that may go with this increased use. In this thesis we focused on the pharmacogenetic epidemiology of statins in an ageing population. We describe genetic factors that modify the response to statins, whereby we discovered new genetic variation and validated previous findings from genome-wide research and other relevant literature on the pharmacogenetics of statins. Furthermore, we describe unintended effects of the use of statins in clinical practice, and methodological approaches to estimate statin effectiveness in observational studies. Overall, in this t

A Large Skull Defect Due to Gorham-Stout Disease: Case Report and Literature Review on Pathogenesis, Diagnosis, and Treatment

A 24-year old man was referred to the Erasmus MC Bone Center because of an asymptomatic increasing skull defect of the left parietal bone. The defect was first noticed at the age of six, and gradually increased over the years. His medical history was unremarkable, without any known trauma and a negative family history for bone diseases. Laboratory tests showed a low vitamin D level without other abnormalities. Particularly, there was no increase in markers of inflammation or bone turnover. CT-scans of the skull showed an osteolytic region of the parietal skull bone, with a two-centimeter increase in diameter over 9 years. Contrast enhanced MRI showed lymphangiogenic invasion, which was compatible with our suspicion of Gorham-Stout disease. The patient was referred to the neurosurgeon for treatment with a bone graft while considering additional drug treatment. Gorham-Stout or vanishing bone disease is a rare entity characterized by progressive osteolysis with lymphangiogenic bone invasion. Although already reported in 1838, currently the diagnosis and treatment of Gorham-Stout disease is still challenging. The underlying pathophysiology is not clarified yet and several theories exist. The disease usually affects persons younger than 40 years and the majority present with bone disease of the maxillofacial region, the upper extremities or the torso. The clinical presentation includes most frequently pain, swelling, and functional impairment of the affected region, but the disease can also be asymptomatic. Laboratory investigations are usually normal, and diagnosis is based upon imaging and sometimes pathology examination of affected bone tissue. Treatment is experimental and there is no general consensus about the best option due to lack of randomized controlled trials. Case reports showed patients treated with bisphosphonates, interferon-alpha, anti-VEGF therapy, mTOR inhibitors, and radiotherapy. There are some reports of surgery with prosthetic or bone grafts but no long-term follow-up data exist. This paper describes a unique case of Gorham-Stout disease of the parietal skull bone and discusses the current state of knowledge about this rare bone disease

Dietary mineral intake and lung cancer risk: the Rotterdam Study

Objective: Limited data are available on the role of mineral intake in the development of lung cancer (LC). We investigated whether dietary calcium, copper, iron, magnesium, selenium and zinc intake were associated with LC risk. Methods: We analyzed data from 5435 participants of the Rotterdam Study, a prospective population-based cohort study among subjects aged 55 years and older. At baseline (1990–1993), diet was measured by a validated food frequency questionnaire. LC events were diagnosed on the basis of pathology data and medical records. Hazard ratios (HRs) on LC for energy-adjusted mineral intake were calculated using Cox regression models while adjusting for potential confounders. Results: During a follow-up period of 22 years, we identified 211 incident cases of LC. A higher zinc intake was associated with 42 % reduction in risk of LC (top tertile vs. first tertile: HR 0.58, 95 % CI 0.35; 0.94, P-for trend = 0.039). Similarly, high intake of iron was associated with reduced risk of LC (top tertile vs. first tertile: HR 0.58, 95 % CI 0.37; 0.92, P-for trend = 0.02