BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for druginduced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A* 33: 01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9 - 3.8; P = 2.4 x 10(-8)) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6 - 2.5; P = 9.7 x 10(-9)). The association with A* 33: 01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A* 33: 01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6 - 2.7; P = 4.8 x 10(-9)). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0 - 9.5; P = 7.1 x 10(-9)). We validated the association between A* 33: 01 terbinafine-and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A* 33: 01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.

Abstract Background Falls are common undesirable events for older adults in institutions. Even though the patient’s fall risk may be scored on admission, the medication-induced fall risk may be ignored. This study developed a preliminary categorization of fall-risk-increasing drugs (FRIDs) to be added as a risk factor to the existing fall risk assessment tool routinely used in geriatric care units. Methods Medication use data of older adults who had experienced at least one fall during a hospital ward or a nursing home stay within a 2-year study period were retrospectively collected from patient records. Medicines used were classified into three risk categories (high, moderate and none) according to the fall risk information in statutory summaries of product characteristics (SmPCs). The fall risk categorization incorporated the relative frequency of such adverse drug effects (ADEs) in SmPCs that were known to be connected to fall risk (sedation, orthostatic hypotension, syncope, dizziness, drowsiness, changes in blood pressure or impaired balance). Also, distribution of fall risk scores assessed on admission without considering medications was counted. Results The fall-experienced patients (n = 188, 128 from the hospital and 60 from nursing home records) used altogether 1748 medicaments, including 216 different active substances. Of the active substances, 102 (47%) were categorized as high risk (category A) for increasing fall risk. Fall-experienced patients (n = 188) received a mean of 3.8 category A medicines (n = 710), 53% (n = 375) of which affected the nervous and 40% (n = 281) the cardiovascular system. Without considering medication-related fall risk, 53% (n = 100) of the patients were scored having a high fall risk (3 or 4 risk scores). Conclusion It was possible to develop a preliminary categorization of FRIDs basing on their adverse drug effect profile in SmPCs and frequency of use in older patients who had experienced at least one documented fall in a geriatric care unit. Even though more than half of the fall-experienced study participants had high fall risk scores on admission, their fall risk might have been underestimated as use of high fall risk medicines was common, even concomitant use. Further studies are needed to develop the FRID categorization and assess its impact on fall risk.

Aims Type 2 diabetes (T2D) is a progressive disease often associated with comorbidities that complicate the management of T2D and affect the achievement of treatment targets. However, adherence to guidelines and individualized treatments can potentially improve treatment outcomes. This study assessed the association between different glucose lowering and lipid lowering medication lines and the achievement of treatment targets with different comorbidities among a T2D cohort in North Karelia, Finland (2011-12 to 2015-16). Methods The data on all diagnosed T2D patients (n = 10,190) in North Karelia were collated retrospectively from regional electronic health records (EHRs). Analyses were performed considering the age, sex, and comorbidities such as cardiovascular diseases (CVD) and any mental disorders (AMD). We analyzed the trends in using glucose lowering and lipid lowering medications and the effect of changes in medication on the achievement of treatment targets among different patient groups. Results Metformin was the most common treatment in all patient groups. The use of only metformin declined and the use of metformin and/or other non-insulin medications increased during the follow-up. A Combination of insulin and non-insulin medication was mostly used by T2D patients with both cardiovascular diseases and mental disorders (T2D + CVD + AMD), and the use of insulin increased among this group in follow-up. Achievement of the glucose treatment target deteriorated even after the intensification of medication among all patient groups during the follow-up. A considerably higher number of patients with T2D + AMD and T2D + CVD + AMD did not use lipid lowering medication when compared to the T2D + CVD patients both at baseline and follow-up. However, the achievement of the LDL treatment target improved during the follow-up. Conclusion Achievement of the glucose target deteriorated even after the intensification of treatment, and especially among patients with multiple diseases. Many T2D patients with AMD and CVD remained without lipid lowering medication, which needs further attention.