Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

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Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

https://cyberleninka.org/article/n/148766.pdf

Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation

The Rotterdam study

Background: Sequence variants, including the e4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. Methods: We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. Results: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P = 3.42×10-10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P = 2.1×10-12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P = 0.003). Conclusions: Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.) Copyright

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Variant of TREM2 associated with the risk of Alzheimer's disease

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation.

/pdf/large-scale-meta-analysis-of-genome-wide-association-data-36gj7mf6gp.pdf

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

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The Rotterdam Study: Objectives and design update

OBJECTIVE: Metformin is transported into the hepatocyte by organic cation transporter 1 (OCT1) and out of the hepatocyte by multidrug and toxin extrusion 1 (MATE1). Recently, we discovered that polymorphisms rs622342 A>C in the SLC22A1 gene, coding for OCT1, and rs2289669 G>A in the SLC47A1 gene, coding for MATE1, are associated with the degree of glucose lowering by metformin. In this study, we assessed whether there exists an interaction between these two polymorphisms. METHODS: We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Multiplicative interaction between the polymorphisms and change in HbA1c levels was analyzed in 98 incident metformin users. RESULTS: In incident metformin users with the OCT1 rs622342 AA genotype, genetic variation at the MATE1 rs2289669 polymorphism was not associated with change in HbA1c levels [-0.10; 95% confidence interval (CI): -0.35 to 0.14; P=0.39]. In users with the OCT1 rs622342 AC genotype, there was a tendency between rs2289669 polymorphisms and change in HbA1c (-0.31; 95% CI: -0.65 to 0.03; P=0.070) and in users with the OCT1 rs622342 CC genotype there was a significant association with change in HbA1c levels (-0.68; 95% CI: -1.06 to -0.30; P=0.005). The multiplicative interaction between these two genotypes was statistically significant (-0.52; 95% CI: -0.94 to -0.11; P=0.015). CONCLUSION: The effect of the MATE1 rs2289669 polymorphism on the glucose lowering effect of metformin is larger in incident users with the OCT1 rs622342 CC genotype than in incident users with the AA genotype. The effect in incident users with the OCT1 rs622342 AC genotype is in between.

Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response.

CYP3A4 is involved in the oxidative metabolism of many drugs and xenobiotics including the HMG-CoA reductase inhibitor simvastatin. The objective of this study was to investigate whether a new CYP3A4 functional single nucleotide polymorphism (SNP) in intron 6 (CYP3A4*22) modifies the effect of simvastatin on total cholesterol (TOTc) or LDL cholesterol (LDLc) reduction in a population-based cohort study.

Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study.

Although the number of clinically relevant drug-drug interactions (DDIs) is probably low, DDIs may be responsible for a substantial number of hospital admissions. In some countries, the pharmacist is responsible for preventing the use of unsafe or non-effective drug regimens. Specifically they should avoid the dispensing of combinations of drugs that may cause serious DDIs. In order to assess the determinants related to community pharmacies and associated with these dispensings, a systematic literature review was conducted. Medline and International Pharmaceutical Abstracts were searched for articles published in English between 1993 and 2003. Additional relevant articles were identified by screening the reference lists of relevant articles. Seven papers were located. The determinants described in the literature were divided into three groups. The first group focussed on the relationship between the pharmacist and the prescriber. The number of prescribers is of importance as well as the number of dispensing pharmacies. Both a high number of primary care physicians and multiple dispensing pharmacies increased the risk of DDIs. The availability, quality and sensitivity of the medication surveillance software appeared to be a second important determinant. Both too many and too few signals increased the risk of dispensing interacting drugs. The third group of determinants was related to the pharmacist and pharmacy organisation. Signals from the surveillance program are usually judged first by technicians and subsequently managed by the pharmacist. Consequently, knowledge, instructions and supervision are important determinants. A fourth group of determinants was identified in literature assessing interventions by pharmacists, including interventions for DDIs. A higher workload was associated with lower intervention rates, which indicated a higher risk of dispensing interacting drugs. The determinants identified in this review can be used to develop strategies to minimise patient harm resulting from DDIs. Further assessment of the relation between these determinants and the dispensing of DDIs and of the relation between DDI-associated dispensing and patient harm is recommended.

Potential Determinants of Drug-Drug Interaction Associated Dispensing in Community Pharmacies

Background: Drug-drug interactions (DDIs) are responsible for a variety of adverse reactions, particularly in an elderly population. Objective: To assess the frequency and potential clinical relevance of DDIs in a population aged ≥55 years. Methods: Exposure to DDIs was assessed in 7842 people participating in the Rotterdam Study, a population-based cohort study. These people were followed between 1 January 1992 and 1 July 2005. The DDI list of the Royal Dutch Association for the Advancement of Pharmacy, in which DDIs are categorized by potential clinical relevance and quality of evidence, was used. Simultaneous use of interacting drug combinations was calculated on the basis of drug dispensing data from community pharmacies. Results: The incidence of a first dispensing of DDIs in the study period was 10.5 per 100 person-years and 2.7 per 100 person-years for potentially life-threatening DDIs. The prevalence of DDIs in people aged ≥70 years increased from 10.5% in 1992 to 19.2% in 2005. Ten DDIs comprised two-thirds of the total exposure time to DDIs. The prevalence of potentially life-threatening DDIs in people aged ≥70 years increased from 1.5% to 2.9%. This increase was most likely caused by an increase in use of spironolactone combined with renin-angiotensin-aldosterone system inhibitors. Conclusion: A large number of people in the Netherlands aged ≥55 years are exposed to DDIs and this number has increased sharply between 1992 and 2005. Healthcare professionals should pay special attention to the potential risks of DDIs in these people, particularly if spironolactone is involved.

Bruno H. Ch. Stricker

Papers

The Rotterdam Study: Objectives and design update

Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response.

Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study.

Potential Determinants of Drug-Drug Interaction Associated Dispensing in Community Pharmacies

Increasing Exposure to Drug-Drug Interactions Between 1992 and 2005 in People Aged ≥55 Years