Genetic susceptibility to adverse drug effects - Epidemiology ...

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4.4 Common variation in the NOS1AP gene is associated with reduced glucose lowering effect and with increased mortality in users of sulfonylurea Abstract Objective. The single nucleotide polymorphism rs10494366 in the NOS1AP gene is associated with QTc prolongation, through an effect on the intracellular Ca 2+ levels. As sulfonylurea stimulate insulin secretion by an increased influx of Ca 2+ , we hypothesized that this polymorphism is associated with glucose lowering effect and mortality risk in sulfonylurea users. Methods. Associations between the NOS1AP polymorphism, prescribed doses and mortality rates in sulfonylurea, metformin and insulin users were assessed in the Rotterdam Study, a population based cohort study of 7,983 elderly people. Results. We identified 619 who were prescribed oral antidiabetic drugs during follow-up. In glibenclamide users carrying the TG genotype, the prescribed doses were higher compared to users carrying the TT genotype (0.38 DDD units, 95% CI 0.14; 0.63). Glibenclamide users with the TG or GG genotype had an increased mortality risk compared to glibenclamide users with the TT genotype (HR 2.80, 95% CI 1.09; 7.22). Tolbutamide users with the TG or GG genotype (HR 0.30, 95% CI 0.14; 0.63) and glimepiride users with the TG or GG genotype (HR 0.18, 95% CI 0.04; 0.74) had a decreased mortality risk compared to users with the TT genotype. Conclusion. In subjects with the TG or GG genotype at rs10494366 in the NOS1AP gene, glibenclamide is less effective in reducing glucose levels and mortality rates were higher compared to glibenclamide users with the TT genotype. In tolbutamide and glimepiride users the TG and GG genotype were associated with a reduced mortality rate. 119
Chapter 4.4 Introduction Sulfonylurea drugs have been used extensively for decades in the treatment of type 2 diabetes. Since the publication of the University Group Diabetes Program trial in 1970, in which tolbutamide treatment was compared with other treatments and placebo, sulfonylurea have been associated with an increased risk of cardiovascular mortality. 1 However, there was criticism on this study in subsequent publications. 2-4 In 1998 the results of another trial with sulfonylurea were published. In this UK Prospective Diabetes Study trial, in which treatment with a sulfonylurea (chlorpropamide, glibenclamide or glipizide) was compared with insulin treatment and conventional policy with diet, no detrimental effects of sulfonylurea were seen. 5 Ever since, controversy remains as to whether sulfonylurea may increase the risk of cardiovascular death. Sulfonylurea stimulate insulin secretion by the pancreatic β-cells. 6-8 The sulfonylurea receptor (SUR) is part of the ATP-sensitive K + (KATP) channel. Binding of the sulfonylurea to SUR causes inhibition of the KATP-channel, decreasing the K + efflux and depolarization of the cell membrane. This triggers the opening of voltage dependent Ca 2+ channels, eliciting Ca 2+ influx and a rise in intracellular Ca 2+ . In the pancreatic β-cell, this rise stimulates the exocytosis of insulin-containing secretory granules. Nitric oxide synthases (NOS) are the enzymes responsible for nitric oxide generation. Nitric oxide regulates cardiovascular homeostasis. 9 Recently, two nearby single nucleotide polymorphism (SNP), rs10494366 and rs10918594, in the gene encoding Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) have been associated with QTc-interval prolongation in electrocardiograms (ECGs). 10-12 NOS1AP is a regulator of neuronal NOS (nNOS encoded by NOS1), one of the isoforms of NOS. The nNOS enzyme is believed to regulate intracellular calcium levels. 9, 13 It is thought that nNOS inhibits the inward Ca 2+ current through voltage dependent calcium channels, reducing the intracellular calcium concentrations. Thereby it suppresses β-adrenoreceptor stimulation of the heart. nNOS has also been associated with insulin release. 14, 15 There are similarities between the effects of nNOS and sulfonylurea. Both nNOS and sulfonylurea influence the calcium influx through voltage dependent calcium channels. Moreover nNOS and sulfonylurea modulate the release of insulin by pancreatic β-cells. Both might be associated with cardiovascular mortality. In view of these similarities we hypothesized that genetic variation in the NOS1AP gene influences the glucose lowering effect of sulfonylurea and mortality risk in patients using sulfonylurea. Methods Setting. The data were obtained from the Rotterdam Study, a prospective population based closed cohort study in the suburb Ommoord in Rotterdam. All inhabitants who were 55 years of age or older and had lived in the district for at least one year, were invited between 1990 and 1993 to participate in the study. Of the 10,275 eligible persons, 7,983 participated and were followed since then. At baseline, trained interviewers administered a questionnaire during a home interview covering socioeconomic background and medical history, among other topics. During subsequent visits to the study center, laboratory assessments and clinical examinations were performed, including recording of ECGs. Follow-up examinations were carried out periodically (every 4 to 5 years). All participants of the Rotterdam Study gave written 120
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Genetic susceptibility to adverse d
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The work presented in this thesis w
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Promotiecommissie Promotoren: Prof.
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1 General Introduction
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Chapter 1 genome. Every SNP represe
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Chapter 1 References 1. 2. 3. 4. 5.
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2 Quantifying the risk of adverse d
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Chapter 2 Introduction The cardiac
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Chapter 2 Table 1 Characteristics o
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Chapter 2 digoxin treatment appears
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Chapter 2 References 1. 2. 3. 4. 5.
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3 Common variants in the ABCB1 gene
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Chapter 3.1 Introduction The ATP-Bi
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Chapter 3.1 Co-variables. Covariate
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Chapter 3.1 Table 3 Frequencies of
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Chapter 3.1 Table 5 Risk of serum d
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Chapter 3.1 Table 6 Other studies o
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Chapter 3.1 References 1. 2. 3. 4.
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3.2 Common ABCB1 variants increase
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Common ABCB1 variants increase QTc
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Chapter 3.3 Introduction The quinol
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Chapter 3.3 In addition to the diar
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Chapter 3.3 Table 1 General charact
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Chapter 3.3 confounding by contrain
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General discussion 169
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7.1 Summary Despite all research ef
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Summary reduced mortality in patien
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Chapter 7.2 steeds aanzienlijk is e
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8 Dankwoord Een proefschrift schrij
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Dankwoord Bijzondere dank aan alle
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10 Bibliography Manuscripts based o
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Bibliography Van der Hooft CS, Diel
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