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  • 1
    Online Resource
    Online Resource
    Homocysteine levels associate with subtle changes in leukocyte DNA methylation: an epigenome-wide analysis
    Future Medicine Ltd ; 2017
    In:  Epigenomics Vol. 9, No. 11 ( 2017-11), p. 1403-1422
    Details
    In: Epigenomics, Future Medicine Ltd, Vol. 9, No. 11 ( 2017-11), p. 1403-1422
    Abstract: Aim: Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes. Methods: Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis. Results: Three differentially methylated positions cg21607669 (SLC27A1), cg26382848 (AJUBA) and cg10701000 (KCNMA1) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methylated regions, the most significant of which was a 1.8-kb spanning domain (TNXB/ATF6B) at chromosome 6. Conclusion: We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.
    Type of Medium: Online Resource
    ISSN: 1750-1911 , 1750-192X
    URL: Article
    DOI: 10.2217/epi-2017-0038
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2017
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Common genetic variation in the ABCB1 gene is associated with the cholesterol-lowering effect of simvastatin in males
    Future Medicine Ltd ; 2009
    In:  Pharmacogenomics Vol. 10, No. 11 ( 2009-11), p. 1743-1751
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 10, No. 11 ( 2009-11), p. 1743-1751
    Abstract: Aims: The cholesterol-lowering drug simvastatin is a substrate for P-glycoprotein (P-gp). P-gp, encoded by ABCB1, is an efflux transporter and genetic variation in ABCB1 is associated with drug levels and response. We examined the Rotterdam Study, which is a population-based cohort study of people aged 55 years and older, to see whether the C1236T, G2677T/A and C3435T polymorphisms and haplotypes in the ABCB1 gene are associated with the total cholesterol and low-density lipoprotein cholesterol-lowering effect of simvastatin. Materials & methods: We identified 85 incident simvastatin users, for whom a cholesterol measurement both before and after the start of simvastatin therapy was available. Associations between the ABCB1 gene variants and reductions in cholesterol levels were analyzed. In our analysis we stratified for gender, because the level of P-gp expression in the liver is higher in men than in women. Results: The three ABCB1 polymorphisms were associated with total cholesterol reduction in the whole population. In men, both the 1236/2677/3435 TTT haplotype and the CGT haplotype were associated with larger reductions in total cholesterol (TTT: -0.40 mmol/l, 95% CI: -0.63 to -0.17; CGT: -0.44 mmol/l, 95% CI: -0.77 to -0.11) and low-density lipoprotein cholesterol levels (TTT: -0.51 mmol/l, 95% CI: -0.81 to -0.22; CGT: -0.53 mmol/l, 95% CI: -0.92 to -0.15) than the reference CGC haplotype. In women, genetic variation in the ABCB1 gene was not associated with total and low-density lipoprotein cholesterol levels. Conclusion: Male simvastatin users with the ABCB1 1236/2677/3435 TTT and CGT haplotype have larger reductions in total cholesterol and low-density lipoprotein cholesterol compared with the wild-type CGC haplotype. For women, no associations were found.
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/pgs.09.105
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2009
    SSG: 15,3
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  • 3
    Online Resource
    Online Resource
    Protective effect of a GRK5 polymorphismon heart failure and its interaction with β-adrenergic receptor antagonists
    Future Medicine Ltd ; 2008
    In:  Pharmacogenomics Vol. 9, No. 10 ( 2008-10), p. 1551-1555
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 9, No. 10 ( 2008-10), p. 1551-1555
    Abstract: Evaluation of: Liggett SB, Cresci S, Kelly RJ et al.: A GRK5 polymorphism that inhibits β-adrenergic receptor signaling is protective in heart failure. Nat. Med. 14, 510–517 (2008). β-adrenoceptor blockade therapy was developed for the treatment of hypertension but is now also a cornerstone in the treatment of heart failure. Based on the mechanisms of action and current knowledge of pathway signaling, Ligget et al. hypothesized that genetic variants within G-protein coupled receptor kinases might alter disease course and response to β-adrenoceptor blockade therapy. Following a multistep approach, a common variant in GRK5 was identified as being important in vitro and in vivo (mouse model) in β-adrenergic desensitization, and was epidemiologically related to survival and therapy response in African–Americans. Although such a variety of research approaches is appealing, owing to the large number of used methods readers remain puzzled on some issues because it is not possible to give all details of each individual study. Therefore, interpretation of the overwhelming amount of results is difficult. In an era of shifting emphasis from classic hypothesis driven pharmacogenetics to genome-wide association studies, this study shows that hypothesis driven translational research is still of high value, especially in phenotypes as investigated here.
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/14622416.9.10.1551
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2008
    SSG: 15,3
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  • 4
    Online Resource
    Online Resource
    Association of the exon 3 deleted/full-length GHR polymorphism with recombinant growth hormone dose in growth hormone-deficient adults
    Future Medicine Ltd ; 2009
    In:  Pharmacogenomics Vol. 10, No. 10 ( 2009-10), p. 1599-1608
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 10, No. 10 ( 2009-10), p. 1599-1608
    Abstract: Aims: Contradictory reports exist regarding the influence of the exon 3 deleted (d3)/full-length (fl) growth hormone receptor (GHR) polymorphism on responsiveness to recombinant human growth-hormone therapy in idiopathic short stature, small for gestational age and GH-deficient children, Turner syndrome patients and GH-deficient adults. In some of these studies, the d3 allele was associated with increased responsiveness to GH. The aim of this study was to test this association in a group of GH-deficient adult patients receiving recombinant GH treatment. Materials & methods: Patients were derived from the prospective German Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. The GHRd3/fl polymorphism was determined in 133 German adult patients (66 men and 67 women; mean age: 45.4 years ± 13.1 standard deviation; majority Caucasian) with a GH-deficiency of different origin. Patients received GH treatment for 12 months with a finished dose-titration of GH and standardized insulin-like growth factor (IGF)-1 measurements in one central laboratory. GH dose after 1 year of treatment, IGF-1 serum concentrations, IGF-1 standard deviation score (SDS) values and anthropometric data were analyzed by GHRd3/fl genotypes. Results: After 1 year of GH treatment, the individually required GH dose was significantly lower in GH-deficient patients carrying one or two d3 alleles, compared with patients with the full-length receptor (p = 0.04). Genotype groups (d3-allele carriers vs noncarriers) showed no significant differences in IGF-1 serum concentrations (p = 0.51), IGF-1 SDS (p = 0.36) nor in gender (p = 0.53), age (p = 0.28), weight (p = 0.13), height (p = 0.53) or BMI (p = 0.15). Conclusion: The d3-allele carriers required approximately 25% less exogenous GH compared with the homozygous fl-allele carriers, which may express an increased responsiveness to exogenous GH. Variability of the individually required GH dose in adult GH-deficient patients may therefore be partly due to the GHRd3/fl polymorphism. Further studies are required to confirm these results.
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/pgs.09.91
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2009
    SSG: 15,3
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  • 5
    Online Resource
    Online Resource
    Growth hormone dose in growth hormone-deficient adults is not associated with IGF-1 gene polymorphisms
    Future Medicine Ltd ; 2009
    In:  Pharmacogenomics Vol. 10, No. 2 ( 2009-02), p. 293-302
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 10, No. 2 ( 2009-02), p. 293-302
    Abstract: Aims: Several SNPs and a microsatellite cytosine–adenine repeat promoter polymorphism of the IGF-1 gene have been reported to be associated with circulating IGF-1 serum concentrations. Variance in IGF-1 concentrations due to genetic variations may affect different response to growth hormone (GH) treatment, resulting in different individually required GH-doses in GH-deficient patients. The aim of this study was to test if the IGF-1 gene polymorphisms are associated with the GH-dose of GH-deficient adults. Materials & methods: A total of nine tagging SNPs, five additionally selected SNPs and a cytosine–adenine repeat polymorphism were determined in 133 German adult patients (66 men, 67 women; mean age 45.4 years ± 13.1 standard deviation; majority Caucasian) with GH-deficiency (GHD) of different origin, derived from the prospective Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. Patients received GH-treatment for 12 months with finished dose-titration of GH and centralized IGF-1 measurements. GH-dose after 1 year of treatment, IGF-1 concentrations, IGF-1-standard deviation score (SDS), the IGF-1:GH ratio and anthropometric data were analyzed by genotype. Results: Except for rs1019731, which showed a significant difference of IGF-1-SDS by genotypes (p = 0.02), all polymorphisms showed no associations with the GH-doses, IGF-1 concentrations, IGF-1-SDS and IGF-1:GH ratio after adjusting for the confounding variables gender, age and BMI. Conclusion: IGF-1 gene polymorphisms were not associated with the responsiveness to exogenous GH in GHD. Therefore, genetic variations of the IGF-1 gene seem not to be major influencing factors of the GH–IGF-axis causing variable response to exogenous GH-treatment.
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/14622416.10.2.293
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2009
    SSG: 15,3
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  • 6
    Online Resource
    Online Resource
    Genetic variation in the PPARA gene is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study
    Future Medicine Ltd ; 2013
    In:  Pharmacogenomics Vol. 14, No. 11 ( 2013-08), p. 1295-1304
    Details
    In: Pharmacogenomics, Future Medicine Ltd, Vol. 14, No. 11 ( 2013-08), p. 1295-1304
    Abstract: Aim: Recently, minor alleles of two strongly linked polymorphisms in the PPARA gene, rs4253728 G 〉 A and rs4823613 A 〉 G, were related to decreased CYP3A4 expression and activity. We studied whether they were associated with the cholesterol-lowering effect of simvastatin. Materials & methods: We identified 123 incident users with cholesterol measurements before and after starting statin therapy in a prospective population-based cohort study. Associations between PPARA polymorphisms and change in total and low-density lipoprotein (LDL)-cholesterol levels were analyzed using linear regression. Results: The minor G allele of the rs4823613 A 〉 G polymorphism was associated with a 0.258 mmol/l (95% CI: -0.470 to -0.046) and a 0.294 mmol/l (95% CI: -0.495 to -0.093) larger reduction in total and LDL-cholesterol, respectively, after starting simvastatin therapy. Results were similar for the rs4253728 G 〉 A polymorphism. Conclusion: The minor alleles of the PPARA rs4253728 and rs4823613 polymorphisms are associated with a better total and LDL-cholesterol-lowering response to simvastatin, possibly through influence on CYP3A4. Original submitted 13 February 2013; Revision submitted 8 May 2013
    Type of Medium: Online Resource
    ISSN: 1462-2416 , 1744-8042
    URL: Article
    DOI: 10.2217/pgs.13.112
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2013
    SSG: 15,3
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  • 7
    Online Resource
    Online Resource
    Genome-wide methylation analysis identifies novel CpG loci for perimembranous ventricular septal defects in human
    Future Medicine Ltd ; 2017
    In:  Epigenomics Vol. 9, No. 3 ( 2017-03), p. 241-251
    Details
    In: Epigenomics, Future Medicine Ltd, Vol. 9, No. 3 ( 2017-03), p. 241-251
    Abstract: Aim: Congenital heart diseases are the most common birth defects worldwide and leading cause of infant mortality. The perimembranous ventricular septal defect is most prevalent. Epigenetics may provide an underlying mechanism of the gene–environment interactions involved. Materials & methods: We examined epigenome-wide DNA methylation using the Illumina HumanMethylation450 BeadChip in 84 case children and 196 control children. Results: We identified differential methylation of a CpG locus (cg17001566) within the PRDM16 gene after Bonferroni correction (p = 9.17 × 10 -8 ). This was validated by bisulfite pyrosequencing. PRDM16 functions as a repressor of TGF-β signaling controlling tissue morphogenesis crucial during cardiogenesis. At 15% false-discovery rate, we identified seven additional CpG loci. Conclusion: These findings provide novel insights in the pathogenesis of perimembranous ventricular septal defect, which is of interest for future prediction and prevention.
    Type of Medium: Online Resource
    ISSN: 1750-1911 , 1750-192X
    URL: Article
    DOI: 10.2217/epi-2016-0093
    Language: English
    Publisher: Future Medicine Ltd
    Publication Date: 2017
    SSG: 12
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