Archive for the ‘Scientific publication’ Category

The role of the cytochrome P450 3A5 enzyme for blood pressure regulation in the general Caucasian population

woensdag, december 7th, 2011
TitleThe role of the cytochrome P450 3A5 enzyme for blood pressure regulation in the general Caucasian population
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Year2005
Estimated date2005-05-01
CategoryScientific Publication
PlatformNone
DescriptionCytochrome P450 3A (CYP3A) enzymes are important for drug metabolism in gut and liver. The CYP3A5 isoenzyme is also expressed in the kidney and has been implicated in renal sodium reabsorption and blood pressure regulation. Its expression and activity is strongly linked to a polymorphism (i.e. 6986G> A). Thus, appreciable expression is found in carriers of the CYP3A5*1 (6986A) but not in homozygous carriers of the CYP3A5*3 (6986G) allele. We tested whether the presence of CYP3A5*1 affects blood pressure in Caucasian individuals who were enrolled in the Prevention of REnal and Vascular ENd stage Disease (PREVEND) study. In addition, we evaluated whether the genetic effect of CYP3A5*1 on blood pressure is modulated by sodium intake. CYP3A5*1 was found in 13.3% (901 individuals) of the cohort (6777 individuals). Diastolic blood pressure was not affected by CYP3A5*1. Overall, systolic and pulse pressure were significantly lower in carriers of CYP3A5*1, both after univariate analysis adjusted for age (P = 0.012 and P = 0.008) and in logistic regression analysis (P = 0.015 and P = 0.012). The effect on systolic blood pressure was significantly modulated by sodium intake (P = 0.038). In separate analysis according to gender, CYP3A5*1 accounted for a significant age adjusted decrease in systolic blood pressure ( – 1.6 mmHg, P= 0.04) and pulse pressure ( – 1.2 mmHg, P = 0.04) in females but not in men. The present study demonstrates that the CYP3A5*1 allele affects systolic blood pressure and pulse pressure in the general population. Its role in hypertensive disease and potential gender differences should be investigated in further studies. Pharmacogenetics and Genomics 15:831–837 c 2005
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LPS-Induced Expression of a Novel Chemokine Receptor (L-CCR) in Mouse Glial Cells In Vitro and In Vivo

woensdag, december 7th, 2011
TitleLPS-Induced Expression of a Novel Chemokine Receptor (L-CCR) in Mouse Glial Cells In Vitro and In Vivo
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Year2003
Estimated date2001-12-01
CategoryScientific Publication
PlatformNone
DescriptionABSTRACT There is increasing evidence that chemokines, specialized regulators of the peripheral immune system, are also involved in the physiology and pathology of the CNS. It is known that glial cells (astrocytes and microglia) express various chemokine receptors like CCR1, -3, -5, and CXCR4. We have investigated the possible expression of the known CC chemokine receptors (CCR1–8 and D6) in murine glial cells. In addition, we examined possible glial expression of the orphan CC chemokine receptor L-CCR that has been identified previously in murine macrophages. We report here expression of L-CCR mRNA in murine astrocytes and microglia. Furthermore, L-CCR mRNA expression was strongly induced after application of bacterial lipopolysaccharide (LPS), both in vitro and in vivo. Functional studies and binding experiments using biotinylated monocyte chemoattractant protein (MCP)-1 (CCL2) indicate that CCL2 could be a candidate chemokine ligand for glial L-CCR. Based on the data presented, it is suggested that L-CCR is a functional glial chemokine receptor that is important in neuroimmunology. GLIA 41:327–336, 2003.
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CCR5 Deletion Protects Against Inflammation- Associated Mortality in Dialysis Patients

woensdag, december 7th, 2011
TitleCCR5 Deletion Protects Against Inflammation- Associated Mortality in Dialysis Patients
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Year2009
Estimated date2009-04-01
CategoryScientific Publication
PlatformNone
DescriptionThe CC-chemokine receptor 5 (CCR5) is a receptor for various proinflammatory chemokines, and a deletion variant of the CCR5 gene (CCR532) leads to deficiency of the receptor. We hypothesized that CCR532 modulates inflammation-driven mortality in patients with ESRD. We studied the interaction between CCR5 genotype and levels of high-sensitivity C-reactive protein (hsCRP) in 603 incident dialysis patients from the multicenter, prospective NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort. CCR5 genotype and hsCRP levels were both available for 413 patients. During 5 yr of follow-up, 170 patients died; 87 from cardiovascular causes. Compared with the reference group of patients who had the wild-type CCR5 genotype and hsCRP  10 mg/L (n  225), those carrying the deletion allele with hsCRP  10 mg/L (n  55) had similar mortality, and those carrying the wild-type genotype with hsCRP  10 mg/L (n  108) had an increased risk for mortality (HR: 1.82; 95% CI: 1.29 to 2.58). However, those carrying the deletion allele with hsCRP  10 mg/L (n  25) had a mortality rate similar to the reference group; this seemingly protective effect of the CCR5 deletion was even more pronounced for cardiovascular mortality. We replicated these findings in an independent Swedish cohort of 302 ESRD patients. In conclusion, the CCR532 polymorphism attenuates the adverse effects of inflammation on overall and cardiovascular mortality in ESRD. J Am Soc Nephrol 20: 1641–1649, 2009. doi: 10.1681/ASN.2008040432
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Expression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8

woensdag, december 7th, 2011
TitleExpression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8
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Year2003
Estimated date2002-08-01
CategoryScientific Publication
PlatformNone
DescriptionAbstract: It has become clear in the past years that chemokines and chemokine receptors are pivotal regulators of cellular communication and trafficking. In addition to the 20 chemokine receptors that have been cloned and described, various orphan receptors with a chemokine receptor-like structure are known. We have investigated the orphan mouse chemokine receptor (L-CCR) in HEK 293 cells, a receptor that was originally described in a mouse macrophage cell line. Cells expressing this receptor show pertussis toxin-sensitive chemotaxis and small intracellular calcium transients in response to the chemokines CCL2, CCL7, CCL8, and CCL5. Biotinylated CCL2 binds to L-CCRexpressing cells, and transfection experiments with an L-CCR–green fluorescent protein fusion protein showed L-CCR expression in the membranes of recombinant HEK 293 cells. Although radioligand binding was not detected, it is suggested that LCCR is a functional chemokine receptor. J. Leukoc. Biol. 74: 243–251; 2003.
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An Increased Coronary Risk Is Paradoxically Associated with Common Cholesteryl Ester Transfer Protein Gene Variations That Relate to Higher High-Density Lipoprotein Cholesterol: A Population-Based Study

woensdag, december 7th, 2011
TitleAn Increased Coronary Risk Is Paradoxically Associated with Common Cholesteryl Ester Transfer Protein Gene Variations That Relate to Higher High-Density Lipoprotein Cholesterol: A Population-Based Study
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Year2006
Estimated date2006-03-01
CategoryScientific Publication
PlatformNone
DescriptionBackground: Several cholesteryl ester transfer protein (CETP) polymorphisms affect high-density lipoprotein (HDL) cholesterol, but the impact of CETP gene variants on incident coronary disease in the general population is uncertain after correction for their effect on HDL cholesterol. Design: We determined relationships between the CETP 629C3A promoter (n  8141), the TaqIB (n  8289), and the I405V (n  8265) polymorphisms, serum lipids, C-reactive protein, and clinical factors with incident coronary heart disease (defined as death from or hospitalization for myocardial infarction, ischemic heart disease, or coronary intervention) during a median of 4.94 yr follow-up. Subjects: A predominantly Caucasian general population was studied. Results: HDL cholesterol was 0.08 mmol/liter higher in 629A carriers than in 629CC homozygotes (P  0.001). The unadjusted coronary hazard was 1.26 [95% confidence interval (CI), 0.95–1.68; P  0.11] in A carriers compared with CC homozygotes and increased to 1.46 (95% CI, 1.10–1.95; P  0.01) after adjustment for HDL cholesterol. This effect remained after additional adjustment for apolipoprotein A-I, triglycerides, C-reactive protein, age, and gender. Likewise, the HDL-cholesterol-adjusted hazard ratio was also higher in AA than in CC homozygotes (hazard ratio, 1.72; 95% CI, 1.22–2.42; P  0.01). Similar findings were obtained with the TaqIB polymorphism. The 405V allele was weakly associated with incident coronary heart disease after HDL cholesterol adjustment (P  0.09). Conclusions: A common CETP promoter polymorphism, which beneficially contributes to higher HDL cholesterol, is paradoxically associated with increased incidence of coronary disease in the general population. Thus, CETP gene variation may affect coronary risk apart from the level of HDL cholesterol. (J Clin Endocrinol Metab 91: 3382–3388, 2006)
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Analysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity

woensdag, december 7th, 2011
TitleAnalysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity
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Year2008
Estimated date2008-04-01
CategoryScientific Publication
PlatformNone
DescriptionABSTRACT Background: Several findings link systemic lupus erythematosus (SLE) with C1q, the first molecule of the classical complement pathway. Polymorphisms of the C1qA gene are associated with low serum C1q levels in patients with cutaneous LE, but C1q polymorphisms have not been studied in patients with systemic lupus. Objective: To determine whether polymorphisms of the C1q genes are associated with SLE, disease phenotypes, serum C1q and CH50 levels. Methods: DNA for genetic analysis was obtained from 103 Caucasian patients with SLE and their family members. Five tag single nucleotide polymorphisms (tag SNPs) served as unique markers for underlying SNPs in the genes of the C1q protein. The pedigree disequilibrium test (PDT) was applied to trios to determine association of markers with SLE, SLE phenotypes, low serum C1q and low CH50. Single SNP association and haplotype analysis was also performed. Results: The PDT revealed a significant association of the tag SNP rs631090 (covering the C1qB gene) with SLE (p=0.02). Rs631090 was moderately associated with low serum C1q levels (p=0.06). In addition, the tag SNPs rs292001 and rs294183 were associated with more severe SLE (Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) damage index score.0; p=0.007 and p=0.02, respectively). Haplotype analysis and single SNP association analysis showed no significant associations, but additional analyses revealed that marker rs587585 is associated with low serum C1q and CH50 levels. Conclusions: C1q polymorphisms are associated with SLE, serum C1q and CH50 levels in a stable founder population of patients with SLE. Although the studied population was small and allele frequencies were low, this is the first study to suggest an association of C1q polymorphisms with SLE. Ann Rheum Dis 2009;68:715–720. doi:10.1136/ard.2007.085688
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Renal Function Dependent Association of AGTR1 Polymorphism (A1166C) and Electrocardiographic Left-Ventricular Hypertrophy

woensdag, december 7th, 2011
TitleRenal Function Dependent Association of AGTR1 Polymorphism (A1166C) and Electrocardiographic Left-Ventricular Hypertrophy
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Year2007
Estimated date2007
CategoryScientific Publication
PlatformNone
DescriptionBackground: The association of renin-angiotensin system (RAS) polymorphisms and left-ventricular hypertrophy (LVH) may depend on the presence of risk factors for LVH, such as renal dysfunction. We studied whether renal function modulates the association between RAS polymorphisms and LVH in a cross-sectional study of 8592 inhabitants of Groningen. Methods: Left-ventricular hypertrophy was determined with electrocardiograms, using the Cornell voltage-duration product. The following RAS polymorphisms were determined: angiotensin II type-1 receptor (AGTR1 A1166C), angiotensin-converting enzyme (ACE) insertion/deletion (I/ D), and angiotensinogen (AGT G-6A). The AGTR1 A1166C and ACE I/D polymorphisms were in Hardy-Weinberg equilibrium. Results: Electrocardiographic LVH was present in 417 (5.0%) subjects. Subjects with LVH were older (53 v 49 years) and overall had more cardiovascular risk factors. Using logistic regression, creatinine clearance interacted with the relationship between the AGTR1 A1166C polymorphism and LVH (, 0.19; P  .033). In subjects with the CC genotype, in contrast to carriers of an A allele, the prevalence of LVH increased with more pronounced renal dysfunction. Creatinine clearance also interacted with the relationship between the ACE I/D polymorphism and LVH (, 0.12; P  .037), although less strongly, and the other way around. Creatinine clearance did not influence the association between the AGT G-6A polymorphism and LVH (, 0.006; P  .491). Conclusions: In this population-based study, the AGTR1 A1166C polymorphism was associated with LVH, dependent on concomitant renal dysfunction. A weaker renal function dependent association between the ACE I/D polymorphism and LVH was also observed. Renal function should be taken into account as a relevant environmental factor for the pathogenetic effects of RAS polymorphisms. Am J Hypertens 2007;20:1097–1103 © 2007 American Journal of Hypertension, Ltd.
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CCR5D32 genotype is associated with outcome in type 2 diabetes mellitus

woensdag, december 7th, 2011
TitleCCR5D32 genotype is associated with outcome in type 2 diabetes mellitus
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Year2009
Estimated date2009-05-01
CategoryScientific Publication
PlatformNone
Descriptiona b s t r a c t Aims: To test whether the genetic variant CCR5D32 in the CC-chemokine receptor 5, which is known to lead to CCR5 deficiency, is associated with mortality in type 2 diabetes patients. Methods: We examined the effect of presence or absence of the CCR5D32 on overall and cardiovascular mortality risk in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort, a type 2 diabetes patient cohort. Results: We studied 756 patients with a mean duration of follow-up of 5.4 ( 1.4) years. 194 patients died during follow up of which 83 were cardiovascular deaths. 144 subjects (19%) carried the CCR5D32 deletion. CCR5D32 carriers had an adjusted hazard ratio of 0.62 (95%CI: 0.40–0.96; p = 0.03) for all-cause mortality and 0.63 (95%CI: 0.33–1.19; p = 0.16) for cardiovascular mortality. Conclusions: The presence of CCR5D32 is associated with better survival in type 2 diabetes patients. These data suggest that it is worthwhile to explore the protective potential of pharmacological blockade of CCR5 in type 2 diabetic patients Muntinghe FL, Gross S, Bakker SJ, Landman GW, van der Harst P, Bilo HJ, Navis G, Zuurman MW. CCR5Delta32 genotype is associated with outcome in type 2 diabetes mellitus. Diabetes Res Clin Pract. 2009 Nov;86(2):140-5. Epub 2009 Sep 9. PubMed PMID: 19744740.
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Chemokines in the brain: neuroimmunology and beyond

woensdag, december 7th, 2011
TitleChemokines in the brain: neuroimmunology and beyond
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Year2002
Estimated date2001-09-01
CategoryScientific Publication
PlatformNone
DescriptionChemokines in the brain have been recognised as essential elements in neurodegenerative diseases and related neuroinflammation. Recent studies suggest that in addition to the orchestration of chemotaxis of immune cells, chemokines are also involved in neurodevelopment and neurophysiological signalling. Biber K, Zuurman MW, Dijkstra IM, Boddeke HW. Chemokines in the brain: neuroimmunology and beyond. Curr Opin Pharmacol. 2002 Feb;2(1):63-8. Review. PubMed PMID: 11786310.
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