Jakub J Regieli

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands

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Publications (10)63 Total impact

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    ABSTRACT: It was investigated whether pharmacogenetic factors, both as single polymorphism and as gene-gene interactions, have an added value over non-genetic factors in predicting statin response. Five common polymorphisms were selected in apolipoprotein E, angiotensin-converting enzyme, hepatic lipase and toll-like receptor 4. Linear regression models were built and compared on R(2) to estimate the added value of single polymorphisms and gene-gene interactions. The selected polymorphisms and the gene-gene interactions had a small added value in predicting change in low-density lipoprotein cholesterol levels (LDL-c) as response to statins over the non-genetic predictors (P=0.104), and also in predicting LDL-c in non-treated patients (P=0.016). Moreover, four gene-gene interactions with statin therapy were identified. The added value of genetic factors over non-genetic variables is for the greater part produced by gene-gene interactions. This underlines the importance to examine gene-gene interactions in future (pharmaco)genetic research.The Pharmacogenomics Journal advance online publication, 1 May 2012; doi:10.1038/tpj.2012.12.
    The Pharmacogenomics Journal 05/2012; · 5.13 Impact Factor
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    ABSTRACT: We prospectively investigated the effects of ATP-binding cassette protein-1 (ABCA1) variants on long-term clinical outcome in patients with coronary artery disease (CAD). ABCA1 is implicated in the etiology of atherothrombosis and may offer a target to reduce cardiovascular risk. However, the impact of ABCA1 on recurrent cardiovascular disease in a secondary prevention setting is as of yet unknown. We studied cause-specific 10-year mortality and quantitative coronary angiography data from the Regression GRowth Evaluation Statin Study (REGRESS), comprising 884 male CAD patients genotyped for promoter variants encompassing a proximal regulatory region (rs2422493, rs1800976, rs2740483 and rs1800977). Kaplan-Meier, proportional hazards and haplotype analyses were used to ascertain single-variant and multi-marker effects on absolute risk and extent of CAD. Protection from 10-year vascular death could be attributed to the rs2422493 genotype (available in 639 patients) T allele with absolute risk decreasing stepwise from 12.2% to 8.6% to 4.7% per each added allele copy, HR 0.64, p=0.03 and HR 0.53, p=0.04 in the TGCC haplotype context. The TGCC (p=0.04) and TCCT (p=0.003) haplotypes exhibited less extensive CAD. On a background of contemporary secondary prevention, variation in the ABCA1 promoter influences 10-year risk of vascular death and angiographic extent of CAD in men. These insights contribute to identification of patients sharing a specific prognosis, understanding of its etiological basis and development of strategies of risk reduction in CAD.
    Atherosclerosis 07/2011; 218(2):457-63. · 3.71 Impact Factor
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    ABSTRACT: We investigated the effects of paraoxonase (PON)-1 variants on long-term clinical outcome in patients with coronary artery disease (CAD). PON-1 is a potential therapeutic target to further reduce cardiovascular risk because it is a detoxifying esterase with antioxidant properties. The PON-1 knockout models result in higher susceptibility to atherosclerosis, and PON activity contributes to cardiovascular risk in humans. Human gene variants determine PON activity; however, the impact of these variants on recurrent cardiovascular events in vascular disease is as of yet unknown. We conducted a 10-year follow-up study of 793 CAD patients in the REGRESS (REgression GRowth Evaluation Statin Study) trial cohort, using nationwide registries. Genotypes were obtained of 2 PON-1 isotypes (L55M, rs854560, and Q192R, rs662), which were previously associated with PON activity. Absolute and relative risks by genotype were estimated using Kaplan-Meier and proportional hazards analyses. Carriership of the PON-1 glutamine isotype at codon 192 and methionine at codon 55 was associated with a higher risk of death due to ischemic heart disease. Hazard ratios per allele copy were 1.71 (95% confidence interval: 1.0 to 2.8, p=0.03) for the glutamine isotype at codon 192 and 1.56 (95% confidence interval: 1.1 to 2.3, p=0.03) for methionine at codon 55. Both isotypes had previously been related to lower PON activity. No effect was observed on all-cause mortality. PON-1 gene variants influence the 10-year risk of fatal complications from CAD in male patients, despite no effect on all-cause mortality. These long-term findings confirm functional data on PON-1 activity, emphasize the relevance of this pathway in vascular disease, and enforce its putative role as a target to modify and estimate cardiovascular risk.
    Journal of the American College of Cardiology 09/2009; 54(14):1238-45. · 14.09 Impact Factor
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    ABSTRACT: Atrial fibrillation (AF) is a major cause of cerebral infarction. Idiopathic AF is strongly associated with the human minor connexin 40 (Cx40) promotor polymorphism. We examined the prevalence of the minor Cx40 allele in patients with cerebral ischemia and no other cardiovascular disease (CVD), as an indication of underlying idiopathic AF. In patients with cerebral ischemia without prior CVD (n = 225), DNA analysis of the Cx40 minor allele (-44 G-->A) was performed. Patients were divided into those with a normal electrocardiographic (ECG) findings (group A, n = 164), with ECG abnormalities (group B, n = 51) and those with normal ECG and documented episodes of AF (group C, n = 10). On the basis of echocardiography (ECHO) data availability, further subgroups were defined: normal ECG and ECHO (group D, n = 45); ECG or ECHO abnormalities (group E, n = 22); and normal ECG and ECHO and documented AF episodes (group F, n = 8). The prevalence of Cx40 promotor polymorphism was compared among all the subgroups. The average age was 58.7 years (+/-11.5) and 64.4% were men. Patients with episodes of AF and those with abnormal ECG or ECHO results (B+C or E+F) did not show a higher prevalence of the minor allele genotype (AA vs. GG) compared with the normal ECG/ECHO groups (A or D) (group A, odds ratio = 1.04, 95% confidence interval: 0.26-4.11 and group D, odds ratio = 0.38, 95% confidence interval: 0.04-3.63). In patients with cerebral ischemic events, without prior CVD, a higher prevalence of the Cx40 gene polymorphism, as a marker of underlying idiopathic AF appeared to be absent.
    European journal of cardiovascular prevention and rehabilitation: official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology 06/2009; 16(5):616-20. · 2.51 Impact Factor
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    ABSTRACT: Activation of peroxisome proliferator-activated receptor (PPAR)-gamma signaling influences metabolic profiles and the propensity toward inflammation. Small-molecule stimulation of PPARgamma is investigated for secondary prevention of cardiovascular disease. The common PPARgamma Pro12Ala variant has functional and prognostic consequences. A protective effect of the 12Ala-allele carriership on diabetes and myocardial infarction in healthy populations has been suggested. The relevance of this pathway also needs exploration in patients with manifest vascular disease. We investigated the effects of carriership of the Pro12Ala variant on angiographic and cardiovascular event outcomes in male patients with symptomatic coronary artery disease (CAD). The Regression Growth Evaluation Statin Study (REGRESS) cohort was genotyped for the Pro12Ala variant (rs1801282). Ten-year follow-up was derived from nation-wide registries, and risks were estimated using proportional hazards. Quantitative coronary angiography measurements were obtained and relations with genotype estimated using a generalized linear model. Genotypes ascertained (n = 679) comprised 540 (80%) Pro/Pro, 126 (19%) Pro/Ala, and 13 (2%) Ala/Ala subjects. The 12Ala allele was associated with less extensive focal (P = 0.001) and diffuse (P = 0.002) atherosclerosis and lower 10-year cardiovascular risk. Hazard ratios were 0.10 (95% CI 0.01-0.70, P = 0.02) for ischemic heart disease and 0.24 (0.08-0.74, P = 0.013) for vascular death, per each added copy of 12Ala, respectively. Carriers of the 12Ala allele of PPARgamma have less widespread CAD and are considerably protected against 10-year (cardio)vascular morbidity and mortality. These long-term findings in patients with manifest CAD support an important role of PPARgamma in determining vascular risk.
    Diabetes care 03/2009; 32(5):839-44. · 7.74 Impact Factor
  • Diabetes Care. 01/2009; 32(6).
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    ABSTRACT: Inhibition of cholesteryl ester transfer protein (CETP) increases HDL-cholesterol. However, its combination with statins may increase mortality by factors incompletely understood. We previously observed that patients with intrinsically low CETP levels (carriers of the TaqIB-B2 allele) may have less benefit from statin therapy, and here tested this pharmacogenetic hypothesis on long-term outcomes. We performed a 10-year follow-up analysis in 812 coronary artery disease (CAD) patients (REGRESS cohort), treated with statins after an initial 2-year study period. Carriers of TaqIB-B2 showed reduced CETP levels and higher HDL-cholesterol (P < 0.001 for both). Despite these lower CETP and higher HDL-cholesterol levels, hazard ratios per B2 copy were 1.59 (P = 0.01) for atherosclerotic disease death, 1.53 (P = 0.03) for ischaemic heart disease death, and 1.30 (P = 0.04) for all-cause mortality. Haplotype-effects analysis provided even stronger basis for the genetics involved: one risk-haplotype was identified that was highly significantly associated with these endpoints. In statin-treated male CAD patients, genetic variation conferring low CETP levels is associated with increased 10-year mortality. This suggests that efficacy of statin therapy to reduce cardiovascular risk depends on CETP genotype and associated CETP plasma levels. This effect may need consideration when administering CETP inhibition to CAD patients.
    European Heart Journal 11/2008; 29(22):2792-9. · 14.10 Impact Factor
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    ABSTRACT: Formation of collateral circulation is an endogenous response to atherosclerosis, and is a natural escape mechanism by re-routing blood. Inflammatory response- related genes underlie the formation of coronary collaterals. We explored the genetic basis of collateral formation in man postulating interaction networks between functional Single Nucleotide Polymorphisms (SNPs) in these inflammatory gene candidates. The contribution of 41 genes as well as the interactions among them was examined in a cohort of 226 coronary artery disease patients, genotyped for 54 candidate SNPs. Patients were classified to the extent of collateral circulation. Stepwise logistic regression analysis and a haplotype entropy procedure were applied to search for haplotype interactions among all 54 polymorphisms. Multiple testing was addressed by using the false discovery rate (FDR) method. The population comprised 84 patients with and 142 without visible collaterals. Among the 41 genes, 16 pairs of SNPs were implicated in the development of collaterals with the FDR of 0.19. Nine SNPs were found to potentially have main effects on collateral formation. Two sets of coupling haplotypes that predispose to collateral formation were suggested. These findings suggest that collateral formation may arise from the interactions between several SNPs in inflammatory response related genes, which may represent targets in future studies of collateral formation. This may enhance developing strategies for risk stratification and therapeutic stimulation of arteriogenesis.
    Human Heredity 08/2008; 66(4):252-64. · 1.57 Impact Factor
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    ABSTRACT: The recruitment of coronary collateral vessels results from an endogenous adaptation to ischemic heart disease (IHD). Presence of collaterals may exert protection at the time of acute or chronic obstructive coronary disease. The protective role of collaterals in patients with extensive coronary artery disease however, has been disputed. We examined the effects of coronary collateral circulation on cardiovascular outcomes, with an emphasis on clinical prognostic value and on a putative role of IHD burden. Data analyzed were obtained in the REGRESS study, involving 879 male participants undergoing coronary angiography and being followed for 24 months. Presence of coronary collaterals spontaneously visible on angiography was assessed. Events included: myocardial infarction (MI), coronary heart disease death and percutaneous or surgical coronary intervention. Estimates of relative risks of outcome events were calculated using proportional hazard analysis, with adjustments for confounding factors and stratification for initial revascularization strategy and factors reflecting extent of IHD burden. Event-free survival after two years was 84% in patients without collaterals, and 92% in patients with collaterals (p=0.0020). The crude HR was 0.48 (95% CI: 0.30-0.77), and 0.38 (0.23-0.65) after adjustment for confounders and cardiovascular risk factors. The protective effect of coronary collaterals was not modified by the extent of IHD burden (interaction p=0.99). The angiographical presence of coronary collaterals is a clinical predictor of cardiovascular prognosis. Collaterals exert a protective effect on outcome in a broad spectrum of patients. Our data suggest that this protective effect is independent of disease burden, and remains present in patients with extensive IHD.
    International journal of cardiology 02/2008; 132(2):257-62. · 7.08 Impact Factor
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    ABSTRACT: In the field of molecular cardiology, recently several determinants of coronary collateral circulation have been identified. Knowing these factors may aid risk-stratification and put forward targets for intervention by stimulating development of collateral blood vessels (arteriogenesis). However, prognostic importance of coronary collaterals is not yet beyond debate, and seems to be modified by the extent of atherosclerotic burden. Combining these insights is essential to increase our understanding of these mechanisms and to proceed with developing strategies for risk-stratification and therapeutic stimulation of arteriogenesis.
    International journal of cardiology 04/2007; 116(2):139-43. · 7.08 Impact Factor