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Radboud Universiteit Nijmegen, 27 januari 2016, Promotores : Heijer, M. den, Hermus, A.R.M.M. Co-promotor : Netea-Maier, R.T., Contains fulltext : 150187.pdf (publisher's version ) (Open Access)

Radboud Universiteit Nijmegen, 27 januari 2016, Promotores : Heijer, M. den, Hermus, A.R.M.M. Co-promotor : Netea-Maier, R.T., Contains fulltext : 150187.pdf (publisher's version ) (Open Access)

Radboud Universiteit Nijmegen, 01 december 2015, Promotores : Verbeek, A.L.M., Heijer, M. den Co-promotor : Atsma, F., Contains fulltext : 149279.pdf (publisher's version ) (Open Access), In this thesis, the possible protective effect of frequent blood donation on cardiovascular disease was studied. Previous research has shown that high iron stores could have damaging effects on developing cardiovascular disease, and that blood donation lowers iron stores. Lowering iron stores through blood donation could therefore reduce cardiovascular disease risk. Apart from the effects on insulin resistance, metabolic syndrome, and subclinical atherosclerosis, the effects on cardiovascular morbidity and –mortality were also studied. For this purpose, data of Dutch blood donors were linked to hospital discharges and death certificates as registered at Statistics Netherlands (CBS). Within the group of people that have remained an active donor for at least 10 years, high-frequency donors (> 20 donations in men, >15 donations in women) have a significantly lower cardiovascular risk than low-frequency donors (<15 donations in men, <12 donations in women). Women appeared to have a 10% lower risk on cardiovascular disease incidence, and even 17% on cardiovascular death. Frequent blood donors are relatively healthy compared to the general population, and high-frequency donors could already have been healthier than low-frequency donors. This Healthy Donor Effect could have influenced the results. Therefore, further research on the protective effect of blood donation on cardiovascular disease is needed. Future research focussed on replicating these results, as well as the underlying causal mechanism, should take differences between men and women into account.

Radboud Universiteit Nijmegen, 01 december 2015, Promotores : Verbeek, A.L.M., Heijer, M. den Co-promotor : Atsma, F., Contains fulltext : 149279.pdf (publisher's version ) (Open Access), In this thesis, the possible protective effect of frequent blood donation on cardiovascular disease was studied. Previous research has shown that high iron stores could have damaging effects on developing cardiovascular disease, and that blood donation lowers iron stores. Lowering iron stores through blood donation could therefore reduce cardiovascular disease risk. Apart from the effects on insulin resistance, metabolic syndrome, and subclinical atherosclerosis, the effects on cardiovascular morbidity and –mortality were also studied. For this purpose, data of Dutch blood donors were linked to hospital discharges and death certificates as registered at Statistics Netherlands (CBS). Within the group of people that have remained an active donor for at least 10 years, high-frequency donors (> 20 donations in men, >15 donations in women) have a significantly lower cardiovascular risk than low-frequency donors (<15 donations in men, <12 donations in women). Women appeared to have a 10% lower risk on cardiovascular disease incidence, and even 17% on cardiovascular death. Frequent blood donors are relatively healthy compared to the general population, and high-frequency donors could already have been healthier than low-frequency donors. This Healthy Donor Effect could have influenced the results. Therefore, further research on the protective effect of blood donation on cardiovascular disease is needed. Future research focussed on replicating these results, as well as the underlying causal mechanism, should take differences between men and women into account.

Radboud Universiteit Nijmegen, 11 oktober 2011, Promotores : Blom, H.J., Heijer, M den Co-promotor : Kapusta, L., Contains fulltext : 97925.pdf (Publisher’s version ) (Open Access)

Radboud Universiteit Nijmegen, 10 juni 2011, Promotor : Thien, Th. Co-promotores : Wollersheim, H.C.H., Heijer, M. den, Janssen, M.C.H., Contains fulltext : 91225.pdf (publisher's version ) (Open Access)

Radboud Universiteit Nijmegen, 11 oktober 2011, Promotores : Blom, H.J., Heijer, M den Co-promotor : Kapusta, L., Contains fulltext : 97925.pdf (Publisher’s version ) (Open Access)

Radboud Universiteit Nijmegen, 05 juli 2011, Promotor : Blom, H.J. Co-promotor : Heijer, M. den, Contains fulltext : 89944.pdf (publisher's version ) (Open Access)

Radboud Universiteit Nijmegen, 10 juni 2011, Promotor : Thien, Th. Co-promotores : Wollersheim, H.C.H., Heijer, M. den, Janssen, M.C.H., Contains fulltext : 91225.pdf (publisher's version ) (Open Access)

Radboud Universiteit Nijmegen, 10 juni 2011, Promotor : Thien, Th. Co-promotores : Wollersheim, H.C.H., Heijer, M. den, Janssen, M.C.H., Contains fulltext : 91225.pdf (publisher's version ) (Open Access)

RU Radboud Universiteit Nijmegen, 12 maart 2010, Promotor : Stalenhoef, A.F.H. Co-promotores : Graaf, J. de, Heijer, M. den, Contains fulltext : 74941.pdf (publisher's version ) (Open Access)

RU Radboud Universiteit Nijmegen, 30 september 2009, Promotores : Kiemeney, L.A.L.M., Hermus, A.R.M.M. Co-promotores : Heijer, M. den, Blom, H.J., Contains fulltext : 80617.pdf (publisher's version ) (Open Access), Homocysteine is a sulphur-containing intermediate in one-carbon metabolism. Plasma total homocysteine (tHcy) concentration is associated to common diseases including venous thrombosis and neural tube defects (NTD). Identification of genetic determinants of plasma tHcy concentration can contribute to clarification of the underlying pathogenic processes. In the last 13 years, a focus on single locus association studies of functional variants has resulted in establishment of the MTHFR677C>T polymorphism as a genetic determinant of plasma tHcy concentrations. In this thesis, we looked beyond the single locus effects of evident candidate DNA variants and beyond the traditional genetic epidemiological study designs. The first part of the thesis describes a linkage study for plasma tHcy and four candidate-gene association studies for plasma tHcy, related metabolites, recurrent venous thrombosis (RVT), and NTD. The genome wide-linkage analysis revealed three regions that might harbour genetic determinants for plasma tHcy. Extensive association studies for over 40 one-carbon metabolism-related genes led to identification of novel candidates and known DNA variants that each had small contributions in plasma tHcy variation (<<2%); these studies also underlined the relative importance of MTHFR677C>T and CBS variants. Using multi-locus analysis we found a strongly associated five-locus interacting genotype that explained 17% of plasma tHcy variation in our population. Simultaneous analysis of candidate genes for plasma tHcy and folate and methionine concentrations indicated heterogeneity in genetic determinants for the three metabolites. The UCP2 45bp del was found to influence recurrent venous thrombosis risk and variants in CUBN and TRDMT1 were associated with NTD but not via plasma tHcy concentration. In the second part of the thesis, a new hybrid design is proposed which is shown to allow a powerful and flexible identification of both maternal and offspring genetic effects c

RU Radboud Universiteit Nijmegen, 10 januari 2008, Promotor : Wevers, R.A. Co-promotores : Blom, H.J., Heijer, M. den, Contains fulltext : 71350.pdf (Publisher’s version ) (Open Access)

RU Radboud Universiteit Nijmegen, 10 januari 2008, Promotor : Wevers, R.A. Co-promotores : Blom, H.J., Heijer, M. den, Contains fulltext : 71350.pdf (Publisher’s version ) (Open Access)

RU Radboud Universiteit Nijmegen, 10 januari 2008, Promotor : Wevers, R.A. Co-promotores : Blom, H.J., Heijer, M. den, Contains fulltext : 71350.pdf (Publisher’s version ) (Open Access)

RU Radboud Universiteit Nijmegen, 11 januari 2007, Promotor : Hermus, A.R.M.M. Co-promotores : Heijer, M. den, Blom, H.J., Item does not contain fulltext, Homocysteine is a intermediary product of protein metabolism. A high concentration of homocysteine in the blood is associated with a higher risk of cardiovascular disease, including venous thrombosis. Homocysteine levels are in part determined by genetic factors and vitamin intake (such as vitamin B12). The main goal of the presented research was to identify genetic factors (polymorphisms) that affect homocysteine levels and to assess if these polymorphisms also increased the risk of recurrent venous thrombosis. In addition, we evaluated vitamin B12 as a risk factor of recurrent venous thrombosis. We investigated a polymorphism in the catechol-O-methyltransferase gene, which is involved in so-called 'transmethylation reactions', in relation to homocysteine levels. Individuals carrying this polymorphism had higher homocysteine levels than subjects that did not carry this variant. In addition, this polymorphism was more common in recurrent venous thrombosis cases than the general population. This supports the hypothesis that high homocysteine reflects a disturbed transmethylation, which increases venous thrombosis risk. We also developed a method to study metabolites in the blood that report on the ability of our body to perform transmethylation reactions. It appeared that the way the blood samples were stabilized was of great importance for the reliability of our method. Future studies will have to point out whether a disturbed transmethylation is involved in the aetiology of venous thrombosis. Finally, we show that a low vitamin B12 status, which is a cause of high homocysteine levels, is associated with an increased risk of recurrent venous thrombosis. Measuring methylmalonic acid, a marker of intracellular vitamin B12 availability, seems more suitable for measuring vitamin B12 status than plasma vitamin B12 itself.

RU Radboud Universiteit Nijmegen, 11 januari 2007, Promotor : Hermus, A.R.M.M. Co-promotores : Heijer, M. den, Blom, H.J., Contains fulltext : 30131_molegeano.pdf (publisher's version ) (Open Access), Homocysteine is a intermediary product of protein metabolism. A high concentration of homocysteine in the blood is associated with a higher risk of cardiovascular disease, including venous thrombosis. Homocysteine levels are in part determined by genetic factors and vitamin intake (such as vitamin B12). The main goal of the presented research was to identify genetic factors (polymorphisms) that affect homocysteine levels and to assess if these polymorphisms also increased the risk of recurrent venous thrombosis. In addition, we evaluated vitamin B12 as a risk factor of recurrent venous thrombosis. We investigated a polymorphism in the catechol-O-methyltransferase gene, which is involved in so-called 'transmethylation reactions', in relation to homocysteine levels. Individuals carrying this polymorphism had higher homocysteine levels than subjects that did not carry this variant. In addition, this polymorphism was more common in recurrent venous thrombosis cases than the general population. This supports the hypothesis that high homocysteine reflects a disturbed transmethylation, which increases venous thrombosis risk. We also developed a method to study metabolites in the blood that report on the ability of our body to perform transmethylation reactions. It appeared that the way the blood samples were stabilized was of great importance for the reliability of our method. Future studies will have to point out whether a disturbed transmethylation is involved in the aetiology of venous thrombosis. Finally, we show that a low vitamin B12 status, which is a cause of high homocysteine levels, is associated with an increased risk of recurrent venous thrombosis. Measuring methylmalonic acid, a marker of intracellular vitamin B12 availability, seems more suitable for measuring vitamin B12 status than plasma vitamin B12 itself.

RU Radboud Universiteit Nijmegen, 29 maart 2007, Promotor : Hermus, A.R.M.M. Co-promotores : Heijer, M. den, Blom, H.J., Borm, G.F., Contains fulltext : 51620.pdf (Publisher’s version ) (Open Access)

RU Radboud Universiteit Nijmegen, 11 januari 2007, Promotor : Hermus, A.R.M.M. Co-promotores : Heijer, M. den, Blom, H.J., Contains fulltext : 30131_molegeano.pdf (publisher's version ) (Open Access), Homocysteine is a intermediary product of protein metabolism. A high concentration of homocysteine in the blood is associated with a higher risk of cardiovascular disease, including venous thrombosis. Homocysteine levels are in part determined by genetic factors and vitamin intake (such as vitamin B12). The main goal of the presented research was to identify genetic factors (polymorphisms) that affect homocysteine levels and to assess if these polymorphisms also increased the risk of recurrent venous thrombosis. In addition, we evaluated vitamin B12 as a risk factor of recurrent venous thrombosis. We investigated a polymorphism in the catechol-O-methyltransferase gene, which is involved in so-called 'transmethylation reactions', in relation to homocysteine levels. Individuals carrying this polymorphism had higher homocysteine levels than subjects that did not carry this variant. In addition, this polymorphism was more common in recurrent venous thrombosis cases than the general population. This supports the hypothesis that high homocysteine reflects a disturbed transmethylation, which increases venous thrombosis risk. We also developed a method to study metabolites in the blood that report on the ability of our body to perform transmethylation reactions. It appeared that the way the blood samples were stabilized was of great importance for the reliability of our method. Future studies will have to point out whether a disturbed transmethylation is involved in the aetiology of venous thrombosis. Finally, we show that a low vitamin B12 status, which is a cause of high homocysteine levels, is associated with an increased risk of recurrent venous thrombosis. Measuring methylmalonic acid, a marker of intracellular vitamin B12 availability, seems more suitable for measuring vitamin B12 status than plasma vitamin B12 itself.

RU Radboud Universiteit Nijmegen, 29 maart 2007, Promotor : Hermus, A.R.M.M. Co-promotores : Heijer, M. den, Blom, H.J., Borm, G.F., Contains fulltext : 51620.pdf (Publisher’s version ) (Open Access)

RU Radboud Universiteit Nijmegen, 11 januari 2007, Promotor : Hermus, A.R.M.M. Co-promotores : Heijer, M. den, Blom, H.J., Item does not contain fulltext, Homocysteine is a intermediary product of protein metabolism. A high concentration of homocysteine in the blood is associated with a higher risk of cardiovascular disease, including venous thrombosis. Homocysteine levels are in part determined by genetic factors and vitamin intake (such as vitamin B12). The main goal of the presented research was to identify genetic factors (polymorphisms) that affect homocysteine levels and to assess if these polymorphisms also increased the risk of recurrent venous thrombosis. In addition, we evaluated vitamin B12 as a risk factor of recurrent venous thrombosis. We investigated a polymorphism in the catechol-O-methyltransferase gene, which is involved in so-called 'transmethylation reactions', in relation to homocysteine levels. Individuals carrying this polymorphism had higher homocysteine levels than subjects that did not carry this variant. In addition, this polymorphism was more common in recurrent venous thrombosis cases than the general population. This supports the hypothesis that high homocysteine reflects a disturbed transmethylation, which increases venous thrombosis risk. We also developed a method to study metabolites in the blood that report on the ability of our body to perform transmethylation reactions. It appeared that the way the blood samples were stabilized was of great importance for the reliability of our method. Future studies will have to point out whether a disturbed transmethylation is involved in the aetiology of venous thrombosis. Finally, we show that a low vitamin B12 status, which is a cause of high homocysteine levels, is associated with an increased risk of recurrent venous thrombosis. Measuring methylmalonic acid, a marker of intracellular vitamin B12 availability, seems more suitable for measuring vitamin B12 status than plasma vitamin B12 itself.

RU Radboud Universiteit Nijmegen, 11 januari 2007, Promotor : Hermus, A.R.M.M. Co-promotores : Heijer, M. den, Blom, H.J., Contains fulltext : 30131_molegeano.pdf (publisher's version ) (Open Access), Homocysteine is a intermediary product of protein metabolism. A high concentration of homocysteine in the blood is associated with a higher risk of cardiovascular disease, including venous thrombosis. Homocysteine levels are in part determined by genetic factors and vitamin intake (such as vitamin B12). The main goal of the presented research was to identify genetic factors (polymorphisms) that affect homocysteine levels and to assess if these polymorphisms also increased the risk of recurrent venous thrombosis. In addition, we evaluated vitamin B12 as a risk factor of recurrent venous thrombosis. We investigated a polymorphism in the catechol-O-methyltransferase gene, which is involved in so-called 'transmethylation reactions', in relation to homocysteine levels. Individuals carrying this polymorphism had higher homocysteine levels than subjects that did not carry this variant. In addition, this polymorphism was more common in recurrent venous thrombosis cases than the general population. This supports the hypothesis that high homocysteine reflects a disturbed transmethylation, which increases venous thrombosis risk. We also developed a method to study metabolites in the blood that report on the ability of our body to perform transmethylation reactions. It appeared that the way the blood samples were stabilized was of great importance for the reliability of our method. Future studies will have to point out whether a disturbed transmethylation is involved in the aetiology of venous thrombosis. Finally, we show that a low vitamin B12 status, which is a cause of high homocysteine levels, is associated with an increased risk of recurrent venous thrombosis. Measuring methylmalonic acid, a marker of intracellular vitamin B12 availability, seems more suitable for measuring vitamin B12 status than plasma vitamin B12 itself.

RU Radboud Universiteit Nijmegen, 29 maart 2007, Promotor : Hermus, A.R.M.M. Co-promotores : Heijer, M. den, Blom, H.J., Borm, G.F., Contains fulltext : 51620.pdf (Publisher’s version ) (Open Access)

KUN Katholieke Universiteit Nijmegen, 04 februari 2005, Promotor : Schalkwijk, J. Co-promotor : Heijer, M. den, Contains fulltext : 49066.pdf (Publisher’s version ) (Open Access)

KUN Katholieke Universiteit Nijmegen, 04 februari 2005, Promotor : Schalkwijk, J. Co-promotor : Heijer, M. den, Contains fulltext : 49066.pdf (Publisher’s version ) (Open Access)

KUN Katholieke Universiteit Nijmegen, 04 februari 2005, Promotor : Schalkwijk, J. Co-promotor : Heijer, M. den, Contains fulltext : 49066.pdf (Publisher’s version ) (Open Access)