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5 results on '"Hof, F.N. van 't"'

1. Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Author

Jones, G.T., Tromp, G., Kuivaniemi, H., Gretarsdottir, S., Baas, A.F., Giusti, B., Strauss, E., Hof, F.N. van 't, Webb, T.R., Erdman, R., Ritchie, M.D., Elmore, J.R., Verma, A., Pendergrass, S., Kullo, I.J., Ye, Z., Peissig, P.L., Gottesman, O., Verma, S.S., Malinowski, J., Rasmussen-Torvik, L.J., Borthwick, K.M., Smelser, D.T., Crosslin, D.R., Andrade, M. de, Ryer, E.J., McCarty, C.A., Bottinger, E.P., Pacheco, J.A., Crawford, D.C., Carrell, D.S., Gerhard, G.S., Franklin, D.P., Carey, D.J., Phillips, V.L., Williams, M.J., Wei, W., Blair, R., Hill, A.A., Vasudevan, T.M., Lewis, D.R., Thomson, I.A., Krysa, J., Hill, G.B., Roake, J., Merriman, T.R., Oszkinis, G., Galora, S., Saracini, C., Abbate, R., Pulli, R., Pratesi, C., Saratzis, A., Verissimo, A.R., Bumpstead, S., Badger, S.A., Clough, R.E., Cockerill, G., Hafez, H., Scott, D.J., Futers, T.S., Romaine, S.P., Bridge, K., Griffin, K.J., Bailey, M.A., Smith, A., Thompson, M.M., Bockxmeer, F.M. van, Matthiasson, S.E., Thorleifsson, G., Thorsteinsdottir, U., Blankensteijn, J.D., Teijink, J.A., Wijmenga, C., Graaf, J. de, Kiemeney, L.A.L.M., Lindholt, J.S., Hughes, A., Bradley, D.T., Stirrups, K., Golledge, J., Norman, P.E., Powell, J.T., Humphries, S.E., Hamby, S.E., Goodall, A.H., Nelson, C.P., Sakalihasan, N., Courtois, A., Ferrell, R.E., Eriksson, P., Folkersen, L., Franco-Cereceda, A., Eicher, J.D., Johnson, A.D., Betsholtz, C., Ruusalepp, A., Franzen, O., Schadt, E.E., and Bjorkegren, J.L.

Subjects
Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], cardiovascular system, cardiovascular diseases
Abstract

Contains fulltext : 169744.pdf (Publisher’s version ) (Open Access) RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

Published
2017

2. Genetic variants associated with type 2 diabetes and adiposity and risk of intracranial and abdominal aortic aneurysms

Author

Hof, F.N. van 't, Vaucher, J., Holmes, M.V., Wilde, A. de, Baas, A.F., Blankensteijn, J.D., Hofman, A., Kiemeney, L.A.L.M., Rivadeneira, F., Uitterlinden, A.G., Vermeulen, S.H., Rinkel, G.J., Bakker, P.I. de, Ruigrok, Y.M., Hof, F.N. van 't, Vaucher, J., Holmes, M.V., Wilde, A. de, Baas, A.F., Blankensteijn, J.D., Hofman, A., Kiemeney, L.A.L.M., Rivadeneira, F., Uitterlinden, A.G., Vermeulen, S.H., Rinkel, G.J., Bakker, P.I. de, and Ruigrok, Y.M.

Abstract

Item does not contain fulltext, Epidemiological studies show that type 2 diabetes (T2D) is inversely associated with intracranial aneurysms (IA) and abdominal aortic aneurysms (AAA). Although adiposity has not been considered a risk factor for IA, there have been inconsistent reports relating adiposity to AAA risk. We assessed whether these observations have a genetic, causal basis. To this end, we extracted genotypes of validated single-nucleotide polymorphisms associated with T2D (n=65), body mass index (BMI) (n=97) and waist-hip ratio adjusted for BMI (WHRadjBMI) (n=47) from genotype data collected in 717 IA cases and 1988 controls, and in 818 AAA cases and 3004 controls, all of Dutch descent. For each of these three traits, we computed genetic risk scores (GRS) for each individual in these case-control data sets by summing the number of risk alleles weighted by their published effect size, and tested whether these GRS were associated with risk of aneurysm. We divided the cohorts into GRS quartiles, and compared IA and AAA risk in the highest with the lowest GRS quartile using logistic regression. We found no evidence for association in IA or AAA risk between top and bottom quartiles for the genetic risk scores for T2D, BMI and WHRadjBMI. However, additional Mendelian randomization analyses suggested a trend to potentially causal associations between BMI and WHRadjBMI and risk of AAA. Overall, our results do not support epidemiological observations relating T2D to aneurysm risk, but may indicate a potential role of adiposity in AAA that requires further investigation.

Published
2017

3. Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Author

Hof, F.N. van 't, Ruigrok, Y.M., Lee, C.H., Ripke, S., Anderson, G., Baas, A.F., Blankensteijn, J.D., Bottinger, E.P., Bown, M.J., Broderick, J., Bijlenga, P., Carrell, D.S., Crawford, D.C., Crosslin, D.R., Ebeling, C., Eriksson, J.G., Fornage, M., Foroud, T., von Und Zu Fraunberg, M., Friedrich, C.M., Gaal, E.I., Gottesman, O., Guo, D.C., Harrison, S.C., Hernesniemi, J., Hofman, A., Inoue, I., Jaaskelainen, J.E., Jones, G.T., Kiemeney, L.A., Kivisaari, R., Ko, N., Koskinen, S., Kubo, M., Kullo, I.J., Kuivaniemi, H., Kurki, M.I., Laakso, A., Lai, D., Leal, S.M., Lehto, H., Lemaire, S.A., Low, S.K., Malinowski, J., McCarty, C.A., Milewicz, D.M., Mosley, T.H., Nakamura, Y., Nakaoka, H., Niemela, M., Pacheco, J., Peissig, P.L., Pera, J., Rasmussen-Torvik, L., Ritchie, M.D., Rivadeneira, F., Rij, A.M. van, Santos-Cortez, R.L., Saratzis, A., Slowik, A., Takahashi, A., Tromp, G., Uitterlinden, A.G., Verma, S.S., Vermeulen, S.H., Wang, G.T., Han, B., Rinkel, G.J., Bakker, P.I. de, Graaf, J. de, et al., Hof, F.N. van 't, Ruigrok, Y.M., Lee, C.H., Ripke, S., Anderson, G., Baas, A.F., Blankensteijn, J.D., Bottinger, E.P., Bown, M.J., Broderick, J., Bijlenga, P., Carrell, D.S., Crawford, D.C., Crosslin, D.R., Ebeling, C., Eriksson, J.G., Fornage, M., Foroud, T., von Und Zu Fraunberg, M., Friedrich, C.M., Gaal, E.I., Gottesman, O., Guo, D.C., Harrison, S.C., Hernesniemi, J., Hofman, A., Inoue, I., Jaaskelainen, J.E., Jones, G.T., Kiemeney, L.A., Kivisaari, R., Ko, N., Koskinen, S., Kubo, M., Kullo, I.J., Kuivaniemi, H., Kurki, M.I., Laakso, A., Lai, D., Leal, S.M., Lehto, H., Lemaire, S.A., Low, S.K., Malinowski, J., McCarty, C.A., Milewicz, D.M., Mosley, T.H., Nakamura, Y., Nakaoka, H., Niemela, M., Pacheco, J., Peissig, P.L., Pera, J., Rasmussen-Torvik, L., Ritchie, M.D., Rivadeneira, F., Rij, A.M. van, Santos-Cortez, R.L., Saratzis, A., Slowik, A., Takahashi, A., Tromp, G., Uitterlinden, A.G., Verma, S.S., Vermeulen, S.H., Wang, G.T., Han, B., Rinkel, G.J., Bakker, P.I. de, Graaf, J. de, and et al.

Abstract

Contains fulltext : 171496.pdf (publisher's version ) (Open Access), BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND RESULTS: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1x10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1x10(-3)). CONCLUSIONS: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.

Published
2016

4. High risk population isolate reveals low frequency variants predisposing to intracranial aneurysms

Author

Kurki, M.I., Gaal, E.I., Kettunen, J., Lappalainen, T., Menelaou, A., Anttila, V., Hof, F.N. van 't, Fraunberg, M. von Und Zu, Helisalmi, S., Hiltunen, M., Lehto, H., Laakso, A., Kivisaari, R., Koivisto, T., Ronkainen, A., Rinne, J., Kiemeney, B., Vermeulen, S., Kaunisto, M.A., Eriksson, J.G., Aromaa, A., Perola, M., Lehtimaki, T., Raitakari, O.T., Salomaa, V., Gunel, M., Dermitzakis, E.T., Ruigrok, Y.M., Rinkel, G.J., Niemela, M., Hernesniemi, J., Ripatti, S., Bakker, P.I. de, Palotie, A., Jaaskelainen, J.E., Kurki, M.I., Gaal, E.I., Kettunen, J., Lappalainen, T., Menelaou, A., Anttila, V., Hof, F.N. van 't, Fraunberg, M. von Und Zu, Helisalmi, S., Hiltunen, M., Lehto, H., Laakso, A., Kivisaari, R., Koivisto, T., Ronkainen, A., Rinne, J., Kiemeney, B., Vermeulen, S., Kaunisto, M.A., Eriksson, J.G., Aromaa, A., Perola, M., Lehtimaki, T., Raitakari, O.T., Salomaa, V., Gunel, M., Dermitzakis, E.T., Ruigrok, Y.M., Rinkel, G.J., Niemela, M., Hernesniemi, J., Ripatti, S., Bakker, P.I. de, Palotie, A., and Jaaskelainen, J.E.

Abstract

Contains fulltext : 138172.pdf (publisher's version ) (Open Access), 3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2x increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p<5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants. Three were associated with the case-control status: 2q23.3 (MAF 2.1%, OR 1.89, p 1.42x10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17x10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87x10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08x-9). Two of the associations (5q31.3, 6q24.2) replicated in the Dutch sample. The 7p22.1 locus was strongly differentiated; the lead variant was more frequent in Finland (4.6%) than in the Netherlands (0.3%). Additionally, we replicated a previously inconclusive locus on 2q33.1 in all samples tested (OR 1.27, p 1.87x10-12). The five loci explain 2.1% of the sIA heritability in Finland, and may relate to, but not explain, the increased incidence of sIA-SAH in Finland. This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.

Published
2014

5. Impact of inherited genetic variants associated with lipid profile, hypertension, and coronary artery disease on the risk of intracranial and abdominal aortic aneurysms

Author

Hof, F.N. van 't, Ruigrok, Y.M., Baas, A.F., Kiemeney, L.A.L.M., Vermeulen, H.H.M., Uitterlinden, A.G., Hofman, A., Rivadeneira, F., Rinkel, G.J., Bakker, P.I. de, Hof, F.N. van 't, Ruigrok, Y.M., Baas, A.F., Kiemeney, L.A.L.M., Vermeulen, H.H.M., Uitterlinden, A.G., Hofman, A., Rivadeneira, F., Rinkel, G.J., and Bakker, P.I. de

Abstract

Item does not contain fulltext, BACKGROUND: Epidemiological studies show that an unfavorable lipid profile and coronary artery disease (CAD) are risk traits for abdominal aortic aneurysms (AAAs) but not for intracranial aneurysms (IAs), and that hypertension is a main risk trait for IAs but not for AAAs. To evaluate these observations, we investigated single-nucleotide polymorphisms associated with serum lipid levels, hypertension, and CAD and tested their contribution to AAA and IA risk. METHODS AND RESULTS: We defined sets of single-nucleotide polymorphisms previously reported to be associated with serum lipid levels, CAD, and blood pressure. From previously collected genome-wide data, we extracted genotypes for these single-nucleotide polymorphism sets in 709 IA cases and 2692 controls and 807 AAA cases and 1905 controls (all of Dutch origin). We computed genetic scores for each individual by summing the observed number of risk alleles weighted by their previously published effect size. Using logistic regression, we tested the genetic scores for association with IAs and AAAs and found significant associations for genetic scores of total cholesterol (P=3.6x10(-)(6)), low-density lipoprotein-cholesterol (P=5.7x10(-)(7)), and CAD (P=0.0014) with AAAs and for the blood pressure score with IAs (P=0.0030). CONCLUSIONS: We demonstrate that genetic risk profiles of lipid factors and CAD are associated with AAAs but not with IAs, and the genetic risk profile of blood pressure is associated with IAs but not with AAAs. These findings are consistent with epidemiological observations.

Published
2013

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