Search

Your search keyword '"Witteman Jcm."' showing total 82 results
Start Over Author "Witteman Jcm." Database OAIster
82 results on '"Witteman Jcm."'

1. Heritabilities, proportions of heritabilities explained by GWAS findings, and implications of cross-phenotype effects on PR interval

Author

Silva Aldana, Claudia, Kors, Jan, Amin, Najaf, Dehghan, Abbas, Witteman, JCM, Willemsen, Ralph, Oostra, Ben, Duijn, Cornelia, Isaacs, Aaron, Silva Aldana, Claudia, Kors, Jan, Amin, Najaf, Dehghan, Abbas, Witteman, JCM, Willemsen, Ralph, Oostra, Ben, Duijn, Cornelia, and Isaacs, Aaron

Abstract

Electrocardiogram (ECG) measurements are a powerful tool for evaluating cardiac function and are widely used for the diagnosis and prediction of a variety of conditions, including myocardial infarction, cardiac arrhythmias, and sudden cardiac death. Recently, genome-wide association studies (GWASs) identified a large number of genes related to ECG parameter variability, specifically for the QT, QRS, and PR intervals. The aims of this study were to establish the heritability of ECG traits, including indices of left ventricular hypertrophy, and to directly assess the proportion of those heritabilities explained by GWAS variants. These analyses were conducted in a large, Dutch family-based cohort study, the Erasmus Rucphen Family study using variance component methods implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) software package. Heritability estimates ranged from 34 % for QRS and Cornell voltage product to 49 % for 12-lead sum. Trait-specific GWAS findings for each trait explained a fraction of their heritability (17 % for QRS, 4 % for QT, 2 % for PR, 3 % for Sokolow-Lyon index, and 4 % for 12-lead sum). The inclusion of all ECG-associated single nucleotide polymorphisms explained an additional 6 % of the heritability of PR. In conclusion, this study shows that, although GWAS explain a portion of ECG trait variability, a large amount of heritability remains to be explained. In addition, larger GWAS for PR are likely to detect loci already identified, particularly those observed for QRS and 12-lead sum.

Published
2015

2. Arterial stiffness and influences of the metabolic syndrome: A cross-countries study

Author

Scuteri, A, Cunha, PG, Rosei, EA, Badariere, J, Bekaert, S, Cockcroft, JR, Cotter, J, Cucca, F, De Buyzere, ML, Meyer, T, Ferrucci, L, Franco, O, Gale, N, Gillebert, TC, Hofman, Bert, Langlois, M, Laucevicius, A, Laurent, S, Mattace Raso, F.U.S., Morrell, CH, Muiesan, ML, Munnery, MM, Navickas, R, Oliveira, P, Orru', M, Pilia, MG, Rietzschel, ER, Ryliskyte, L, Salvetti, M, Schlessinger, D, Sousa, N, Stefanadis, C, Strait, J, Van Daele, C, Villa, I, Vlachopoulos, C, Witteman, JCM, Xaplanteris, P, Nilsson, P, Lakatta, EG, Scuteri, A, Cunha, PG, Rosei, EA, Badariere, J, Bekaert, S, Cockcroft, JR, Cotter, J, Cucca, F, De Buyzere, ML, Meyer, T, Ferrucci, L, Franco, O, Gale, N, Gillebert, TC, Hofman, Bert, Langlois, M, Laucevicius, A, Laurent, S, Mattace Raso, F.U.S., Morrell, CH, Muiesan, ML, Munnery, MM, Navickas, R, Oliveira, P, Orru', M, Pilia, MG, Rietzschel, ER, Ryliskyte, L, Salvetti, M, Schlessinger, D, Sousa, N, Stefanadis, C, Strait, J, Van Daele, C, Villa, I, Vlachopoulos, C, Witteman, JCM, Xaplanteris, P, Nilsson, P, and Lakatta, EG

Abstract

Specific clusters of metabolic syndrome (MetS) components impact differentially on arterial stiffness, indexed as pulse wave velocity (PWV). Of note, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium the occurrence of specific clusters of MetS differed markedly across Europe and the US. The aim of the present study was to investigate whether specific clusters of MetS are consistently associated with stiffer arteries in different populations. We studied 20,570 subjects from 9 cohorts representing 8 different European countries and the US participating in the MARE Consortium. MetS was defined in accordance with NCEP ATPIII criteria as the simultaneous alteration in >= 3 of the 5 components: abdominal obesity (W), high triglycerides (T), low HDL cholesterol (H), elevated blood pressure (B), and elevated fasting glucose (G). PWV measured in each cohort was "normalized" to account for different acquisition methods. MetS had an overall prevalence of 24.2% (4985 subjects). MetS accelerated the age-associated increase in PWV levels at any age, and similarly in men and women. MetS clusters TBW, GBW, and GTBW are consistently associated with significantly stiffer arteries to an extent similar or greater than observed in subjects with alteration in all the five MetS components - even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus - in all the MARE cohorts. In conclusion, different component clusters of MetS showed varying associations with arterial stiffness (PWV). (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Published
2014

3. Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study

Author

Leening, Maarten, Ferket, Bart, Steyerberg, Ewout, Kavousi, Maryam, Deckers, Jaap, Nieboer, Daan, Heeringa, Jan, Portegies, Marileen, Hofman, Bert, Ikram, Arfan, Hunink, Myriam, Franco Duran, OH, Stricker, Bruno, Witteman, JCM, Roos - Hesselink, Jolien, Leening, Maarten, Ferket, Bart, Steyerberg, Ewout, Kavousi, Maryam, Deckers, Jaap, Nieboer, Daan, Heeringa, Jan, Portegies, Marileen, Hofman, Bert, Ikram, Arfan, Hunink, Myriam, Franco Duran, OH, Stricker, Bruno, Witteman, JCM, and Roos - Hesselink, Jolien

Abstract

Objective To evaluate differences in first manifestations of cardiovascular disease between men and women in a competing risks framework. Design Prospective population based cohort study. Setting People living in the community in Rotterdam, the Netherlands. Participants 8419 participants (60.9% women) aged >= 55 and free from cardiovascular disease at baseline. Main outcome measures First diagnosis of coronary heart disease (myocardial infarction, revascularisation, and coronary death), cerebrovascular disease (stroke, transient ischaemic attack, and carotid revascularisation), heart failure, or other cardiovascular death; or death from non-cardiovascular causes. Data were used to calculate lifetime risks of cardiovascular disease and its first incident manifestations adjusted for competing non-cardiovascular death. Results During follow-up of up to 20.1 years, 2888 participants developed cardiovascular disease (826 coronary heart disease, 1198 cerebrovascular disease, 762 heart failure, and 102 other cardiovascular death). At age 55, overall lifetime risks of cardiovascular disease were 67.1% (95% confidence interval 64.7% to 69.5%) for men and 66.4% (64.2% to 68.7%) for women. Lifetime risks of first incident manifestations of cardiovascular disease in men were 27.2% (24.1% to 30.3%) for coronary heart disease, 22.8% (20.4% to 25.1%) for cerebrovascular disease, 14.9% (13.3% to 16.6%) for heart failure, and 2.3% (1.6% to 2.9%) for other deaths from cardiovascular disease. For women the figures were 16.9% (13.5% to 20.4%), 29.8% (27.7% to 31.9%), 17.5% (15.9% to 19.2%), and 2.1% (1.6% to 2.7%), respectively. Differences in the number of events that developed over the lifespan in women compared with men (per 1000) were -7 for any cardiovascular disease, -102 for coronary heart disease, 70 for cerebrovascular disease, 26 for heart failure, and -1 for other cardiovascular death; all outcomes manifested at a higher age in women. Patterns were similar when analyses were

Published
2014

4. Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations

Author

O'Seaghdha, CM, Wu, HS, Yang, Q, Kapur, K, Guessous, I, Zuber, AM, Kottgen, A, Stoudmann, C, Teumer, A, Kutalik, Z, Mangino, M, Dehghan, Abbas, Zhang, WH, Eiriksdottir, G, Li, G (Guo), Tanaka, T, Portas, L, Lopez, LM, Hayward, C, Lohman, K, Matsuda, K, Padmanabhan, S, Firsov, D, Sorice, R, Ulivi, S, Brockhaus, AC, Kleber, ME, Mahajan, A, Ernst, FD, Gudnason, V, Launer, LJ (Lenore), Mace, A, Boerwinckle, E, Arking, DE, Tanikawa, C, Nakamura, Y, Brown, MJ, Gaspoz, JM, Theler, JM, Siscovick, DS, Psaty, BM, Bergmann, S, Vollenweider, P, Vitart, V, Wright, AF, Zemunik, T, Boban, M, Kolcic, I, Navarro, P, Brown, EM, Estrada Gil, Karol, Ding, JZ (Jing Zhong), Harris, TB, Bandinelli, S, Hernandez, D, Singleton, AB, Girotto, G, Ruggiero, D, d'Adamo, AP, Robino, A, Meitinger, T, Meisinger, C, Davies, G, Starr, JM, Chambers, JC, Boehm, BO, Winkelmann, BR, Huang, J, Murgia, F, Wild, SH, Campbell, H, Morris, AP, Franco Duran, OH, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Volker, U, Hannemann, A, Biffar, R, Hoffmann, W, Shin, SY, Lescuyer, P, Henry, H, Schurmann, C, Munroe, PB, Gasparini, P, Pirastu, N, Ciullo, M, Gieger, C, Marz, W, Lind, L, Spector, TD, Smith, AV, Rudan, I, Wilson, JF, Polasek, O, Deary, IJ, Pirastu, M, Ferrucci, L, Liu, YM, Kestenbaum, B, Kooner, JS, Witteman, JCM, Nauck, M, Kao, WHL, Wallaschofski, H, Bonny, O, Fox, CS, Bochud, M, O'Seaghdha, CM, Wu, HS, Yang, Q, Kapur, K, Guessous, I, Zuber, AM, Kottgen, A, Stoudmann, C, Teumer, A, Kutalik, Z, Mangino, M, Dehghan, Abbas, Zhang, WH, Eiriksdottir, G, Li, G (Guo), Tanaka, T, Portas, L, Lopez, LM, Hayward, C, Lohman, K, Matsuda, K, Padmanabhan, S, Firsov, D, Sorice, R, Ulivi, S, Brockhaus, AC, Kleber, ME, Mahajan, A, Ernst, FD, Gudnason, V, Launer, LJ (Lenore), Mace, A, Boerwinckle, E, Arking, DE, Tanikawa, C, Nakamura, Y, Brown, MJ, Gaspoz, JM, Theler, JM, Siscovick, DS, Psaty, BM, Bergmann, S, Vollenweider, P, Vitart, V, Wright, AF, Zemunik, T, Boban, M, Kolcic, I, Navarro, P, Brown, EM, Estrada Gil, Karol, Ding, JZ (Jing Zhong), Harris, TB, Bandinelli, S, Hernandez, D, Singleton, AB, Girotto, G, Ruggiero, D, d'Adamo, AP, Robino, A, Meitinger, T, Meisinger, C, Davies, G, Starr, JM, Chambers, JC, Boehm, BO, Winkelmann, BR, Huang, J, Murgia, F, Wild, SH, Campbell, H, Morris, AP, Franco Duran, OH, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Volker, U, Hannemann, A, Biffar, R, Hoffmann, W, Shin, SY, Lescuyer, P, Henry, H, Schurmann, C, Munroe, PB, Gasparini, P, Pirastu, N, Ciullo, M, Gieger, C, Marz, W, Lind, L, Spector, TD, Smith, AV, Rudan, I, Wilson, JF, Polasek, O, Deary, IJ, Pirastu, M, Ferrucci, L, Liu, YM, Kestenbaum, B, Kooner, JS, Witteman, JCM, Nauck, M, Kao, WHL, Wallaschofski, H, Bonny, O, Fox, CS, and Bochud, M

Abstract

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

Published
2013

5. Serum Uric Acid and Chronic Kidney Disease: The Role of Hypertension

Author

Sedaghat, S, Hoorn, Ewout, van Rooij, FJA, Hofman, Bert, Franco Duran, OH, Witteman, JCM, Dehghan, Abbas, Sedaghat, S, Hoorn, Ewout, van Rooij, FJA, Hofman, Bert, Franco Duran, OH, Witteman, JCM, and Dehghan, Abbas

Abstract

Background: There are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association. Methods: We included 2601 subjects aged 55 years and over from the Rotterdam Study. Serum uric acid and estimated glomerular filtration rate (eGFR) were assessed at baseline. After average 6.5 years of follow-up, second eGFR was assessed. CKD was defined as eGFR <60 ml/min/1.73 m(2). All associations were corrected for socio-demographic and cardiovascular factors. Results: Each unit (mg/dL) increase in serum uric acid was associated with 0.19 ml/min per 1.73 m(2) faster annual decline in eGFR. While the association between serum uric acid and incidence of CKD was not significant in our study population (Hazard Ratio: 1.12, 95% confidence interval [CI]: 0.98-1.28), incorporating our results in a meta-analysis with eleven published studies revealed a significant association (Relative Risk: 1.18, 95%CI: 1.15-1.22). In the stratified analyses, we observed tha Conclusions: Our findings suggest that hyperuricemia is independently associated with a decline in renal function. Stronger association in hypertensive individuals may indicate that hypertension mediates the association between serum uric acid and CKD.

Published
2013

6. The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Author

Fall, T, Hagg, S, Magi, R, Ploner, A, Fischer, K (Kirsten), Horikoshi, M, Sarin, AP, Thorleifsson, G, Ladenvall, C, Kals, M, Kuningas, Maris, Draisma, HHM, Ried, JS, van Zuydam, NR, Huikari, V, Mangino, M, Sonestedt, E, Benyamin, B, Nelson, CP, Rivera, NV, Kristiansson, K, Shen, HY, Havulinna, AS, Dehghan, Abbas, Donnelly, LA, Kaakinen, M, Nuotio, ML, Robertson, N, Bruijn, Renee, Ikram, Arfan, Amin, Najaf, Balmforth, AJ, Braund, PS, Doney, ASF, Doring, A, Elliott, P, Esko, T, Franco Duran, OH, Gretarsdottir, S, Hartikainen, AL, Heikkila, K, Herzig, KH, Holm, H, Hottenga, JJ (Jouke Jan), Hypponen, E, Illig, T, Isaacs, Aaron, Isomaa, B, Karssen, Lennart, Kettunen, J, Koenig, W, Kuulasmaa, K, Laatikainen, T, Laitinen, J, Lindgren, C, Lyssenko, V, Laara, E, Rayner, NW, Mannisto, S, Pouta, A, Rathmann, W, Rivadeneira, Fernando, Ruokonen, A, Savolainen, MJ, Sijbrands, E.J.G., Small, KS, Smit, JH, Steinthorsdottir, V, Syvanen, AC, Taanila, A, Tobin, MD, Uitterlinden, André, Willems, SM, Willemsen, G, Witteman, JCM, Perola, M, Evans, A, Ferrieres, J, Virtamo, J, Kee, F, Tregouet, DA, Arveiler, D, Amouyel, P, Ferrario, MM, Brambilla, P, Hall, AS, Heath, A, Madden, PAF, Martin, NG, Montgomery, GW, Whitfield, JB, Jula, A, Knekt, P, Oostra, Ben, Duijn, Cornelia, Penninx, BWJH, Smith, GD, Kaprio, J, Samani, NJ, Gieger, C, Peters, A, Wichmann, HE, Boomsma, DI, de Geus, EJC, Tuomi, T, Power, C, Hammond, CJ, Spector, TD, Lind, L, Orho-Melander, M, Palmer, CNA, Morris, AD, Groop, L, Jarvelin, MR, Salomaa, V, Vartiainen, E, Hofman, Bert, Ripatti, S, Metspalu, A, Thorsteinsdottir, U, Stefansson, K, Pedersen, NL, McCarthy, MI, Ingelsson, E, Prokopenko, I, Fall, T, Hagg, S, Magi, R, Ploner, A, Fischer, K (Kirsten), Horikoshi, M, Sarin, AP, Thorleifsson, G, Ladenvall, C, Kals, M, Kuningas, Maris, Draisma, HHM, Ried, JS, van Zuydam, NR, Huikari, V, Mangino, M, Sonestedt, E, Benyamin, B, Nelson, CP, Rivera, NV, Kristiansson, K, Shen, HY, Havulinna, AS, Dehghan, Abbas, Donnelly, LA, Kaakinen, M, Nuotio, ML, Robertson, N, Bruijn, Renee, Ikram, Arfan, Amin, Najaf, Balmforth, AJ, Braund, PS, Doney, ASF, Doring, A, Elliott, P, Esko, T, Franco Duran, OH, Gretarsdottir, S, Hartikainen, AL, Heikkila, K, Herzig, KH, Holm, H, Hottenga, JJ (Jouke Jan), Hypponen, E, Illig, T, Isaacs, Aaron, Isomaa, B, Karssen, Lennart, Kettunen, J, Koenig, W, Kuulasmaa, K, Laatikainen, T, Laitinen, J, Lindgren, C, Lyssenko, V, Laara, E, Rayner, NW, Mannisto, S, Pouta, A, Rathmann, W, Rivadeneira, Fernando, Ruokonen, A, Savolainen, MJ, Sijbrands, E.J.G., Small, KS, Smit, JH, Steinthorsdottir, V, Syvanen, AC, Taanila, A, Tobin, MD, Uitterlinden, André, Willems, SM, Willemsen, G, Witteman, JCM, Perola, M, Evans, A, Ferrieres, J, Virtamo, J, Kee, F, Tregouet, DA, Arveiler, D, Amouyel, P, Ferrario, MM, Brambilla, P, Hall, AS, Heath, A, Madden, PAF, Martin, NG, Montgomery, GW, Whitfield, JB, Jula, A, Knekt, P, Oostra, Ben, Duijn, Cornelia, Penninx, BWJH, Smith, GD, Kaprio, J, Samani, NJ, Gieger, C, Peters, A, Wichmann, HE, Boomsma, DI, de Geus, EJC, Tuomi, T, Power, C, Hammond, CJ, Spector, TD, Lind, L, Orho-Melander, M, Palmer, CNA, Morris, AD, Groop, L, Jarvelin, MR, Salomaa, V, Vartiainen, E, Hofman, Bert, Ripatti, S, Metspalu, A, Thorsteinsdottir, U, Stefansson, K, Pedersen, NL, McCarthy, MI, Ingelsson, E, and Prokopenko, I

Published
2013

9. Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

Author

Gibson, G, Pattaro, C, Koettgen, A, Teumer, A, Garnaas, M, Boeger, CA, Fuchsberger, C, Olden, M, Chen, M-H, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, MC, O'Seaghdha, CM, Glazer, N, Isaacs, A, Liu, C-T, Smith, AV, O'Connell, JR, Struchalin, M, Tanaka, T, Li, G, Johnson, AD, Gierman, HJ, Feitosa, M, Hwang, S-J, Atkinson, EJ, Lohman, K, Cornelis, MC, Johansson, A, Toenjes, A, Dehghan, A, Chouraki, V, Holliday, EG, Sorice, R, Kutalik, Z, Lehtimaeki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, AY, Murgia, F, Trompet, S, Imboden, M, Kollerits, B, Pistis, G, Harris, TB, Launer, LJ, Aspelund, T, Eiriksdottir, G, Mitchell, BD, Boerwinkle, E, Schmidt, H, Cavalieri, M, Rao, M, Hu, FB, Demirkan, A, Oostra, BA, de Andrade, M, Turner, ST, Ding, J, Andrews, JS, Freedman, BI, Koenig, W, Illig, T, Doering, A, Wichmann, H-E, Kolcic, I, Zemunik, T, Boban, M, Minelli, C, Wheeler, HE, Igl, W, Zaboli, G, Wild, SH, Wright, AF, Campbell, H, Ellinghaus, D, Nothlings, U, Jacobs, G, Biffar, R, Endlich, K, Ernst, F, Homuth, G, Kroemer, HK, Nauck, M, Stracke, S, Voelker, U, Voelzke, H, Kovacs, P, Stumvoll, M, Magi, R, Hofman, A, Uitterlinden, AG, Rivadeneira, F, Aulchenko, YS, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, JJ, Ruggiero, D, Bergmann, S, Kaehoenen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, A, Giulianini, F, Kraemer, BK, Portas, L, Ford, I, Buckley, BM, Adam, M, Thun, G-A, Paulweber, B, Haun, M, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, SK, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, P, Pirastu, M, Jukema, JW, Probst-Hensch, NM, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, AR, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, DS, van Duijn, CM, Borecki, I, Kardia, SLR, Liu, Y, Curhan, GC, Rudan, I, Gyllensten, U, Wilson, JF, Franke, A, Pramstaller, PP, Rettig, R, Prokopenko, I, Witteman, JCM, Hayward, C, Ridker, P, Parsa, A, Bochud, M, Heid, IM, Goessling, W, Chasman, DI, Kao, WHL, Fox, CS, Gibson, G, Pattaro, C, Koettgen, A, Teumer, A, Garnaas, M, Boeger, CA, Fuchsberger, C, Olden, M, Chen, M-H, Tin, A, Taliun, D, Li, M, Gao, X, Gorski, M, Yang, Q, Hundertmark, C, Foster, MC, O'Seaghdha, CM, Glazer, N, Isaacs, A, Liu, C-T, Smith, AV, O'Connell, JR, Struchalin, M, Tanaka, T, Li, G, Johnson, AD, Gierman, HJ, Feitosa, M, Hwang, S-J, Atkinson, EJ, Lohman, K, Cornelis, MC, Johansson, A, Toenjes, A, Dehghan, A, Chouraki, V, Holliday, EG, Sorice, R, Kutalik, Z, Lehtimaeki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, AY, Murgia, F, Trompet, S, Imboden, M, Kollerits, B, Pistis, G, Harris, TB, Launer, LJ, Aspelund, T, Eiriksdottir, G, Mitchell, BD, Boerwinkle, E, Schmidt, H, Cavalieri, M, Rao, M, Hu, FB, Demirkan, A, Oostra, BA, de Andrade, M, Turner, ST, Ding, J, Andrews, JS, Freedman, BI, Koenig, W, Illig, T, Doering, A, Wichmann, H-E, Kolcic, I, Zemunik, T, Boban, M, Minelli, C, Wheeler, HE, Igl, W, Zaboli, G, Wild, SH, Wright, AF, Campbell, H, Ellinghaus, D, Nothlings, U, Jacobs, G, Biffar, R, Endlich, K, Ernst, F, Homuth, G, Kroemer, HK, Nauck, M, Stracke, S, Voelker, U, Voelzke, H, Kovacs, P, Stumvoll, M, Magi, R, Hofman, A, Uitterlinden, AG, Rivadeneira, F, Aulchenko, YS, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, JJ, Ruggiero, D, Bergmann, S, Kaehoenen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, A, Giulianini, F, Kraemer, BK, Portas, L, Ford, I, Buckley, BM, Adam, M, Thun, G-A, Paulweber, B, Haun, M, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, SK, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, P, Pirastu, M, Jukema, JW, Probst-Hensch, NM, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, AR, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, DS, van Duijn, CM, Borecki, I, Kardia, SLR, Liu, Y, Curhan, GC, Rudan, I, Gyllensten, U, Wilson, JF, Franke, A, Pramstaller, PP, Rettig, R, Prokopenko, I, Witteman, JCM, Hayward, C, Ridker, P, Parsa, A, Bochud, M, Heid, IM, Goessling, W, Chasman, DI, Kao, WHL, and Fox, CS

Abstract

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

Published
2012

10. Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM

Author

Amin, Najaf, Byrne, E, Johnson, J, Chenevix-Trench, G, Walter, Stefan, Nolte, IM (Ilja), Vink, JM, Rawal, R, Mangino, M, Teumer, A, Keers, JC, Verwoert, G, Baumeister, S, Biffar, R, Petersmann, A, Dahmen, N, Doering, A, Isaacs, Aaron, Broer, Linda, Wray, NR, Montgomery, GW, Levy, D, Psaty, BM, Gudnason, V, Chakravarti, A, Sulem, P, Gudbjartsson, DF, Kiemeney, LA, Thorsteinsdottir, U, Stefansson, K, van Rooij, FJA, Aulchenko, YS, Hottenga, JJ (Jouke Jan), Rivadeneira, FR, Hofman, Bert, Uitterlinden, André, Hammond, CJ, Shin, SY, Ikram, A, Witteman, JCM, Janssens, Cecile, Snieder, H, Tiemeier, Henning, Wolfenbuttel, BHR, Oostra, Ben, Heath, AC, Wichmann, E, Spector, TD, Grabe, HJ, Boomsma, DI, Martin, NG, Duijn, Cornelia, Amin, Najaf, Byrne, E, Johnson, J, Chenevix-Trench, G, Walter, Stefan, Nolte, IM (Ilja), Vink, JM, Rawal, R, Mangino, M, Teumer, A, Keers, JC, Verwoert, G, Baumeister, S, Biffar, R, Petersmann, A, Dahmen, N, Doering, A, Isaacs, Aaron, Broer, Linda, Wray, NR, Montgomery, GW, Levy, D, Psaty, BM, Gudnason, V, Chakravarti, A, Sulem, P, Gudbjartsson, DF, Kiemeney, LA, Thorsteinsdottir, U, Stefansson, K, van Rooij, FJA, Aulchenko, YS, Hottenga, JJ (Jouke Jan), Rivadeneira, FR, Hofman, Bert, Uitterlinden, André, Hammond, CJ, Shin, SY, Ikram, A, Witteman, JCM, Janssens, Cecile, Snieder, H, Tiemeier, Henning, Wolfenbuttel, BHR, Oostra, Ben, Heath, AC, Wichmann, E, Spector, TD, Grabe, HJ, Boomsma, DI, Martin, NG, and Duijn, Cornelia

Abstract

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N = 18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values = 1.6 x 10(-11) and 2.7 x 10(-11)), which were also in strong linkage disequilibrium (r(2) = 0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value = 3.9 x 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value = 7.1 x 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value = 2.2 x 10(-05)) and Parkinson's disease pathways (P-value = 3.6 x 10(-05)). Molecular Psychiatry (2012) 17, 1116-1129; doi: 10.1038/mp.2011.101; published online 30 August 2011

Published
2012

11. Discovery and Fine Mapping of Serum Protein Loci through Transethnic Meta-analysis

Author

Franceschini, N, van Rooij, FJA, Prins, BP, Feitosa, MF, Karakas, M, Eckfeldt, JH, Folsom, AR, Kopp, J, Vaez, A, Andrews, JS, Baumert, J, Boraska, V, Broer, Linda, Hayward, C, Ngwa, JS, Okada, Y, Polasek, O, Westra, HJ, Wang, YA, Del Greco, F, Glazer, NL, Kapur, K, Id, P, Lopez, LM, Schillert, A, Smith, AV, Winkler, CA, Zgaga, L, Bandinelli, S, Bergmann, S, Boban, M, Bochud, M, Chen, YD, Davies, G, Dehghan, Abbas, Ding, JZ (Jing Zhong), Doering, A, Durda, JP, Ferrucci, L, Franco Duran, OH, Franke, L, Gunjaca, G, Hofman, Bert, Hsu, FC, Kolcic, I, Kraja, A, Kubo, M, Lackner, KJ, Launer, L, Loehr, LR, Li, G (Guo), Meisinger, C, Nakamura, Y, Schwienbacher, C, Starr, JM, Takahashi, A, Torlak, V, Uitterlinden, André, Vitart, V, Waldenberger, M, Wild, PS, Kirin, M, Zeller, T, Zemunik, T, Zhang, QY, Ziegler, A, Blankenberg, S, Boerwinkle, E, Borecki, IB, Campbell, H, Deary, IJ, Frayling, TM, Gieger, C, Harris, TB, Hicks, AA, Koenig, W, O'Donnell, CJ, Fox, CS, Pramstaller, PP, Psaty, BM, Reiner, AP, Rotter, JI, Rudan, I, Snieder, H, Tanaka, T, Duijn, Cornelia, Vollenweider, P, Waeber, G, Wilson, JF, Witteman, JCM, Wolffenbuttel, BHR, Wright, AF, Wu, QY, Liu, YM, Jenny, NS, North, KE, Felix, Janine, Alizadeh, BZ, Cupples, LA, Perry, JRB, Morris, AP, Franceschini, N, van Rooij, FJA, Prins, BP, Feitosa, MF, Karakas, M, Eckfeldt, JH, Folsom, AR, Kopp, J, Vaez, A, Andrews, JS, Baumert, J, Boraska, V, Broer, Linda, Hayward, C, Ngwa, JS, Okada, Y, Polasek, O, Westra, HJ, Wang, YA, Del Greco, F, Glazer, NL, Kapur, K, Id, P, Lopez, LM, Schillert, A, Smith, AV, Winkler, CA, Zgaga, L, Bandinelli, S, Bergmann, S, Boban, M, Bochud, M, Chen, YD, Davies, G, Dehghan, Abbas, Ding, JZ (Jing Zhong), Doering, A, Durda, JP, Ferrucci, L, Franco Duran, OH, Franke, L, Gunjaca, G, Hofman, Bert, Hsu, FC, Kolcic, I, Kraja, A, Kubo, M, Lackner, KJ, Launer, L, Loehr, LR, Li, G (Guo), Meisinger, C, Nakamura, Y, Schwienbacher, C, Starr, JM, Takahashi, A, Torlak, V, Uitterlinden, André, Vitart, V, Waldenberger, M, Wild, PS, Kirin, M, Zeller, T, Zemunik, T, Zhang, QY, Ziegler, A, Blankenberg, S, Boerwinkle, E, Borecki, IB, Campbell, H, Deary, IJ, Frayling, TM, Gieger, C, Harris, TB, Hicks, AA, Koenig, W, O'Donnell, CJ, Fox, CS, Pramstaller, PP, Psaty, BM, Reiner, AP, Rotter, JI, Rudan, I, Snieder, H, Tanaka, T, Duijn, Cornelia, Vollenweider, P, Waeber, G, Wilson, JF, Witteman, JCM, Wolffenbuttel, BHR, Wright, AF, Wu, QY, Liu, YM, Jenny, NS, North, KE, Felix, Janine, Alizadeh, BZ, Cupples, LA, Perry, JRB, and Morris, AP

Abstract

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 x 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMDS-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.

Published
2012

12. Insulin Resistance and the Risk of Stroke and Stroke Subtypes in the Nondiabetic Elderly

Author

Wieberdink, Renske, Koudstaal, Peter, Hofman, Bert, Witteman, JCM, Breteler, Monique, Ikram, Arfan, Wieberdink, Renske, Koudstaal, Peter, Hofman, Bert, Witteman, JCM, Breteler, Monique, and Ikram, Arfan

Abstract

Insulin resistance, which plays a key role in the development of diabetes mellitus, is a putative modifiable risk factor for stroke. The aim of this study was to investigate if markers of insulin resistance were associated with risk of stroke in the general elderly population. This study was part of the large population-based Rotterdam Study and included 5,234 participants who were aged 55 years or older and stroke free and diabetes free at baseline (19972001). Fasting insulin levels and homeostasis model assessment for insulin resistance were used as markers for insulin resistance. Cox regression was used to determine associations between insulin resistance markers and stroke risk, adjusted for age, sex, and potential confounders. During 42,806 person-years of follow-up (median: 8.6 years), 366 first-ever strokes occurred, of which 225 were cerebral infarctions, 42 were intracerebral hemorrhages, and 99 were unspecified strokes. Fasting insulin levels were not associated with risk of any stroke, cerebral infarction, or intracerebral hemorrhage. Homeostasis model assessment for insulin resistance, which almost perfectly correlated with fasting insulin levels, was also not associated with risk of stroke or stroke subtypes. In conclusion, in this population-based cohort study among nondiabetic elderly, insulin resistance markers were not associated with risk of stroke or any of its subtypes.

Published
2012

13. Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations

Author

Demirkan, Ayse, Duijn, Cornelia, Ugocsai, P, Isaacs, Aaron, Pramstaller, PP, Liebisch, G, Wilson, JF, Johansson, A, Rudan, I, Aulchenko, YS, Kirichenko, AV, Janssens, Cecile, Jansen, RC, Gnewuch, C, Domingues, FS, Pattaro, C, Wild, SH, Jonasson, I, Polasek, O, Zorkoltseva, IV, Hofman, Bert, Karssen, Lennart, Struchalin, M, Floyd, J, Igl, W, Biloglav, Z, Broer, Linda, Pfeufer, A, Pichler, I, Campbell, S, Zaboli, G, Kolcic, I, Rivadeneira, Fernando, Huffman, J, Hastie, ND, Uitterlinden, André, Franke, L, Franklin, CS, Vitart, V, Nelson, CP, Preuss, M, Bis, JC, O'Donnell, CJ, Franceschini, N, Witteman, JCM, Axenovich, T, Oostra, Ben, Meitinger, T, Hicks, AA, Hayward, C, Wright, AF, Gyllensten, U, Campbell, H, Schmitz, G, Demirkan, Ayse, Duijn, Cornelia, Ugocsai, P, Isaacs, Aaron, Pramstaller, PP, Liebisch, G, Wilson, JF, Johansson, A, Rudan, I, Aulchenko, YS, Kirichenko, AV, Janssens, Cecile, Jansen, RC, Gnewuch, C, Domingues, FS, Pattaro, C, Wild, SH, Jonasson, I, Polasek, O, Zorkoltseva, IV, Hofman, Bert, Karssen, Lennart, Struchalin, M, Floyd, J, Igl, W, Biloglav, Z, Broer, Linda, Pfeufer, A, Pichler, I, Campbell, S, Zaboli, G, Kolcic, I, Rivadeneira, Fernando, Huffman, J, Hastie, ND, Uitterlinden, André, Franke, L, Franklin, CS, Vitart, V, Nelson, CP, Preuss, M, Bis, JC, O'Donnell, CJ, Franceschini, N, Witteman, JCM, Axenovich, T, Oostra, Ben, Meitinger, T, Hicks, AA, Hayward, C, Wright, AF, Gyllensten, U, Campbell, H, and Schmitz, G

Abstract

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88 x 10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10 x 10(-57)). After a correction for multiple comparisons (P-value, 2.2 x 10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study iden

Published
2012

14. Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

Author

Pattaro, C, Kottgen, A, Teumer, A, Garnaas, M, Boger, CA, Fuchsberger, C, Olden, M, Chen, MH, Tin, A, Taliun, D, Li, M, Gao, XY, Gorski, M, Yang, Q, Hundertmark, C, Foster, MC, O'Seaghdha, CM, Glazer, N, Isaacs, Aaron, Liu, CT, Smith, AV, O'Connell, JR, Struchalin, M, Tanaka, T, Li, G (Guo), Johnson, AD, Gierman, HJ, Feitosa, M, Hwang, SJ, Atkinson, EJ, Lohman, K, Cornelis, MC, Johansson, A, Tonjes, A, Dehghan, Abbas, Chouraki, V, Holliday, EG, Sorice, R, Kutalik, Z, Lehtimaki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, AY, Murgia, F, Trompet, S, Imboden, M, Kollerits, B, Pistis, G, Harris, TB, Launer, LJ (Lenore), Aspelund, T, Eiriksdottir, G, Mitchell, BD, Boerwinkle, E, Schmidt, Heléna, Cavalieri, M, Rao, M, Hu, FB, Demirkan, Ayse, Oostra, Ben, de Andrade, M, Turner, ST, Ding, JZ (Jing Zhong), Andrews, JS, Freedman, BI, Koenig, W, Illig, T, Doring, A, Wichmann, HE, Kolcic, I, Zemunik, T, Boban, M, Minelli, C, Wheeler, HE, Igl, W, Zaboli, G, Wild, SH, Wright, AF, Campbell, H, Ellinghaus, D, Nothlings, U, Jacobs, Gunar, Biffar, R, Endlich, K, Ernst, F, Homuth, G, Kroemer, HK, Nauck, M, Stracke, S, Volker, U, Volzke, H, Kovacs, P, Stumvoll, M, Magi, R, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Aulchenko, YS, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, JJ, Ruggiero, D, Bergmann, S, Kahonen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, A, Giulianini, F, Kramer, BK, Portas, L, Ford, I, Buckley, BM, Adam, M, Thun, GA, Paulweber, B, Haun, M, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, SK, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, P, Pirastu, M, Jukema, JW, Probst-Hensch, NM, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, AR, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, DS, Duijn, Cornelia, Borecki, I, Kardia, SLR, Liu, YM, Curhan, GC, Rudan, I, Gyllensten, U, Wilson, JF, Franke, A, Pramstaller, PP, Rettig, R, Prokopenko, I, Witteman, JCM, Hayward, C, Ridker, P, Parsa, A, Bochud, M, Heid, IM, Goessling, W, Chasman, DI, Kao, WHL, Fox, CS, Pattaro, C, Kottgen, A, Teumer, A, Garnaas, M, Boger, CA, Fuchsberger, C, Olden, M, Chen, MH, Tin, A, Taliun, D, Li, M, Gao, XY, Gorski, M, Yang, Q, Hundertmark, C, Foster, MC, O'Seaghdha, CM, Glazer, N, Isaacs, Aaron, Liu, CT, Smith, AV, O'Connell, JR, Struchalin, M, Tanaka, T, Li, G (Guo), Johnson, AD, Gierman, HJ, Feitosa, M, Hwang, SJ, Atkinson, EJ, Lohman, K, Cornelis, MC, Johansson, A, Tonjes, A, Dehghan, Abbas, Chouraki, V, Holliday, EG, Sorice, R, Kutalik, Z, Lehtimaki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, AY, Murgia, F, Trompet, S, Imboden, M, Kollerits, B, Pistis, G, Harris, TB, Launer, LJ (Lenore), Aspelund, T, Eiriksdottir, G, Mitchell, BD, Boerwinkle, E, Schmidt, Heléna, Cavalieri, M, Rao, M, Hu, FB, Demirkan, Ayse, Oostra, Ben, de Andrade, M, Turner, ST, Ding, JZ (Jing Zhong), Andrews, JS, Freedman, BI, Koenig, W, Illig, T, Doring, A, Wichmann, HE, Kolcic, I, Zemunik, T, Boban, M, Minelli, C, Wheeler, HE, Igl, W, Zaboli, G, Wild, SH, Wright, AF, Campbell, H, Ellinghaus, D, Nothlings, U, Jacobs, Gunar, Biffar, R, Endlich, K, Ernst, F, Homuth, G, Kroemer, HK, Nauck, M, Stracke, S, Volker, U, Volzke, H, Kovacs, P, Stumvoll, M, Magi, R, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Aulchenko, YS, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, JJ, Ruggiero, D, Bergmann, S, Kahonen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, A, Giulianini, F, Kramer, BK, Portas, L, Ford, I, Buckley, BM, Adam, M, Thun, GA, Paulweber, B, Haun, M, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, SK, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, P, Pirastu, M, Jukema, JW, Probst-Hensch, NM, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, AR, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, DS, Duijn, Cornelia, Borecki, I, Kardia, SLR, Liu, YM, Curhan, GC, Rudan, I, Gyllensten, U, Wilson, JF, Franke, A, Pramstaller, PP, Rettig, R, Prokopenko, I, Witteman, JCM, Hayward, C, Ridker, P, Parsa, A, Bochud, M, Heid, IM, Goessling, W, Chasman, DI, Kao, WHL, and Fox, CS

Abstract

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

Published
2012

15. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Author

Manning, AK, Hivert, MF, Scott, RA, Grimsby, JL, Bouatia-Naji, N, Chen, H, Rybin, D, Liu, CT, Bielak, LF, Prokopenko, I, Amin, Najaf, Barnes, D, Cadby, G, Hottenga, JJ (Jouke Jan), Ingelsson, E, Jackson, AU, Johnson, T, Kanoni, S, Ladenvall, C, Lagou, V, Lahti, J, Lecoeur, C, Liu, YM, Martinez-Larrad, MT, Montasser, ME, Navarro, P, Perry, JRB, Rasmussen-Torvik, LJ, Salo, P, Sattar, N, Shungin, D, Strawbridge, RJ, Tanaka, T, Duijn, Cornelia, An, P, de Andrade, M, Andrews, JS, Aspelund, T, Atalay, M, Aulchenko, Yuriy, Balkau, B, Bandinelli, S, Beckmann, JS, Beilby, JP, Bellis, C, Bergman, RN, Blangero, J, Boban, M, Boehnke, M, Boerwinkle, E, Bonnycastle, LL, Boomsma, DI, Borecki, IB, Boettcher, Y, Bouchard, C, Brunner, E, Budimir, D, Campbell, H, Carlson, O, Chines, PS, Clarke, R, Collins, FS, Corbaton-Anchuelo, A, Couper, D, de Faire, U, Dedoussis, GV, Deloukas, P, Dimitriou, M, Egan, JM, Eiriksdottir, G, Erdos, MR, Eriksson, JG, Eury, E, Ferrucci, L, Ford, I, Forouhi, NG, Fox, CS, Franzosi, MG, Franks, PW, Frayling, TM, Froguel, P, Galan, P, de Geus, ED, Gigante, B, Glazer, NL, Goel, A, Groop, L, Gudnason, V, Hallmans, G, Hamsten, A, Hansson, O, Harris, TB, Hayward, C, Heath, S, Hercberg, S, Hicks, AA, Hingorani, A, Hofman, Bert, Hui, J, Hung, J, Jarvelin, MR, Jhun, MA, Johnson, PCD, Jukema, JW, Jula, A, Kao, WH, Kaprio, J, Kardia, SLR, Keinanen-Kiukaanniemi, S, Kivimaki, M, Kolcic, I, Kovacs, P, Kumari, M, Kuusisto, J, Kyvik, KO, Laakso, M, Lakka, T, Lannfelt, L, Lathrop, GM, Launer, LJ (Lenore), Leander, K, Li, G (Guo), Lind, L, Lindstrom, J, Lobbens, S, Loos, RJF, Luan, JA, Lyssenko, V, Magi, R, Magnusson, PKE, Marmot, M, Meneton, P, Mohlke, KL, Mooser, V, Morken, MA, Miljkovic, I, Narisu, N, O'Connell, J, Ong, KK, Oostra, Ben, Palmer, LJ, Palotie, A, Pankow, JS, Peden, JF, Pedersen, NL, Pehlic, M, Peltonen, L, Penninx, B, Pericic, M, Perola, M, Perusse, L, Peyser, PA, Polasek, O, Pramstaller, PP, Province, MA, Raikkonen, K, Rauramaa, R, Rehnberg, E, Rice, K, Rotter, JI, Rudan, I, Ruokonen, A, Saaristo, T, Sabater-Lleal, M, Salomaa, V, Savage, DB, Saxena, R, Schwarz, P, Seedorf, U, Sennblad, B, Serrano-Rios, M, Shuldiner, AR, Sijbrands, E.J.G., Siscovick, DS, Smit, JH, Small, KS, Smith, NL, Smith, AV, Stancakova, A, Stirrups, K, Stumvoll, M, Sun, YV, Swift, AJ, Toenjes, A, Tuomilehto, J, Trompet, S, Uitterlinden, André, Uusitupa, M, Vikstrom, M, Vitart, V, Vohl, MC, Voight, BF, Vollenweider, P, Waeber, G, Waterworth, DM, Watkins, H, Wheeler, E, Widen, E, Wild, SH, Willems, SM, Willemsen, G, Wilson, JF, Witteman, JCM, Wright, AF, Yaghootkar, H, Zelenika, D, Zemunik, T, Zgaga, L, Wareham, NJ, McCarthy, MI, Barroso, I, Watanabe, RM, Florez, JC, Dupuis, J, Meigs, JB, Langenberg, C, Manning, AK, Hivert, MF, Scott, RA, Grimsby, JL, Bouatia-Naji, N, Chen, H, Rybin, D, Liu, CT, Bielak, LF, Prokopenko, I, Amin, Najaf, Barnes, D, Cadby, G, Hottenga, JJ (Jouke Jan), Ingelsson, E, Jackson, AU, Johnson, T, Kanoni, S, Ladenvall, C, Lagou, V, Lahti, J, Lecoeur, C, Liu, YM, Martinez-Larrad, MT, Montasser, ME, Navarro, P, Perry, JRB, Rasmussen-Torvik, LJ, Salo, P, Sattar, N, Shungin, D, Strawbridge, RJ, Tanaka, T, Duijn, Cornelia, An, P, de Andrade, M, Andrews, JS, Aspelund, T, Atalay, M, Aulchenko, Yuriy, Balkau, B, Bandinelli, S, Beckmann, JS, Beilby, JP, Bellis, C, Bergman, RN, Blangero, J, Boban, M, Boehnke, M, Boerwinkle, E, Bonnycastle, LL, Boomsma, DI, Borecki, IB, Boettcher, Y, Bouchard, C, Brunner, E, Budimir, D, Campbell, H, Carlson, O, Chines, PS, Clarke, R, Collins, FS, Corbaton-Anchuelo, A, Couper, D, de Faire, U, Dedoussis, GV, Deloukas, P, Dimitriou, M, Egan, JM, Eiriksdottir, G, Erdos, MR, Eriksson, JG, Eury, E, Ferrucci, L, Ford, I, Forouhi, NG, Fox, CS, Franzosi, MG, Franks, PW, Frayling, TM, Froguel, P, Galan, P, de Geus, ED, Gigante, B, Glazer, NL, Goel, A, Groop, L, Gudnason, V, Hallmans, G, Hamsten, A, Hansson, O, Harris, TB, Hayward, C, Heath, S, Hercberg, S, Hicks, AA, Hingorani, A, Hofman, Bert, Hui, J, Hung, J, Jarvelin, MR, Jhun, MA, Johnson, PCD, Jukema, JW, Jula, A, Kao, WH, Kaprio, J, Kardia, SLR, Keinanen-Kiukaanniemi, S, Kivimaki, M, Kolcic, I, Kovacs, P, Kumari, M, Kuusisto, J, Kyvik, KO, Laakso, M, Lakka, T, Lannfelt, L, Lathrop, GM, Launer, LJ (Lenore), Leander, K, Li, G (Guo), Lind, L, Lindstrom, J, Lobbens, S, Loos, RJF, Luan, JA, Lyssenko, V, Magi, R, Magnusson, PKE, Marmot, M, Meneton, P, Mohlke, KL, Mooser, V, Morken, MA, Miljkovic, I, Narisu, N, O'Connell, J, Ong, KK, Oostra, Ben, Palmer, LJ, Palotie, A, Pankow, JS, Peden, JF, Pedersen, NL, Pehlic, M, Peltonen, L, Penninx, B, Pericic, M, Perola, M, Perusse, L, Peyser, PA, Polasek, O, Pramstaller, PP, Province, MA, Raikkonen, K, Rauramaa, R, Rehnberg, E, Rice, K, Rotter, JI, Rudan, I, Ruokonen, A, Saaristo, T, Sabater-Lleal, M, Salomaa, V, Savage, DB, Saxena, R, Schwarz, P, Seedorf, U, Sennblad, B, Serrano-Rios, M, Shuldiner, AR, Sijbrands, E.J.G., Siscovick, DS, Smit, JH, Small, KS, Smith, NL, Smith, AV, Stancakova, A, Stirrups, K, Stumvoll, M, Sun, YV, Swift, AJ, Toenjes, A, Tuomilehto, J, Trompet, S, Uitterlinden, André, Uusitupa, M, Vikstrom, M, Vitart, V, Vohl, MC, Voight, BF, Vollenweider, P, Waeber, G, Waterworth, DM, Watkins, H, Wheeler, E, Widen, E, Wild, SH, Willems, SM, Willemsen, G, Wilson, JF, Witteman, JCM, Wright, AF, Yaghootkar, H, Zelenika, D, Zemunik, T, Zgaga, L, Wareham, NJ, McCarthy, MI, Barroso, I, Watanabe, RM, Florez, JC, Dupuis, J, Meigs, JB, and Langenberg, C

Abstract

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Published
2012

16. Methods of data collection and definitions of cardiac outcomes in the Rotterdam Study

Author

Leening, Maarten, Kavousi, Maryam, Heeringa, Jan, van Rooij, FJA, van Heemst, J, Deckers, Jaap, Mattace Raso, F.U.S., Ziere, Bert, Hofman, Bert, Stricker, Bruno, Witteman, JCM, Leening, Maarten, Kavousi, Maryam, Heeringa, Jan, van Rooij, FJA, van Heemst, J, Deckers, Jaap, Mattace Raso, F.U.S., Ziere, Bert, Hofman, Bert, Stricker, Bruno, and Witteman, JCM

Abstract

The prevalence of cardiovascular diseases is rising. Therefore, adequate risk prediction and identification of its determinants is increasingly important. The Rotterdam Study is a prospective population-based cohort study ongoing since 1990 in the city of Rotterdam, The Netherlands. One of the main targets of the Rotterdam Study is to identify the determinants and prognosis of cardiovascular diseases. Case finding in epidemiological studies is strongly depending on various sources of follow-up and clear outcome definitions. The sources used for collection of data in the Rotterdam Study are diverse and the definitions of outcomes in the Rotterdam Study have changed due to the introduction of novel diagnostics and therapeutic interventions. This article gives the methods for data collection and the up-to-date definitions of the cardiac outcomes based on international guidelines, including the recently adopted cardiovascular disease mortality definitions. In all, detailed description of cardiac outcome definitions enhances the possibility to make comparisons with other studies in the field of cardiovascular research and may increase the strength of collaborations.

Published
2012

17. Orthostatic hypotension and novel blood pressure-associated gene variants: Genetics of Postural Hemodynamics (GPH) Consortium

Author

Fedorowski, A, Franceschini, N, Brody, J, Liu, CY, Verwoert, Germaine, Boerwinkle, E, Couper, D, Rice, KM, Rotter, JI, Mattace Raso, F.U.S., Uitterlinden, André, Hofman, Bert, Almgren, P, Sjogren, M, Hedblad, B, Larson, MG, Newton-Cheh, C, Wang, TJ, Rose, KM, Psaty, BM, Levy, D, Witteman, JCM, Melander, O, Fedorowski, A, Franceschini, N, Brody, J, Liu, CY, Verwoert, Germaine, Boerwinkle, E, Couper, D, Rice, KM, Rotter, JI, Mattace Raso, F.U.S., Uitterlinden, André, Hofman, Bert, Almgren, P, Sjogren, M, Hedblad, B, Larson, MG, Newton-Cheh, C, Wang, TJ, Rose, KM, Psaty, BM, Levy, D, Witteman, JCM, and Melander, O

Abstract

Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown. A total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8) met the diagnostic criteria for OH (systolic/diastolic BP drop epsilon 20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse var The overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components.

Published
2012

18. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Author

Ehret, GB, Munroe, PB, Rice, KM, Bochud, M, Johnson, AD, Chasman, DI, Smith, AV, Tobin, MD, Verwoert, GC, Hwang, S-J, Pihur, V, Vollenweider, P, O'Reilly, PF, Amin, N, Bragg-Gresham, JL, Teumer, A, Glazer, NL, Launer, L, Zhao, JH, Aulchenko, Y, Heath, S, Sober, S, Parsa, A, Luan, J, Arora, P, Dehghan, A, Zhang, F, Lucas, G, Hicks, AA, Jackson, AU, Peden, JF, Tanaka, T, Wild, SH, Rudan, I, Igl, W, Milaneschi, Y, Parker, AN, Fava, C, Chambers, JC, Fox, ER, Kumari, M, Go, MJ, van der Harst, P, Kao, WHL, Sjogren, M, Vinay, DG, Alexander, M, Tabara, Y, Shaw-Hawkins, S, Whincup, PH, Liu, Y, Shi, G, Kuusisto, J, Tayo, B, Seielstad, M, Sim, X, Khanh-Dung, HN, Lehtimaki, T, Matullo, G, Wu, Y, Gaunt, TR, Onland-Moret, NC, Cooper, MN, Platou, CGP, Org, E, Hardy, R, Dahgam, S, Palmen, J, Vitart, V, Braund, PS, Kuznetsova, T, Uiterwaal, CSPM, Adeyemo, A, Palmas, W, Campbell, H, Ludwig, B, Tomaszewski, M, Tzoulaki, I, Palmer, ND, Aspelund, T, Garcia, M, Chang, Y-PC, O'Connell, JR, Steinle, NI, Grobbee, DE, Arking, DE, Kardia, SL, Morrison, AC, Hernandez, D, Najjar, S, McArdle, WL, Hadley, D, Brown, MJ, Connell, JM, Hingorani, AD, Day, INM, Lawlor, DA, Beilby, JP, Lawrence, RW, Clarke, R, Hopewell, JC, Ongen, H, Dreisbach, AW, Li, Y, Young, JH, Bis, JC, Kahonen, M, Viikari, J, Adair, LS, Lee, NR, Chen, M-H, Olden, M, Pattaro, C, Bolton, JAH, Koettgen, A, Bergmann, S, Mooser, V, Chaturvedi, N, Frayling, TM, Islam, M, Jafar, TH, Erdmann, J, Kulkarni, SR, Bornstein, SR, Graessler, J, Groop, L, Voight, BF, Kettunen, J, Howard, P, Taylor, A, Guarrera, S, Ricceri, F, Emilsson, V, Plump, A, Barroso, IS, Khaw, K-T, Weder, AB, Hunt, SC, Sun, YV, Bergman, RN, Collins, FS, Bonnycastle, LL, Scott, LJ, Stringham, HM, Peltonen, L, Perola, M, Vartiainen, E, Brand, S-M, Staessen, JA, Wang, TJ, Burton, PR, Artigas, MS, Dong, Y, Snieder, H, Wang, X, Zhu, H, Lohman, KK, Rudock, ME, Heckbert, SR, Smith, NL, Wiggins, KL, Doumatey, A, Shriner, D, Veldre, G, Viigimaa, M, Kinra, S, Prabhakaran, D, Tripathy, V, Langefeld, CD, Rosengren, A, Thelle, DS, Corsi, AM, Singleton, A, Forrester, T, Hilton, G, McKenzie, CA, Salako, T, Iwai, N, Kita, Y, Ogihara, T, Ohkubo, T, Okamura, T, Ueshima, H, Umemura, S, Eyheramendy, S, Meitinger, T, Wichmann, H-E, Cho, YS, Kim, H-L, Lee, J-Y, Scott, J, Sehmi, JS, Zhang, W, Hedblad, B, Nilsson, P, Smith, GD, Wong, A, Narisu, N, Stancakova, A, Raffel, LJ, Yao, J, Kathiresan, S, O'Donnell, CJ, Schwartz, SM, Ikram, MA, Longstreth, WT, Mosley, TH, Seshadri, S, Shrine, NRG, Wain, LV, Morken, MA, Swift, AJ, Laitinen, J, Prokopenko, I, Zitting, P, Cooper, JA, Humphries, SE, Danesh, J, Rasheed, A, Goel, A, Hamsten, A, Watkins, H, Bakker, SJL, van Gilst, WH, Janipalli, CS, Mani, KR, Yajnik, CS, Hofman, A, Mattace-Raso, FUS, Oostra, BA, Demirkan, A, Isaacs, A, Rivadeneira, F, Lakatta, EG, Orru, M, Scuteri, A, Ala-Korpela, M, Kangas, AJ, Lyytikainen, L-P, Soininen, P, Tukiainen, T, Wurtz, P, Ong, RT-H, Doerr, M, Kroemer, HK, Voelker, U, Voelzke, H, Galan, P, Hercberg, S, Lathrop, M, Zelenika, D, Deloukas, P, Mangino, M, Spector, TD, Zhai, G, Meschia, JF, Nalls, MA, Sharma, P, Terzic, J, Kumar, MVK, Denniff, M, Zukowska-Szczechowska, E, Wagenknecht, LE, Fowkes, FGR, Charchar, FJ, Schwarz, PEH, Hayward, C, Guo, X, Rotimi, C, Bots, ML, Brand, E, Samani, NJ, Polasek, O, Talmud, PJ, Nyberg, F, Kuh, D, Laan, M, Hveem, K, Palmer, LJ, van der Schouw, YT, Casas, JP, Mohlke, KL, Vineis, P, Raitakari, O, Ganesh, SK, Wong, TY, Tai, ES, Cooper, RS, Laakso, M, Rao, DC, Harris, TB, Morris, RW, Dominiczak, AF, Kivimaki, M, Marmot, MG, Miki, T, Saleheen, D, Chandak, GR, Coresh, J, Navis, G, Salomaa, V, Han, B-G, Zhu, X, Kooner, JS, Melander, O, Ridker, PM, Bandinelli, S, Gyllensten, UB, Wright, AF, Wilson, JF, Ferrucci, L, Farrall, M, Tuomilehto, J, Pramstaller, PP, Elosua, R, Soranzo, N, Sijbrands, EJG, Altshuler, D, Loos, RJF, Shuldiner, AR, Gieger, C, Meneton, P, Uitterlinden, AG, Wareham, NJ, Gudnason, V, Rotter, JI, Rettig, R, Uda, M, Strachan, DP, Witteman, JCM, Hartikainen, A-L, Beckmann, JS, Boerwinkle, E, Vasan, RS, Boehnke, M, Larson, MG, Jarvelin, M-R, Psaty, BM, Abecasis, GR, Chakravarti, A, Elliott, P, van Duijn, CM, Newton-Cheh, C, Levy, D, Caulfield, MJ, Johnson, T, Ehret, GB, Munroe, PB, Rice, KM, Bochud, M, Johnson, AD, Chasman, DI, Smith, AV, Tobin, MD, Verwoert, GC, Hwang, S-J, Pihur, V, Vollenweider, P, O'Reilly, PF, Amin, N, Bragg-Gresham, JL, Teumer, A, Glazer, NL, Launer, L, Zhao, JH, Aulchenko, Y, Heath, S, Sober, S, Parsa, A, Luan, J, Arora, P, Dehghan, A, Zhang, F, Lucas, G, Hicks, AA, Jackson, AU, Peden, JF, Tanaka, T, Wild, SH, Rudan, I, Igl, W, Milaneschi, Y, Parker, AN, Fava, C, Chambers, JC, Fox, ER, Kumari, M, Go, MJ, van der Harst, P, Kao, WHL, Sjogren, M, Vinay, DG, Alexander, M, Tabara, Y, Shaw-Hawkins, S, Whincup, PH, Liu, Y, Shi, G, Kuusisto, J, Tayo, B, Seielstad, M, Sim, X, Khanh-Dung, HN, Lehtimaki, T, Matullo, G, Wu, Y, Gaunt, TR, Onland-Moret, NC, Cooper, MN, Platou, CGP, Org, E, Hardy, R, Dahgam, S, Palmen, J, Vitart, V, Braund, PS, Kuznetsova, T, Uiterwaal, CSPM, Adeyemo, A, Palmas, W, Campbell, H, Ludwig, B, Tomaszewski, M, Tzoulaki, I, Palmer, ND, Aspelund, T, Garcia, M, Chang, Y-PC, O'Connell, JR, Steinle, NI, Grobbee, DE, Arking, DE, Kardia, SL, Morrison, AC, Hernandez, D, Najjar, S, McArdle, WL, Hadley, D, Brown, MJ, Connell, JM, Hingorani, AD, Day, INM, Lawlor, DA, Beilby, JP, Lawrence, RW, Clarke, R, Hopewell, JC, Ongen, H, Dreisbach, AW, Li, Y, Young, JH, Bis, JC, Kahonen, M, Viikari, J, Adair, LS, Lee, NR, Chen, M-H, Olden, M, Pattaro, C, Bolton, JAH, Koettgen, A, Bergmann, S, Mooser, V, Chaturvedi, N, Frayling, TM, Islam, M, Jafar, TH, Erdmann, J, Kulkarni, SR, Bornstein, SR, Graessler, J, Groop, L, Voight, BF, Kettunen, J, Howard, P, Taylor, A, Guarrera, S, Ricceri, F, Emilsson, V, Plump, A, Barroso, IS, Khaw, K-T, Weder, AB, Hunt, SC, Sun, YV, Bergman, RN, Collins, FS, Bonnycastle, LL, Scott, LJ, Stringham, HM, Peltonen, L, Perola, M, Vartiainen, E, Brand, S-M, Staessen, JA, Wang, TJ, Burton, PR, Artigas, MS, Dong, Y, Snieder, H, Wang, X, Zhu, H, Lohman, KK, Rudock, ME, Heckbert, SR, Smith, NL, Wiggins, KL, Doumatey, A, Shriner, D, Veldre, G, Viigimaa, M, Kinra, S, Prabhakaran, D, Tripathy, V, Langefeld, CD, Rosengren, A, Thelle, DS, Corsi, AM, Singleton, A, Forrester, T, Hilton, G, McKenzie, CA, Salako, T, Iwai, N, Kita, Y, Ogihara, T, Ohkubo, T, Okamura, T, Ueshima, H, Umemura, S, Eyheramendy, S, Meitinger, T, Wichmann, H-E, Cho, YS, Kim, H-L, Lee, J-Y, Scott, J, Sehmi, JS, Zhang, W, Hedblad, B, Nilsson, P, Smith, GD, Wong, A, Narisu, N, Stancakova, A, Raffel, LJ, Yao, J, Kathiresan, S, O'Donnell, CJ, Schwartz, SM, Ikram, MA, Longstreth, WT, Mosley, TH, Seshadri, S, Shrine, NRG, Wain, LV, Morken, MA, Swift, AJ, Laitinen, J, Prokopenko, I, Zitting, P, Cooper, JA, Humphries, SE, Danesh, J, Rasheed, A, Goel, A, Hamsten, A, Watkins, H, Bakker, SJL, van Gilst, WH, Janipalli, CS, Mani, KR, Yajnik, CS, Hofman, A, Mattace-Raso, FUS, Oostra, BA, Demirkan, A, Isaacs, A, Rivadeneira, F, Lakatta, EG, Orru, M, Scuteri, A, Ala-Korpela, M, Kangas, AJ, Lyytikainen, L-P, Soininen, P, Tukiainen, T, Wurtz, P, Ong, RT-H, Doerr, M, Kroemer, HK, Voelker, U, Voelzke, H, Galan, P, Hercberg, S, Lathrop, M, Zelenika, D, Deloukas, P, Mangino, M, Spector, TD, Zhai, G, Meschia, JF, Nalls, MA, Sharma, P, Terzic, J, Kumar, MVK, Denniff, M, Zukowska-Szczechowska, E, Wagenknecht, LE, Fowkes, FGR, Charchar, FJ, Schwarz, PEH, Hayward, C, Guo, X, Rotimi, C, Bots, ML, Brand, E, Samani, NJ, Polasek, O, Talmud, PJ, Nyberg, F, Kuh, D, Laan, M, Hveem, K, Palmer, LJ, van der Schouw, YT, Casas, JP, Mohlke, KL, Vineis, P, Raitakari, O, Ganesh, SK, Wong, TY, Tai, ES, Cooper, RS, Laakso, M, Rao, DC, Harris, TB, Morris, RW, Dominiczak, AF, Kivimaki, M, Marmot, MG, Miki, T, Saleheen, D, Chandak, GR, Coresh, J, Navis, G, Salomaa, V, Han, B-G, Zhu, X, Kooner, JS, Melander, O, Ridker, PM, Bandinelli, S, Gyllensten, UB, Wright, AF, Wilson, JF, Ferrucci, L, Farrall, M, Tuomilehto, J, Pramstaller, PP, Elosua, R, Soranzo, N, Sijbrands, EJG, Altshuler, D, Loos, RJF, Shuldiner, AR, Gieger, C, Meneton, P, Uitterlinden, AG, Wareham, NJ, Gudnason, V, Rotter, JI, Rettig, R, Uda, M, Strachan, DP, Witteman, JCM, Hartikainen, A-L, Beckmann, JS, Boerwinkle, E, Vasan, RS, Boehnke, M, Larson, MG, Jarvelin, M-R, Psaty, BM, Abecasis, GR, Chakravarti, A, Elliott, P, van Duijn, CM, Newton-Cheh, C, Levy, D, Caulfield, MJ, and Johnson, T

Abstract

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Published
2011

19. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

Author

Chambers, JC, Zhang, WH, Sehmi, J, Li, XZ, Wass, MN, van der Harst, P, Holm, H, Sanna, S, Kavousi, Maryam, Baumeister, SE, Coin, LJ, Deng, GH, Gieger, C, Heard-Costa, NL, Hottenga, JJ (Jouke Jan), Kuhnel, B, Kumar, V, Lagou, V, Liang, LM, Luan, JA, Vidal, PM, Leach, IM, O'Reilly, PF, Peden, JF, Rahmioglu, N, Soininen, P, Speliotes, EK, Yuan, X, Thorleifsson, G, Alizadeh, BZ, Atwood, LD, Borecki, IB, Brown, MJ, Charoen, P, Cucca, F, Das, Devashish, de Geus, EJC, Dixon, AL, Doering, A, Ehret, G, Eyjolfsson, GI, Farrall, M, Forouhi, NG, Friedrich, N, Goessling, W, Gudbjartsson, DF, Harris, TB, Hartikainen, AL, Heath, S, Hirschfield, GM, Hofman, Bert, Homuth, G, Hypponen, E, Janssen, HLA, Johnson, T, Kangas, AJ, Kema, IP, Kuhn, JP, Lai, S, Lathrop, M, Lerch, MM, Li, Yunlei, Liang, TJ, Lin, JP, Loos, RJF, Martin, NG, Moffatt, MF, Montgomery, GW, Munroe, PB, Musunuru, K, Nakamura, Y, O'Donnell, CJ, Olafsson, I, Penninx, BW, Pouta, A, Prins, BP, Prokopenko, I, Puls, R, Ruokonen, A, Savolainen, MJ, Schlessinger, D, Schouten, Jeoffrey, Seedorf, U, Sen-Chowdhry, S, Siminovitch, KA, Smit, JH, Spector, TD, Tan, WT, Teslovich, TM, Tukiainen, T, Uitterlinden, André, van der Klauw, MM (Melanie), Vasan, RS, Wallace, C, Wallaschofski, H, Wichmann, HE, Willemsen, G, Wurtz, P, Xu, C, Yerges-Armstrong, LM, Abecasis, GR, Ahmadi, KR, Boomsma, DI, Caulfield, M, Cookson, WO, Duijn, Cornelia, Froguel, P, Matsuda, K, McCarthy, MI, Meisinger, C, Mooser, V, Pietilainen, KH, Schumann, G, Snieder, H, Sternberg, MJE, Stolk, RP (Ronald), Thomas, HC, Thorsteinsdottir, U, Uda, M, Waeber, G, Wareham, NJ, Waterworth, DM, Watkins, H, Whitfield, JB, Witteman, JCM, Wolffenbuttel, BHR, Fox, CS, Ala-Korpela, M, Stefansson, K, Vollenweider, P, Volzke, H, Schadt, EE, Scott, J, Jarvelin, MR, Elliott, P, Kooner, JS, Chambers, JC, Zhang, WH, Sehmi, J, Li, XZ, Wass, MN, van der Harst, P, Holm, H, Sanna, S, Kavousi, Maryam, Baumeister, SE, Coin, LJ, Deng, GH, Gieger, C, Heard-Costa, NL, Hottenga, JJ (Jouke Jan), Kuhnel, B, Kumar, V, Lagou, V, Liang, LM, Luan, JA, Vidal, PM, Leach, IM, O'Reilly, PF, Peden, JF, Rahmioglu, N, Soininen, P, Speliotes, EK, Yuan, X, Thorleifsson, G, Alizadeh, BZ, Atwood, LD, Borecki, IB, Brown, MJ, Charoen, P, Cucca, F, Das, Devashish, de Geus, EJC, Dixon, AL, Doering, A, Ehret, G, Eyjolfsson, GI, Farrall, M, Forouhi, NG, Friedrich, N, Goessling, W, Gudbjartsson, DF, Harris, TB, Hartikainen, AL, Heath, S, Hirschfield, GM, Hofman, Bert, Homuth, G, Hypponen, E, Janssen, HLA, Johnson, T, Kangas, AJ, Kema, IP, Kuhn, JP, Lai, S, Lathrop, M, Lerch, MM, Li, Yunlei, Liang, TJ, Lin, JP, Loos, RJF, Martin, NG, Moffatt, MF, Montgomery, GW, Munroe, PB, Musunuru, K, Nakamura, Y, O'Donnell, CJ, Olafsson, I, Penninx, BW, Pouta, A, Prins, BP, Prokopenko, I, Puls, R, Ruokonen, A, Savolainen, MJ, Schlessinger, D, Schouten, Jeoffrey, Seedorf, U, Sen-Chowdhry, S, Siminovitch, KA, Smit, JH, Spector, TD, Tan, WT, Teslovich, TM, Tukiainen, T, Uitterlinden, André, van der Klauw, MM (Melanie), Vasan, RS, Wallace, C, Wallaschofski, H, Wichmann, HE, Willemsen, G, Wurtz, P, Xu, C, Yerges-Armstrong, LM, Abecasis, GR, Ahmadi, KR, Boomsma, DI, Caulfield, M, Cookson, WO, Duijn, Cornelia, Froguel, P, Matsuda, K, McCarthy, MI, Meisinger, C, Mooser, V, Pietilainen, KH, Schumann, G, Snieder, H, Sternberg, MJE, Stolk, RP (Ronald), Thomas, HC, Thorsteinsdottir, U, Uda, M, Waeber, G, Wareham, NJ, Waterworth, DM, Watkins, H, Whitfield, JB, Witteman, JCM, Wolffenbuttel, BHR, Fox, CS, Ala-Korpela, M, Stefansson, K, Vollenweider, P, Volzke, H, Schadt, EE, Scott, J, Jarvelin, MR, Elliott, P, and Kooner, JS

Abstract

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

Published
2011

20. Renal Function Is Related to Severity of Coronary Artery Calcification in Elderly Persons: The Rotterdam Study

Author

el Barzouhi, A, Smale, Suzette, Dehghan, Abbas, Vliegenthart-Proenca, R, Oudkerk, M, Hofman, Bert, Witteman, JCM, el Barzouhi, A, Smale, Suzette, Dehghan, Abbas, Vliegenthart-Proenca, R, Oudkerk, M, Hofman, Bert, and Witteman, JCM

Abstract

Background: Coronary artery calcification (CAC) has been proposed to be the underlying mechanism of the increased risk of coronary heart disease with reductions in glomerular filtration rate (GFR). Since renal function diminishes with aging we examined the association between GFR and CAC in the Rotterdam Study, a population-based study of elderly individuals. Methods: The study was performed in 1703 subjects without a history of coronary heart disease. GFR was estimated using the modification of diet in renal disease equation. We used analysis of covariance to test for mean differences in CAC between GFR tertiles. Results: The mean CAC scores in the middle and lowest GFR tertile did not significantly differ from the mean CAC score in the highest GFR tertile (geometric mean CAC score 4.1 and 4.3 vs 4.2). In a multivariable model the mean CAC score did also not differ between the GFR tertiles. As the interaction term between age and GFR was significant (P = 0.037), we divided the population in two age categories based on median age of 70 years. Below 70 years, the mean CAC scores did not differ between the GFR tertiles. Above median age, mean CAC score in the lowest GFR tertile was significantly higher than the mean CAC score in the highest tertile in a multivariable model (CAC 4.9 vs 4.5, p = 0.010). Conclusion: In this population-based study we observed that the association between CAC and GFR is modified by age. In participants at least 70 years of age, a decrease in GFR was associated with increased CAC.

Published
2011

21. The Rotterdam Study: 2012 objectives and design update

Author

Hofman, Bert, Duijn, Cornelia, Franco Duran, OH, Ikram, Arfan, Janssen, HLA, Klaver, Caroline, Kuipers, Ernst, Nijsten, Tamar, Stricker, Bruno, Tiemeier, Henning, Uitterlinden, André, Vernooij, Meike, Witteman, JCM, Hofman, Bert, Duijn, Cornelia, Franco Duran, OH, Ikram, Arfan, Janssen, HLA, Klaver, Caroline, Kuipers, Ernst, Nijsten, Tamar, Stricker, Bruno, Tiemeier, Henning, Uitterlinden, André, Vernooij, Meike, and Witteman, JCM

Abstract

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Published
2011

22. Association of an APOC3 promoter variant with type 2 diabetes risk and need for insulin treatment in lean persons

Author

van Hoek, Mandy, van Herpt, TW, Dehghan, Abbas, Hofman, Bert, Lieverse, AG, Duijn, Cornelia, Witteman, JCM, Sijbrands, E.J.G., van Hoek, Mandy, van Herpt, TW, Dehghan, Abbas, Hofman, Bert, Lieverse, AG, Duijn, Cornelia, Witteman, JCM, and Sijbrands, E.J.G.

Abstract

An APOC3 promoter haplotype has been previously associated with type 1 diabetes. In this population-based study, we investigated whether APOC3 polymorphisms increase type 2 diabetes risk and need for insulin treatment in lean participants. In the Rotterdam Study, a population-based prospective cohort (n = 7,983), Cox and logistic regression models were used to analyse the associations and interactive effects of APOC3 promoter variants (-482C > T, -455T > C) and BMI on type 2 diabetes risk and insulin treatment. Analyses were followed by replication in an independent case-control sample (1,817 cases, 2,292 controls) and meta-analysis. In lean participants, the -482T allele was associated with increased risk of prevalent and incident type 2 diabetes: OR -482CT 1.47 (95% CI 1.13-1.92), -482TT 1.40 (95% CI 0.83-2.35), p = 0.009 for trend; HR -482CT 1.35 (95% CI 0.96-1.89), -482TT 1.68 (95% CI 0.91-3.1), p = 0.03 for trend, respectively. These results were confirmed by replication. Meta-analysis was highly significant (-482T meta-analysis p = 1.1 x 10(-4)). A borderline significant interaction was observed for insulin use among participants with type 2 diabetes (-482CT*BMI p = 0.06, -455TC*BMI p = 0.02). At a population-based level, the influence of APOC3 promoter variants on type 2 diabetes risk varies with the level of adiposity. Lean carriers of the -482T allele had increased type 2 diabetes risk, while such an effect was not observed in overweight participants. Conversely, in overweight participants the -455C allele seemed protective against type 2 diabetes. The interaction of the variants with need for insulin treatment may indicate beta cell involvement in lean participants. Our findings suggest overlap in the genetic backgrounds of type 1 diabetes and type 2 diabetes in lean patients.

Published
2011

23. Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Author

Arking, DE, Junttila, MJ, Goyette, P, Huertas-Vazquez, A, Eijgelsheim, Mark, Blom, MT, Newton-Cheh, C, Reinier, K, Teodorescu, C, Uy-Evanado, A, Carter-Monroe, N, Kaikkonen, KS, Kortelainen, ML, Boucher, G, Lagace, C, Moes, A (Anna), Zhao, XQ, Kolodgie, F, Rivadeneira, Fernando, Hofman, Bert, Witteman, JCM, Uitterlinden, André, Marsman, RF, Pazoki, Raha, Bardai, Abdenasser, Koster, RW, Dehghan, Abbas, Hwang, SJ, Bhatnagar, P, Post, W, Hilton, G, Prineas, RJ, Li, M, Kottgen, A, Ehret, G, Boerwinkle, E, Coresh, J, Kao, WHL, Psaty, BM, Tomaselli, GF, Sotoodehnia, N, Siscovick, DS, Burke, GL, Marban, E, Spooner, PM, Cupples, LA, Jui, J, Gunson, K, Kesaniemi, YA, Wilde, AAM, Tardif, JC, O'Donnell, CJ, Bezzina, CR, Virmani, R, Stricker, Bruno, Tan, HL, Albert, CM, Chakravarti, A, Rioux, JD, Huikuri, HV, Chugh, SS, Arking, DE, Junttila, MJ, Goyette, P, Huertas-Vazquez, A, Eijgelsheim, Mark, Blom, MT, Newton-Cheh, C, Reinier, K, Teodorescu, C, Uy-Evanado, A, Carter-Monroe, N, Kaikkonen, KS, Kortelainen, ML, Boucher, G, Lagace, C, Moes, A (Anna), Zhao, XQ, Kolodgie, F, Rivadeneira, Fernando, Hofman, Bert, Witteman, JCM, Uitterlinden, André, Marsman, RF, Pazoki, Raha, Bardai, Abdenasser, Koster, RW, Dehghan, Abbas, Hwang, SJ, Bhatnagar, P, Post, W, Hilton, G, Prineas, RJ, Li, M, Kottgen, A, Ehret, G, Boerwinkle, E, Coresh, J, Kao, WHL, Psaty, BM, Tomaselli, GF, Sotoodehnia, N, Siscovick, DS, Burke, GL, Marban, E, Spooner, PM, Cupples, LA, Jui, J, Gunson, K, Kesaniemi, YA, Wilde, AAM, Tardif, JC, O'Donnell, CJ, Bezzina, CR, Virmani, R, Stricker, Bruno, Tan, HL, Albert, CM, Chakravarti, A, Rioux, JD, Huikuri, HV, and Chugh, SS

Abstract

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8610 210). The risk allele, while ancestral, has a frequency of similar to 1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Published
2011

24. Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD

Author

Boger, CA, Gorski, M, Li, M, Hoffmann, MM, Huang, CM, Yang, Q, Teumer, A, Krane, V, O'Seaghdha, CM, Kutalik, Z, Wichmann, HE, Haak, T, Boes, E, Coassin, S, Coresh, J, Kollerits, B, Haun, M, Paulweber, B, Kottgen, A, Li, G (Guo), Shlipak, MG, Powe, N, Hwang, SJ, Dehghan, Abbas, Rivadeneira, Fernando, Uitterlinden, André, Hofman, Bert, Beckmann, JS, Kramer, BK, Witteman, JCM, Bochud, M, Siscovick, D, Rettig, R, Kronenberg, F, Wanner, C, Thadhani, RI, Heid, IM, Fox, CS, Kao, WH, Boger, CA, Gorski, M, Li, M, Hoffmann, MM, Huang, CM, Yang, Q, Teumer, A, Krane, V, O'Seaghdha, CM, Kutalik, Z, Wichmann, HE, Haak, T, Boes, E, Coassin, S, Coresh, J, Kollerits, B, Haun, M, Paulweber, B, Kottgen, A, Li, G (Guo), Shlipak, MG, Powe, N, Hwang, SJ, Dehghan, Abbas, Rivadeneira, Fernando, Uitterlinden, André, Hofman, Bert, Beckmann, JS, Kramer, BK, Witteman, JCM, Bochud, M, Siscovick, D, Rettig, R, Kronenberg, F, Wanner, C, Thadhani, RI, Heid, IM, Fox, CS, and Kao, WH

Abstract

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

Published
2011

25. A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol

Author

Surakka, I, Isaacs, Aaron, Karssen, Lennart, Laurila, PPP, Middelberg, RPS, Tikkanen, E, Ried, JS, Lamina, C, Mangino, M, Igl, W, Hottenga, JJ (Jouke Jan), Lagou, V, van der Harst, P, Leach, IM, Esko, T, Kutalik, Z, Wainwright, NW, Struchalin, Maksim, Sarin, AP, Kangas, AJ, Viikari, JS, Perola, M, Rantanen, T, Petersen, AK, Soininen, P, Johansson, A, Soranzo, N, Heath, AC, Papamarkou, T, Prokopenko, I, Tonjes, A, Kronenberg, F, Doring, A, Rivadeneira, Fernando, Montgomery, GW, Whitfield, JB, Kahonen, M, Lehtimaki, T, Freimer, NB, Willemsen, G, de Geus, EJC, Palotie, A, Sandhu, MS, Waterworth, DM, Metspalu, A, Stumvoll, M, Uitterlinden, André, Jula, A, Navis, G, Wijmenga, C, Wolffenbuttel, BHR, Taskinen, MR, Ala-Korpela, M, Kaprio, J, Kyvik, KO, Boomsma, DI, Pedersen, NL, Gyllensten, U, Wilson, JF, Rudan, I, Campbell, H, Pramstaller, PP, Spector, TD, Witteman, JCM, Eriksson, JG, Salomaa, V, Oostra, Ben, Raitakari, OT, Wichmann, HE, Gieger, C, Jarvelin, MR, Martin, NG, Hofman, Bert, McCarthy, MI, Peltonen, L, Duijn, Cornelia, Aulchenko, YS, Ripatti, S, Surakka, I, Isaacs, Aaron, Karssen, Lennart, Laurila, PPP, Middelberg, RPS, Tikkanen, E, Ried, JS, Lamina, C, Mangino, M, Igl, W, Hottenga, JJ (Jouke Jan), Lagou, V, van der Harst, P, Leach, IM, Esko, T, Kutalik, Z, Wainwright, NW, Struchalin, Maksim, Sarin, AP, Kangas, AJ, Viikari, JS, Perola, M, Rantanen, T, Petersen, AK, Soininen, P, Johansson, A, Soranzo, N, Heath, AC, Papamarkou, T, Prokopenko, I, Tonjes, A, Kronenberg, F, Doring, A, Rivadeneira, Fernando, Montgomery, GW, Whitfield, JB, Kahonen, M, Lehtimaki, T, Freimer, NB, Willemsen, G, de Geus, EJC, Palotie, A, Sandhu, MS, Waterworth, DM, Metspalu, A, Stumvoll, M, Uitterlinden, André, Jula, A, Navis, G, Wijmenga, C, Wolffenbuttel, BHR, Taskinen, MR, Ala-Korpela, M, Kaprio, J, Kyvik, KO, Boomsma, DI, Pedersen, NL, Gyllensten, U, Wilson, JF, Rudan, I, Campbell, H, Pramstaller, PP, Spector, TD, Witteman, JCM, Eriksson, JG, Salomaa, V, Oostra, Ben, Raitakari, OT, Wichmann, HE, Gieger, C, Jarvelin, MR, Martin, NG, Hofman, Bert, McCarthy, MI, Peltonen, L, Duijn, Cornelia, Aulchenko, YS, and Ripatti, S

Abstract

Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain similar to 25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79 x 10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.

Published
2011

26. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Teslovich, TM, Musunuru, K, Smith, AV, Edmondson, AC, Stylianou, IM, Koseki, M, Pirruccello, JP, Ripatti, S, Chasman, DI, Willer, CJ, Johansen, CT, Fouchier, SW, Isaacs, A, Peloso, GM, Barbalic, M, Ricketts, SL, Bis, JC, Aulchenko, YS, Thorleifsson, G, Feitosa, MF, Chambers, J, Orho-Melander, M, Melander, O, Johnson, T, Li, X, Guo, X, Li, M, Cho, YS, Go, MJ, Kim, YJ, Lee, J-Y, Park, T, Kim, K, Sim, X, Ong, RT-H, Croteau-Chonka, DC, Lange, LA, Smith, JD, Song, K, Zhao, JH, Yuan, X, Luan, J, Lamina, C, Ziegler, A, Zhang, W, Zee, RYL, Wright, AF, Witteman, JCM, Wilson, JF, Willemsen, G, Wichmann, H-E, Whitfield, JB, Waterworth, DM, Wareham, NJ, Waeber, G, Vollenweider, P, Voight, BF, Vitart, V, Uitterlinden, AG, Uda, M, Tuomilehto, J, Thompson, JR, Tanaka, T, Surakka, I, Stringham, HM, Spector, TD, Soranzo, N, Smit, JH, Sinisalo, J, Silander, K, Sijbrands, EJG, Scuteri, A, Scott, J, Schlessinger, D, Sanna, S, Salomaa, V, Saharinen, J, Sabatti, C, Ruokonen, A, Rudan, I, Rose, LM, Roberts, R, Rieder, M, Psaty, BM, Pramstaller, PP, Pichler, I, Perola, M, Penninx, BWJH, Pedersen, NL, Pattaro, C, Parker, AN, Pare, G, Oostra, BA, O'Donnell, CJ, Nieminen, MS, Nickerson, DA, Montgomery, GW, Meitinger, T, McPherson, R, McCarthy, MI, McArdle, W, Masson, D, Martin, NG, Marroni, F, Mangino, M, Magnusson, PKE, Lucas, G, Luben, R, Loos, RJF, Lokki, M-L, Lettre, G, Langenberg, C, Launer, LJ, Lakatta, EG, Laaksonen, R, Kyvik, KO, Kronenberg, F, Koenig, IR, Khaw, K-T, Kaprio, J, Kaplan, LM, Johansson, A, Jarvelin, M-R, Janssens, ACJW, Ingelsson, E, Igi, W, Hovingh, GK, Hottenga, J-J, Hofman, A, Hicks, AA, Hengstenberg, C, Heid, IM, Hayward, C, Havulinna, AS, Hastie, ND, Harris, TB, Haritunians, T, Hall, AS, Gyllensten, U, Guiducci, C, Groop, LC, Gonzalez, E, Gieger, C, Freimer, NB, Ferrucci, L, Erdmann, J, Elliott, P, Ejebe, KG, Doering, A, Dominiczak, AF, Demissie, S, Deloukas, P, de Geus, EJC, de Faire, U, Crawford, G, Collins, FS, Chen, Y-DI, Caulfield, MJ, Campbell, H, Burtt, NP, Bonnycastle, LL, Boomsma, DI, Boekholdt, SM, Bergman, RN, Barroso, I, Bandinelli, S, Ballantyne, CM, Assimes, TL, Quertermous, T, Altshuler, D, Seielstad, M, Wong, TY, Tai, E-S, Feranil, AB, Kuzawa, CW, Adair, LS, Taylor, HA, Borecki, IB, Gabriel, SB, Wilson, JG, Holm, H, Thorsteinsdottir, U, Gudnason, V, Krauss, RM, Mohlke, KL, Ordovas, JM, Munroe, PB, Kooner, JS, Tall, AR, Hegele, RA, Kastelein, JJP, Schadt, EE, Rotter, JI, Boerwinkle, E, Strachan, DP, Mooser, V, Stefansson, K, Reilly, MP, Samani, NJ, Schunkert, H, Cupples, LA, Sandhu, MS, Ridker, PM, Rader, DJ, van Duijn, CM, Peltonen, L, Abecasis, GR, Boehnke, M, Kathiresan, S, Teslovich, TM, Musunuru, K, Smith, AV, Edmondson, AC, Stylianou, IM, Koseki, M, Pirruccello, JP, Ripatti, S, Chasman, DI, Willer, CJ, Johansen, CT, Fouchier, SW, Isaacs, A, Peloso, GM, Barbalic, M, Ricketts, SL, Bis, JC, Aulchenko, YS, Thorleifsson, G, Feitosa, MF, Chambers, J, Orho-Melander, M, Melander, O, Johnson, T, Li, X, Guo, X, Li, M, Cho, YS, Go, MJ, Kim, YJ, Lee, J-Y, Park, T, Kim, K, Sim, X, Ong, RT-H, Croteau-Chonka, DC, Lange, LA, Smith, JD, Song, K, Zhao, JH, Yuan, X, Luan, J, Lamina, C, Ziegler, A, Zhang, W, Zee, RYL, Wright, AF, Witteman, JCM, Wilson, JF, Willemsen, G, Wichmann, H-E, Whitfield, JB, Waterworth, DM, Wareham, NJ, Waeber, G, Vollenweider, P, Voight, BF, Vitart, V, Uitterlinden, AG, Uda, M, Tuomilehto, J, Thompson, JR, Tanaka, T, Surakka, I, Stringham, HM, Spector, TD, Soranzo, N, Smit, JH, Sinisalo, J, Silander, K, Sijbrands, EJG, Scuteri, A, Scott, J, Schlessinger, D, Sanna, S, Salomaa, V, Saharinen, J, Sabatti, C, Ruokonen, A, Rudan, I, Rose, LM, Roberts, R, Rieder, M, Psaty, BM, Pramstaller, PP, Pichler, I, Perola, M, Penninx, BWJH, Pedersen, NL, Pattaro, C, Parker, AN, Pare, G, Oostra, BA, O'Donnell, CJ, Nieminen, MS, Nickerson, DA, Montgomery, GW, Meitinger, T, McPherson, R, McCarthy, MI, McArdle, W, Masson, D, Martin, NG, Marroni, F, Mangino, M, Magnusson, PKE, Lucas, G, Luben, R, Loos, RJF, Lokki, M-L, Lettre, G, Langenberg, C, Launer, LJ, Lakatta, EG, Laaksonen, R, Kyvik, KO, Kronenberg, F, Koenig, IR, Khaw, K-T, Kaprio, J, Kaplan, LM, Johansson, A, Jarvelin, M-R, Janssens, ACJW, Ingelsson, E, Igi, W, Hovingh, GK, Hottenga, J-J, Hofman, A, Hicks, AA, Hengstenberg, C, Heid, IM, Hayward, C, Havulinna, AS, Hastie, ND, Harris, TB, Haritunians, T, Hall, AS, Gyllensten, U, Guiducci, C, Groop, LC, Gonzalez, E, Gieger, C, Freimer, NB, Ferrucci, L, Erdmann, J, Elliott, P, Ejebe, KG, Doering, A, Dominiczak, AF, Demissie, S, Deloukas, P, de Geus, EJC, de Faire, U, Crawford, G, Collins, FS, Chen, Y-DI, Caulfield, MJ, Campbell, H, Burtt, NP, Bonnycastle, LL, Boomsma, DI, Boekholdt, SM, Bergman, RN, Barroso, I, Bandinelli, S, Ballantyne, CM, Assimes, TL, Quertermous, T, Altshuler, D, Seielstad, M, Wong, TY, Tai, E-S, Feranil, AB, Kuzawa, CW, Adair, LS, Taylor, HA, Borecki, IB, Gabriel, SB, Wilson, JG, Holm, H, Thorsteinsdottir, U, Gudnason, V, Krauss, RM, Mohlke, KL, Ordovas, JM, Munroe, PB, Kooner, JS, Tall, AR, Hegele, RA, Kastelein, JJP, Schadt, EE, Rotter, JI, Boerwinkle, E, Strachan, DP, Mooser, V, Stefansson, K, Reilly, MP, Samani, NJ, Schunkert, H, Cupples, LA, Sandhu, MS, Ridker, PM, Rader, DJ, van Duijn, CM, Peltonen, L, Abecasis, GR, Boehnke, M, and Kathiresan, S

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Published
2010

27. Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels

Author

Meyer, TE, Verwoert, GC, Hwang, SJ, Glazer, NL, Smith, AV, van Rooij, FJA, Ehret, GB, Boerwinkle, E, Felix, JF, Leak, TS, Harris, TB, Yang, Q, Dehghan, A, Aspelund, T, Katz, R, Homuth, G, Kocher, T, Rettig, R, Ried, JS, Gieger, C, Prucha, H, Pfeufer, A, Meitinger, T, Coresh, J, Hofman, A, Sarnak, MJ, Chen, YDI, Uitterlinden, AG, Chakravarti, A, Psaty, BM, van Duijn, CM, Linda-Kao, WH, Witteman, JCM, Gudnason, V, Siscovick, DS, Fox, CS, Köttgen, A, Meyer, TE, Verwoert, GC, Hwang, SJ, Glazer, NL, Smith, AV, van Rooij, FJA, Ehret, GB, Boerwinkle, E, Felix, JF, Leak, TS, Harris, TB, Yang, Q, Dehghan, A, Aspelund, T, Katz, R, Homuth, G, Kocher, T, Rettig, R, Ried, JS, Gieger, C, Prucha, H, Pfeufer, A, Meitinger, T, Coresh, J, Hofman, A, Sarnak, MJ, Chen, YDI, Uitterlinden, AG, Chakravarti, A, Psaty, BM, van Duijn, CM, Linda-Kao, WH, Witteman, JCM, Gudnason, V, Siscovick, DS, Fox, CS, and Köttgen, A

Abstract

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ~2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5×10-8) or suggestive associations (p<4×10-7) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4×10-7. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

Published
2010

28. Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels

Author

Meyer, TE, Verwoert, GC, Hwang, SJ, Glazer, NL, Smith, AV, van Rooij, FJA, Ehret, GB, Boerwinkle, E, Felix, JF, Leak, TS, Harris, TB, Yang, Q, Dehghan, A, Aspelund, T, Katz, R, Homuth, G, Kocher, T, Rettig, R, Ried, JS, Gieger, C, Prucha, H, Pfeufer, A, Meitinger, T, Coresh, J, Hofman, A, Sarnak, MJ, Chen, YDI, Uitterlinden, AG, Chakravarti, A, Psaty, BM, van Duijn, CM, Linda-Kao, WH, Witteman, JCM, Gudnason, V, Siscovick, DS, Fox, CS, Köttgen, A, Meyer, TE, Verwoert, GC, Hwang, SJ, Glazer, NL, Smith, AV, van Rooij, FJA, Ehret, GB, Boerwinkle, E, Felix, JF, Leak, TS, Harris, TB, Yang, Q, Dehghan, A, Aspelund, T, Katz, R, Homuth, G, Kocher, T, Rettig, R, Ried, JS, Gieger, C, Prucha, H, Pfeufer, A, Meitinger, T, Coresh, J, Hofman, A, Sarnak, MJ, Chen, YDI, Uitterlinden, AG, Chakravarti, A, Psaty, BM, van Duijn, CM, Linda-Kao, WH, Witteman, JCM, Gudnason, V, Siscovick, DS, Fox, CS, and Köttgen, A

Abstract

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ~2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5×10-8) or suggestive associations (p<4×10-7) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4×10-7. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

Published
2010

29. Genome-Wide Association Studies of Serum Magnesium, Potassium, and Sodium Concentrations Identify Six Loci Influencing Serum Magnesium Levels

Author

Meyer, TE, Verwoert, Germaine, Hwang, SJ, Glazer, NL, Smith, AV, van Rooij, FJA, Ehret, GB, Boerwinkle, E, Felix, Janine, Leak, TS, Harris, TB, Yang, Q, Dehghan, Abbas, Aspelund, T, Katz, R, Homuth, G, Kocher, T, Rettig, R, Ried, JS, Gieger, C, Prucha, H, Pfeufer, A, Meitinger, T, Coresh, J, Hofman, Bert, Sarnak, MJ, Chen, YDI, Uitterlinden, André, Chakravarti, A, Psaty, BM, Duijn, Cornelia, Kao, WHL, Witteman, JCM, Gudnason, V, Siscovick, DS, Fox, CS, Kottgen, A, Meyer, TE, Verwoert, Germaine, Hwang, SJ, Glazer, NL, Smith, AV, van Rooij, FJA, Ehret, GB, Boerwinkle, E, Felix, Janine, Leak, TS, Harris, TB, Yang, Q, Dehghan, Abbas, Aspelund, T, Katz, R, Homuth, G, Kocher, T, Rettig, R, Ried, JS, Gieger, C, Prucha, H, Pfeufer, A, Meitinger, T, Coresh, J, Hofman, Bert, Sarnak, MJ, Chen, YDI, Uitterlinden, André, Chakravarti, A, Psaty, BM, Duijn, Cornelia, Kao, WHL, Witteman, JCM, Gudnason, V, Siscovick, DS, Fox, CS, and Kottgen, A

Abstract

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using similar to 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5x10(-8)) or suggestive associations (p<4x10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4x10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

Published
2010

30. Heart failure and the risk of stroke: the Rotterdam Study

Author

Alberts, VP, Bos, Michiel, Koudstaal, Peter, Hofman, Bert, Witteman, JCM, Stricker, Bruno, Breteler, Monique, Alberts, VP, Bos, Michiel, Koudstaal, Peter, Hofman, Bert, Witteman, JCM, Stricker, Bruno, and Breteler, Monique

Abstract

Patients with heart failure used to have an increased risk of stroke, but this may have changed with current treatment regimens. We assessed the association between heart failure and the risk of stroke in a population-based cohort that was followed since 1990. The study uses the cohort of the Rotterdam Study and is based on 7,546 participants who at baseline (1990-1993) were aged 55 years or over and free from stroke. The associations between heart failure and risk of stroke were assessed using time-dependent Cox proportional hazards models, adjusted for cardiovascular risk factors (smoking, diabetes mellitus, BMI, ankle brachial index, blood pressure, atrial fibrillation, myocardial infarction and relevant medication). At baseline, 233 participants had heart failure. During an average follow-up time of 9.7 years, 1,014 persons developed heart failure, and 827 strokes (470 ischemic, 75 hemorrhagic, 282 unclassified) occurred. The risk of ischemic stroke was more than five-fold increased in the first month after diagnosis of heart failure (age and sex adjusted HR 5.79, 95% CI 2.15-15.62), but attenuated over time (age and sex adjusted HR 3.50 [95% CI 1.96-6.25] after 1-6 months and 0.83 [95% CI 0.53-1.29] after 0.5-6 years). Additional adjustment for cardiovascular risk factors only marginally attenuated these risks. In conclusion, the risk of ischemic stroke is strongly increased shortly after the diagnosis of heart failure but returns to normal within 6 months after onset of heart failure.

Published
2010

31. The association of serum testosterone levels and ventricular repolarization

Author

Noord, Charlotte, Dorr, M, Sturkenboom, MCJM, Straus, Sabine, Reffelmann, T, Felix, SB, Hofman, Bert, Kors, Jan, Haring, R, Jong, Frank, Nauck, M, Uitterlinden, André, Wallaschofski, H, Witteman, JCM, Volzke, H, Stricker, Bruno, Noord, Charlotte, Dorr, M, Sturkenboom, MCJM, Straus, Sabine, Reffelmann, T, Felix, SB, Hofman, Bert, Kors, Jan, Haring, R, Jong, Frank, Nauck, M, Uitterlinden, André, Wallaschofski, H, Witteman, JCM, Volzke, H, and Stricker, Bruno

Abstract

It is assumed that testosterone is an important regulator of gender-related differences in ventricular repolarization. Therefore, our aim was to study whether serum levels of testosterone are associated with QTc, QT and RR interval variation. Setting: two independent population-based cohort studies. Participants: 445 male participants (a parts per thousand yen55 years) from the Rotterdam study cohort and 1,428 male participants from the study of health in Pomerania (SHIP) with an electrocardiogram who were randomly sampled for assessment of serum testosterone at baseline, after exclusion of participants with testosterone altering drugs, QTc prolonging drugs or dig(it)oxin, left ventricular hypertrophy and left and right bundle branch block. Endpoints: length of the QTc, QT and RR intervals. Analysis: linear regression model, adjusted for the two individual studies and a pooled analysis of both studies. The pooled analysis of the Rotterdam study and SHIP showed that the QTc interval gradually decreased among the tertiles (P value for trend 0.024). The third tertile of serum testosterone was associated with a lower QTc interval compared to the first tertile [-3.4 ms (-6.5; -0.3)]. However, the third tertile of serum testosterone was not associated with a lower QT interval compared to the first tertile [-0.7 ms (-3.1; 1.8)]. The RR interval gradually increased among the tertiles (P value for trend 0.002) and the third tertile of serum testosterone showed an increased RR interval compared to the first tertile [33.5 ms (12.2; 54.8)]. In the pooled analysis of two population-based studies, serum testosterone levels were not associated with the QT interval, which could be due to a lack of power. Lower QTc intervals in men with higher serum testosterone levels could be due to the association of serum testosterone with prolongation of the RR interval.

Published
2010

32. Variance heterogeneity analysis for detection of potentially interacting genetic loci: method and its limitations

Author

Struchalin, Maksim, Dehghan, Abbas, Witteman, JCM, Duijn, Cornelia, Aulchenko, YS, Struchalin, Maksim, Dehghan, Abbas, Witteman, JCM, Duijn, Cornelia, and Aulchenko, YS

Abstract

Background: Presence of interaction between a genotype and certain factor in determination of a trait's value, it is expected that the trait's variance is increased in the group of subjects having this genotype. Thus, test of heterogeneity of variances can be used as a test to screen for potentially interacting single-nucleotide polymorphisms (SNPs). In this work, we evaluated statistical properties of variance heterogeneity analysis in respect to the detection of potentially interacting SNPs in a case when an interaction variable is unknown. Results: Through simulations, we investigated type I error for Bartlett's test, Bartlett's test with prior rank transformation of a trait to normality, and Levene's test for different genetic models. Additionally, we derived an analytical expression for power estimation. We showed that Bartlett's test has acceptable type I error in the case of trait following a normal distribution, whereas Levene's test kept nominal Type I error under all scenarios investigated. For the power of variance homogeneity test, we showed (as opposed to the power of direct test which uses information about known interacting factor) that, given the same interaction effect, the power can vary widely depending on the non-estimable direct effect of the unobserved interacting variable. Thus, for a given interaction effect, only very wide limits of power of the variance homogeneity test can be estimated. Also we applied Levene's approach to test genome-wide homogeneity of variances of the C-reactive protein in the Rotterdam Study population (n = 5959). In this analysis, we replicate previous results of Pare and colleagues (2010) for the SNP rs12753193 (n = 21, 799). Conclusions: Screening for differences in variances among genotypes of a SNP is a promising approach as a number of biologically interesting models may lead to the heterogeneity of variances. However, it should be kept in mind that the absence of variance heterogeneity for a SNP can not be inter

Published
2010

33. Risk factors for coronary, aortic arch and carotid calcification; The Rotterdam Study

Author

Odink, Arlette, van der Lugt, Aad, Hofman, Bert, Hunink, Myriam, Breteler, Monique, Krestin, Gabriel, Witteman, JCM, Odink, Arlette, van der Lugt, Aad, Hofman, Bert, Hunink, Myriam, Breteler, Monique, Krestin, Gabriel, and Witteman, JCM

Abstract

This study was performed to examine the association of cardiovascular risk factors with calcification in the coronary arteries, aortic arch and carotid arteries, assessed by multislice computed tomography (MSCT). This study was embedded in the Rotterdam Study, a population-based study in subjects aged 55 years and over. From October 2003 until December 2004, subjects were invited to undergo a MSCT scan. Coronary, aortic arch and carotid calcification were quantified according to the Agatston score. Analyses were performed in the first 1003 subjects. Age and current smoking were the strongest independent risk factors for arterial calcification. The odds ratio (OR) for age in women, irrespective of the vessel bed, was 1.1 (P<0.001) and in men it was 1.2 with aortic arch and 1.1 with carotid calcification (both P<0.001). Current smoking was associated with aortic arch calcification with an OR of 3.5 in women and of 4.7 in men ( both P<0.001); and with carotid calcification with an OR of 2.1 in women (P<0.05) and of 4.1 in men (P<0.01). Hypertension, hypercholesterolemia and diabetes were also independently related to calcification, although not consistent across all vessel beds and for men and women. Obesity tended to be inversely related to arterial calcification in women, whereas low high-density lipoprotein-cholesterol showed no relation with arterial calcification. In conclusion, although associations were not completely consistent across the different vessel beds and for men and women, our results indicate that generally the same risk factors are present for atherosclerosis in the coronary, aortic arch and carotid circulation. Journal of Human Hypertension ( 2010) 24, 86-92; doi:10.1038/jhh.2009.42; published online 4 June 2009

Published
2010

34. Independent Susceptibility Markers for Atrial Fibrillation on Chromosome 4q25

Author

Lubitz, SA, Sinner, MF, Lunetta, KL, Makino, S, Pfeufer, A, Rahman, R, Veltman, Caroline, Barnard, J, Bis, JC, Danik, SP, Sonni, A, Shea, MA, del Monte, F, Perz, S, Muller, M (Majon), Peters, A, Greenberg, SM, Furie, KL, Noord, Charlotte, Boerwinkle, E, Stricker, Bruno, Witteman, JCM, Smith, JD, Chung, MK, Heckbert, SR, Benjamin, EJ, Rosand, J, Arking, DE, Alonso, A, Kaab, S, Ellinor, PT, Lubitz, SA, Sinner, MF, Lunetta, KL, Makino, S, Pfeufer, A, Rahman, R, Veltman, Caroline, Barnard, J, Bis, JC, Danik, SP, Sonni, A, Shea, MA, del Monte, F, Perz, S, Muller, M (Majon), Peters, A, Greenberg, SM, Furie, KL, Noord, Charlotte, Boerwinkle, E, Stricker, Bruno, Witteman, JCM, Smith, JD, Chung, MK, Heckbert, SR, Benjamin, EJ, Rosand, J, Arking, DE, Alonso, A, Kaab, S, and Ellinor, PT

Abstract

Background-Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus. Methods and Results-Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P = 1.2x10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals. Conclusions-We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF. (Circulation. 2010;122:976-984.)

Published
2010

35. HFE gene mutations increase the risk of coronary heart disease in women

Author

Pardo Silva, MC, Njajou, OT, Alizadeh, BZ, Hofman, Bert, Witteman, JCM, Duijn, Cornelia, Janssens, Cecile, Pardo Silva, MC, Njajou, OT, Alizadeh, BZ, Hofman, Bert, Witteman, JCM, Duijn, Cornelia, and Janssens, Cecile

Abstract

The purpose of the present study is to examine HFE gene mutations in relation to newly diagnosed (incident) coronary heart disease (CHD). In a population-based follow-up study of 7,983 individuals aged 55 years and older, we compared the risk of incident CHD between HFE carriers and non-carriers, overall and stratified by sex and smoking status. HFE mutations were significantly associated with an increased risk of incident CHD in women but not in men (hazard ratio [HR] for women = 1.7, 95% confidence interval [CI] 1.2-2.4 versus HR for men = 0.9, 95% CI 0.7-1.2). This increased CHD risk associated with HFE mutations in women was statistically significant in never smokers (HR = 1.8, 95% CI 1.1-2.8) and current smokers (HR = 3.1, 95% CI 1.4-7.1), but not in former smokers (HR = 1.3, 95% CI 0.7-2.4). HFE mutations are associated with increased risk of incident CHD in women.

Published
2010

36. Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Author

Hicks, AA, Pramstaller, PP, Johansson, A, Vitart, V, Rudan, I, Ugocsai, P, Aulchenko, Yuriy, Franklin, CS, Liebisch, G, Erdmann, J, Jonasson, I, Zorkoltseva, IV, Pattaro, C, Hayward, C, Isaacs, Aaron, Hengstenberg, C, Campbell, S, Gnewuch, C, Janssens, Cecile, Kirichenko, AV, Konig, IR, Marroni, F, Polasek, O, Demirkan, Ayse, Kolcic, I, Schwienbacher, C, Igl, W, Biloglav, Z, Witteman, JCM, Pichler, I, Zaboli, G, Axenovich, TI, Peters, A, Schreiber, S, Wichmann, HE, Schunkert, H, Hastie, N, Oostra, Ben, Wild, SH, Meitinger, T, Gyllensten, U, Duijn, Cornelia, Wilson, JF, Wright, A, Schmitz, G, Campbell, H, Hicks, AA, Pramstaller, PP, Johansson, A, Vitart, V, Rudan, I, Ugocsai, P, Aulchenko, Yuriy, Franklin, CS, Liebisch, G, Erdmann, J, Jonasson, I, Zorkoltseva, IV, Pattaro, C, Hayward, C, Isaacs, Aaron, Hengstenberg, C, Campbell, S, Gnewuch, C, Janssens, Cecile, Kirichenko, AV, Konig, IR, Marroni, F, Polasek, O, Demirkan, Ayse, Kolcic, I, Schwienbacher, C, Igl, W, Biloglav, Z, Witteman, JCM, Pichler, I, Zaboli, G, Axenovich, TI, Peters, A, Schreiber, S, Wichmann, HE, Schunkert, H, Hastie, N, Oostra, Ben, Wild, SH, Meitinger, T, Gyllensten, U, Duijn, Cornelia, Wilson, JF, Wright, A, Schmitz, G, and Campbell, H

Abstract

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested f

Published
2009

37. A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels

Author

Richards, JB, Waterworth, D, O'Rahilly, S, Hivert, MF, Loos, RJF, Perry, JRB, Tanaka, T, Timpson, NJ, Semple, RK, Soranzo, N, Song, K, Rocha, N, Grundberg, E, Dupuis, J, Florez, JC, Langenberg, C, Prokopenko, I, Saxena, R, Sladek, R, Aulchenko, Yuriy, Evans, D, Waeber, G, Erdmann, J, Burnett, MS, Sattar, N, Devaney, J, Willenborg, C, Hingorani, A, Witteman, JCM, Vollenweider, P, Glaser, B, Hengstenberg, C, Ferrucci, L, Melzer, D, Stark, K, Deanfield, J, Winogradow, J, Grassl, M, Hall, AS, Egan, JM, Thompson, JR, Ricketts, SL, Konig, IR, Reinhard, W, Grundy, S, Wichmann, HE, Barter, P, Mahley, R, Kesaniemi, YA, Rader, DJ, Reilly, MP, Epstein, SE, Stewart, AFR, Duijn, Cornelia, Schunkert, H, Burling, K, Deloukas, P, Pastinen, T, Samani, NJ, McPherson, R, Smith, GD, Frayling, TM, Wareham, NJ, Meigs, JB, Mooser, V, Spector, TD, Richards, JB, Waterworth, D, O'Rahilly, S, Hivert, MF, Loos, RJF, Perry, JRB, Tanaka, T, Timpson, NJ, Semple, RK, Soranzo, N, Song, K, Rocha, N, Grundberg, E, Dupuis, J, Florez, JC, Langenberg, C, Prokopenko, I, Saxena, R, Sladek, R, Aulchenko, Yuriy, Evans, D, Waeber, G, Erdmann, J, Burnett, MS, Sattar, N, Devaney, J, Willenborg, C, Hingorani, A, Witteman, JCM, Vollenweider, P, Glaser, B, Hengstenberg, C, Ferrucci, L, Melzer, D, Stark, K, Deanfield, J, Winogradow, J, Grassl, M, Hall, AS, Egan, JM, Thompson, JR, Ricketts, SL, Konig, IR, Reinhard, W, Grundy, S, Wichmann, HE, Barter, P, Mahley, R, Kesaniemi, YA, Rader, DJ, Reilly, MP, Epstein, SE, Stewart, AFR, Duijn, Cornelia, Schunkert, H, Burling, K, Deloukas, P, Pastinen, T, Samani, NJ, McPherson, R, Smith, GD, Frayling, TM, Wareham, NJ, Meigs, JB, Mooser, V, and Spector, TD

Abstract

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms ( SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P <= 5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P <= 0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5610 26, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

Published
2009

38. NRXN3 Is a Novel Locus for Waist Circumference: A Genome-Wide Association Study from the CHARGE Consortium

Author

Heard-Costa, NL, Zillikens, M.C., Monda, KL, Johansson, A, Harris, TB, Fu, M, Haritunians, T, Feitosa, MF, Aspelund, T, Eiriksdottir, G, Garcia, M, Launer, LJ (Lenore), Smith, AV, Mitchell, BD, McArdle, PF, Shuldiner, AR, Bielinski, SJ, Boerwinkle, E, Brancati, F, Demerath, EW, Pankow, JS, Arnold, AM, Chen, YDI, Glazer, NL, McKnight, B, Psaty, BM, Rotter, JI, Amin, Najaf, Campbell, H, Gyllensten, U, Pattaro, C, Pramstaller, PP, Rudan, I, Struchalin, Maksim, Vitart, V, Gao, XY, Kraja, A, Province, MA, Zhang, QY, Atwood, LD, Dupuis, J, Hirschhorn, JN, Jaquish, CE, O'Donnell, CJ, Vasan, RS, White, CC, Aulchenko, YS, Estrada Gil, Karol, Hofman, Bert, Rivadeneira, Fernando, Uitterlinden, André, Witteman, JCM, Oostra, Ben, Kaplan, RC, Gudnason, V, O'Connell, JR, Borecki, IB, Duijn, Cornelia, Cupples, LA, Fox, CS, North, KE, Heard-Costa, NL, Zillikens, M.C., Monda, KL, Johansson, A, Harris, TB, Fu, M, Haritunians, T, Feitosa, MF, Aspelund, T, Eiriksdottir, G, Garcia, M, Launer, LJ (Lenore), Smith, AV, Mitchell, BD, McArdle, PF, Shuldiner, AR, Bielinski, SJ, Boerwinkle, E, Brancati, F, Demerath, EW, Pankow, JS, Arnold, AM, Chen, YDI, Glazer, NL, McKnight, B, Psaty, BM, Rotter, JI, Amin, Najaf, Campbell, H, Gyllensten, U, Pattaro, C, Pramstaller, PP, Rudan, I, Struchalin, Maksim, Vitart, V, Gao, XY, Kraja, A, Province, MA, Zhang, QY, Atwood, LD, Dupuis, J, Hirschhorn, JN, Jaquish, CE, O'Donnell, CJ, Vasan, RS, White, CC, Aulchenko, YS, Estrada Gil, Karol, Hofman, Bert, Rivadeneira, Fernando, Uitterlinden, André, Witteman, JCM, Oostra, Ben, Kaplan, RC, Gudnason, V, O'Connell, JR, Borecki, IB, Duijn, Cornelia, Cupples, LA, Fox, CS, and North, KE

Abstract

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

Published
2009

39. The Rationale and Design of the Perindopril Genetic Association Study (PERGENE): A Pharmacogenetic Analysis of Angiotensin-Converting Enzyme Inhibitor Therapy in Patients with Stable Coronary Artery Disease

Author

Brugts, Jasper, de Maat, Moniek, Boersma, Eric, Witteman, JCM, van Duijn, C, Uitterlinden, André, Bertrand, M, Remme, W, Fox, K, Ferrari, R, Danser, Jan, Simoons, Maarten, Brugts, Jasper, de Maat, Moniek, Boersma, Eric, Witteman, JCM, van Duijn, C, Uitterlinden, André, Bertrand, M, Remme, W, Fox, K, Ferrari, R, Danser, Jan, and Simoons, Maarten

Abstract

Angiotensin-converting enzyme (ACE) inhibitors reduce clinical symptoms and improve outcome in patients with hypertension, heart failure, and stable coronary artery disease (CAD) and are among the most frequently used drugs in these patient groups. For hypertension, treatment is guided by the level of blood pressure. In the secondary prevention setting, there are no means of guiding therapy. Prior attempts to target ACE-inhibitors to those patients that are most likely to benefit have not been successful, mainly due to the consistency in the treatment effect in clinical subgroups. Still, for prolonged prophylactic treatment with ACE-inhibitors it would be best to target treatment to only those patients most likely to benefit, which would considerably lower the number needed to treat and increase cost-effectiveness. A new approach for such "tailored-therapy" may be to integrate information on the genetic variation between patients. Until now, pharmacogenetic research of the efficacy of ACE-inhibitor therapy in CAD patients is still in a preliminary stage. The PERindopril GENEtic association study (PERGENE) is a substudy of the EUROPA trial, a randomized double-blind placebo-controlled multicentre clinical trial which demonstrated a beneficial effect of the ACE-inhibitor perindopril in reducing cardiovascular morbidity and mortality in 12.218 patients with stable coronary artery disease (mean follow-up 4.2 years). Blood tubes were received from patients at the beginning of the EUROPA trial and buffy coats were stored at -40A degrees C at the central core laboratory. Candidate genes were selected in the renin-angiotensin-system and bradykinin pathways. Polymorphisms were selected based on haplotype tagging principles using the HapMap genome project, Seattle and other up-to-date genetic database platforms to comprehensively cover all common genetic variation within the genes. Selection also took into consideration the functionality of SNP's, location within the gene (pr

Published
2009

40. The Rotterdam Study: 2010 objectives and design update

Author

Hofman, Bert, Breteler, Monique, Duijn, Cornelia, Janssen, HLA, Krestin, Gabriel, Kuipers, Ernst, Stricker, Bruno, Tiemeier, Henning, Uitterlinden, André, Vingerling, Hans, Witteman, JCM, Hofman, Bert, Breteler, Monique, Duijn, Cornelia, Janssen, HLA, Krestin, Gabriel, Kuipers, Ernst, Stricker, Bruno, Tiemeier, Henning, Uitterlinden, André, Vingerling, Hans, and Witteman, JCM

Published
2009

41. Orthostatic hypotension and risk of cardiovascular disease in elderly people: The Rotterdam study

Author

Verwoert, Germaine, Mattace Raso, F.U.S., Hofman, Bert, Heeringa, Jan, Stricker, Bruno, Breteler, Monique, Witteman, JCM, Verwoert, Germaine, Mattace Raso, F.U.S., Hofman, Bert, Heeringa, Jan, Stricker, Bruno, Breteler, Monique, and Witteman, JCM

Abstract

OBJECTIVES: To determine the prognostic role of orthostatic hypotension for cardiovascular disease (CVD) and all-cause mortality in elderly people. DESIGN: Prospective Study. SETTING: Community based. PARTICIPANTS: Five thousand sixty-four subjects from the Rotterdam study aged 55 and older. MEASUREMENTS: Orthostatic hypotension was measured using a Dinamap automatic blood pressure recorder. Orthostatic hypotension is defined as a decline in systolic blood pressure of 20 mmHg or more or a decline in diastolic blood pressure of 10 mmHg or more from supine to standing position at any of three measurements taken 1, 2, and 3 minutes after standing. RESULTS: At baseline, 901 subjects had orthostatic hypotension. During follow-up, 668 subjects had coronary heart disease (CHD) (mean follow-up 6.0 +/- 3.5 years), and 1,835.subjects died (mean follow-up period 7.8 +/- 3.8 years). Orthostatic hypotension increased the risk of CHD (hazard ratio (HR) = 1.31, 95% confidence interval (CI) = 1.08-1.57) and all-cause mortality (HR = 1.22, 95% CI = 1.09-1.36), in models adjusted for age and sex. The risk was slightly lower after additional adjustment for cardiovascular risk factors. In analyses stratified for age, the HRs for all-cause mortality were 1.80 (95% Cl 1.25-2.60), 1.13 (0.89-1.42), and 1.27 (95% Cl = 1.11-1.44), in the first, second, and third tertile of age, respectively. CONCLUSION: Orthostatic hypotension increases the risk of CHD and all-cause mortality in elderly people. I-lie risk of CVD and mortality is strongest in younger and very old subjects.

Published
2008

42. Lack of association of two common polymorphisms on 9p21 with risk of coronary heart disease and myocardial infarction; results from a prospective cohort study

Author

Dehghan, Abbas, van der Hoek, M, Sijbrands, E.J.G., Oostra, Ben, Hofman, Bert, Duijn, Cornelia, Witteman, JCM, Dehghan, Abbas, van der Hoek, M, Sijbrands, E.J.G., Oostra, Ben, Hofman, Bert, Duijn, Cornelia, and Witteman, JCM

Abstract

Background: Recent genome wide association (GWA) studies identified two Single Nucleotide Polymorphisms ( SNP) (rs10757278 and rs10757274) in the region of the CDK2NA and CDK2NB genes to be consistently associated with the risks of coronary heart disease (CHD) and myocardial infarction (MI). We examined the SNPs in relation to the risk of CHD and MI in a large population based study of elderly population. Methods: The Rotterdam Study is a population-based, prospective cohort study among 7983 participants aged 55 years and older. Associations of the polymorphisms with CHD and MI were assessed by use of Cox proportional hazards analyses. Results: In an additive model, the age and sex adjusted hazard ratios (HRs) (95% confidence interval) for CHD and MI were 1.03 (0.90, 1.18) and 0.94 (0.82, 1.08) per copy of the G allele of rs10757274. The corresponding HRs were 1.03 ( 0.90, 1.18) and 0.93 (0.81, 1.06) for the G allele of rs10757278. The association of the SNPs with CHD and MI was not significant in any of the subgroups of CHD risk factors. Conclusion: we were not able to show an association of the studied SNPs with risks of CHD and MI. This may be due to differences in genes involved in the occurrence of CHD in young and older people.

Published
2008

43. An RBP4 promoter polymorphism increases risk of type 2 diabetes

Author

van der Hoek, M, Dehghan, Abbas, Zillikens, M.C., Hofman, Bert, Witteman, JCM, Sijbrands, E.J.G., van der Hoek, M, Dehghan, Abbas, Zillikens, M.C., Hofman, Bert, Witteman, JCM, and Sijbrands, E.J.G.

Abstract

Aims/hypothesis Retinol-binding protein 4 (RBP4), originally known for retinol transport, was recently identified as an adipokine affecting insulin resistance. The RBP4 -803GA promoter polymorphism influences binding of hepatic nuclear factor la and is associated with type 2 diabetes in case-control studies. We hypothesised that the RBP4 -803GA polymorphism increases type 2 diabetes risk at a population-based level. In addition, information on retinol intake and plasma vitamin A levels enabled us to explore the possible underlying mechanism. Methods In the Rotterdam Study, a prospective, population-based, follow-up study, the -803GA polymorphism was genotyped. In Cox proportional hazards models, associations of the -803GA polymorphism and retinol intake with type 2 diabetes risk were examined. Moreover, the interaction of the polymorphism with retinol intake on type 2 diabetes risk was assessed. In a subgroup of participants the association of the polymorphism and vitamin A plasma levels was investigated. Results Homozygous carriers of the -803A allele had increased risk of type 2 diabetes (HR 1.83; 95% CI 1.26-2.66). Retinol intake was not associated with type 2 diabetes risk and showed no interaction with the RBP4 -803GA polymorphism. Furthermore, there was no significant association of the polymorphism with plasma vitamin A levels. Conclusions/interpretation Our results provide evidence that homozygosity for the RBP4 -803A allele is associated with increased risk of type 2 diabetes in the Rotterdam population. This relationship was not clearly explained by retinol intake and vitamin A plasma levels. Therefore, we cannot differentiate between a retinol-dependent or -independent mechanism of this RBP4 variant.

Published
2008

44. Apolipoprotein E gene is related to mortality only in normal weight individuals: The Rotterdam study

Author

Pardo Silva, MC, Janssens, Cecile, Hofman, Bert, Witteman, JCM, Duijn, Cornelia, Pardo Silva, MC, Janssens, Cecile, Hofman, Bert, Witteman, JCM, and Duijn, Cornelia

Abstract

Objective To investigate the relationship between the apolipoprotein E (APOE) gene and the risk of mortality in normal weight, overweight and obese individuals. Methods and Results In a population-based study of 7,983 individuals aged 55 years and older, we compared the risks of all-cause and coronary heart disease (CHD) mortality by APOE genotype, both overall and in subgroups defined by body mass index (BMI). We found significant evidence for interaction between APOE and BMI in relation to total cholesterol (p = 0.04) and HDL cholesterol (p < 0.001). Overall, APOE*2 carriers showed a decreased risk of all-cause mortality. Analyses within BMI strata showed a beneficial effect of APOE*2 only in normal weight persons (adjusted hazard ratio (HR) 0.7[95% CI 0.5-0.9]). APOE*2 was not associated with a lower risk of all-cause mortality in overweight or obese persons. The effect of APOE*2 in normal weight individuals tended to be due to the risk of CHD mortality (adjusted HR 0.5 [95% CI 0.2-1.2]). Conclusion The APOE*2 allele confers a lower risk of all-cause mortality only to normal weight individuals.

Published
2008

45. The Rotterdam Study: Objectives and design update

Author

Hofman, Bert, Breteler, Monique, Duijn, Cornelia, Krestin, Gabriel, Pols, Huib, Stricker, Bruno, Tiemeier, Henning, Uitterlinden, André, Vingerling, Hans, Witteman, JCM, Hofman, Bert, Breteler, Monique, Duijn, Cornelia, Krestin, Gabriel, Pols, Huib, Stricker, Bruno, Tiemeier, Henning, Uitterlinden, André, Vingerling, Hans, and Witteman, JCM

Published
2007

Catalog

Books, media, physical & digital resources
See catalog results