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51. 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

52. Genetic determinants of serum testosterone concentrations in men

Author

Ohlsson, C, Wallaschofski, H, Lunetta, KL, Stolk, L, Perry, JRB, Koster, A, Petersen, AK, Eriksson, J, Lehtimäki, T, Huhtaniemi, IT, Hammond, GL, Maggio, M, Coviello, AD, Emas Study Group, Ferrucci, L, Heier, M, Hofman, A, Holliday, KL, Jansson, JO, Kähönen, M, Karasik, D, Karlsson, MK, Kiel, DP, Liu, Y, Ljunggren, O, Lorentzon, M, Lyytikäinen, LP, Meitinger, T, Mellström, D, Melzer, D, Miljkovic, I, Nauck, M, Nilsson, M, Penninx, B, Pye, SR, Vasan, RS, Reincke, M, Rivadeneira, F, Tajar, A, Teumer, A, Uitterlinden, AG, Ulloor, J, Viikari, J, Völker, U, Völzke, H, Wichmann, HE, Wu, TS, Zhuang, WV, Ziv, E, Wu, FCW, Raitakari, O, Eriksson, A, Bidlingmaier, M, Harris, TB, Murray, A, de Jong, FH, Murabito, JM, Bhasin, S, Vandenput, L, Haring, R, Ohlsson, C, Wallaschofski, H, Lunetta, KL, Stolk, L, Perry, JRB, Koster, A, Petersen, AK, Eriksson, J, Lehtimäki, T, Huhtaniemi, IT, Hammond, GL, Maggio, M, Coviello, AD, Emas Study Group, Ferrucci, L, Heier, M, Hofman, A, Holliday, KL, Jansson, JO, Kähönen, M, Karasik, D, Karlsson, MK, Kiel, DP, Liu, Y, Ljunggren, O, Lorentzon, M, Lyytikäinen, LP, Meitinger, T, Mellström, D, Melzer, D, Miljkovic, I, Nauck, M, Nilsson, M, Penninx, B, Pye, SR, Vasan, RS, Reincke, M, Rivadeneira, F, Tajar, A, Teumer, A, Uitterlinden, AG, Ulloor, J, Viikari, J, Völker, U, Völzke, H, Wichmann, HE, Wu, TS, Zhuang, WV, Ziv, E, Wu, FCW, Raitakari, O, Eriksson, A, Bidlingmaier, M, Harris, TB, Murray, A, de Jong, FH, Murabito, JM, Bhasin, S, Vandenput, L, and Haring, R

Abstract

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10 -41 and rs6258, p = 2.3×10 -22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10 -16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.

Published
2011

53. Genome-Wide association study of coronary heart disease and its risk factors in 8,090 african americans: The nhlbi CARe project

Author

Lettre, G, Palmer, CD, Young, T, Ejebe, KG, Allayee, H, Benjamin, EJ, Bennett, F, Bowden, DW, Chakravarti, A, Dreisbach, A, Farlow, DN, Folsom, AR, Fornage, M, Forrester, T, Fox, E, Haiman, CA, Hartiala, J, Harris, TB, Hazen, SL, Heckbert, SR, Henderson, BE, Hirschhorn, JN, Keating, BJ, Kritchevsky, SB, Larkin, E, Li, M, Rudock, ME, McKenzie, CA, Meigs, JB, Meng, YA, Mosley, TH, Newman, AB, Newton-Cheh, CH, Paltoo, DN, Papanicolaou, GJ, Patterson, N, Post, WS, Psaty, BM, Qasim, AN, Qu, L, Rader, DJ, Redline, S, Reilly, MP, Reiner, AP, Rich, SS, Rotter, JI, Liu, Y, Shrader, P, Siscovick, DS, Tang, WHW, Taylor, HA, Tracy, RP, Vasan, RS, Waters, KM, Wilks, R, Wilson, JG, Fabsitz, RR, Gabriel, SB, Kathiresan, S, Boerwinkle, E, Lettre, G, Palmer, CD, Young, T, Ejebe, KG, Allayee, H, Benjamin, EJ, Bennett, F, Bowden, DW, Chakravarti, A, Dreisbach, A, Farlow, DN, Folsom, AR, Fornage, M, Forrester, T, Fox, E, Haiman, CA, Hartiala, J, Harris, TB, Hazen, SL, Heckbert, SR, Henderson, BE, Hirschhorn, JN, Keating, BJ, Kritchevsky, SB, Larkin, E, Li, M, Rudock, ME, McKenzie, CA, Meigs, JB, Meng, YA, Mosley, TH, Newman, AB, Newton-Cheh, CH, Paltoo, DN, Papanicolaou, GJ, Patterson, N, Post, WS, Psaty, BM, Qasim, AN, Qu, L, Rader, DJ, Redline, S, Reilly, MP, Reiner, AP, Rich, SS, Rotter, JI, Liu, Y, Shrader, P, Siscovick, DS, Tang, WHW, Taylor, HA, Tracy, RP, Vasan, RS, Waters, KM, Wilks, R, Wilson, JG, Fabsitz, RR, Gabriel, SB, Kathiresan, S, and Boerwinkle, E

Abstract

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.

Published
2011

54. Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms

Author

Zhai, GJ, Teumer, A, Stolk, Lisette, Perry, JRB, Vandenput, L, Coviello, AD, Koster, A, Bell, JT, Bhasin, S, Eriksson, J, Eriksson, A, Ernst, F, Ferrucci, L, Frayling, TM, Glass, D, Grundberg, E, Haring, R, Hedman, AK, Hofman, Bert, Kiel, DP, Kroemer, HK, Liu, YM, Lunetta, KL, Maggio, M, Lorentzon, M, Mangino, M, Melzer, D, Miljkovic, I, Nica, A, Penninx, BWJH, Vasan, RS, Rivadeneira, Fernando, Small, KS, Soranzo, N, Uitterlinden, André, Volzke, H, Wilson, SG, Xi, L, Zhuang, WV, Harris, TB, Murabito, JM, Ohlsson, C, Murray, A, Jong, Frank, Spector, TD, Wallaschofski, H, Zhai, GJ, Teumer, A, Stolk, Lisette, Perry, JRB, Vandenput, L, Coviello, AD, Koster, A, Bell, JT, Bhasin, S, Eriksson, J, Eriksson, A, Ernst, F, Ferrucci, L, Frayling, TM, Glass, D, Grundberg, E, Haring, R, Hedman, AK, Hofman, Bert, Kiel, DP, Kroemer, HK, Liu, YM, Lunetta, KL, Maggio, M, Lorentzon, M, Mangino, M, Melzer, D, Miljkovic, I, Nica, A, Penninx, BWJH, Vasan, RS, Rivadeneira, Fernando, Small, KS, Soranzo, N, Uitterlinden, André, Volzke, H, Wilson, SG, Xi, L, Zhuang, WV, Harris, TB, Murabito, JM, Ohlsson, C, Murray, A, Jong, Frank, Spector, TD, and Wallaschofski, H

Abstract

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15610(-36)), SULT2A1 (rs2637125; p = 2.61610(-19)), ARPC1A (rs740160; p = 1.56610(-16)), TRIM4 (rs17277546; p = 4.50610(-11)), BMF (rs7181230; p = 5.44610(-11)), HHEX (rs2497306; p = 4.64610(-9)), BCL2L11 ( rs6738028; p = 1.72610(-8)), and CYP2C9 (rs2185570; p = 2.29610(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.

Published
2011

55. Common genetic determinants of vitamin D insufficiency: A genome-wide association study

Author

Wang, TJ, Zhang, F, Richards, JB, Kestenbaum, B, Van Meurs, JB, Berry, D, Kiel, DP, Streeten, EA, Ohlsson, C, Koller, DL, Peltonen, L, Cooper, JD, O'Reilly, PF, Houston, DK, Glazer, NL, Vandenput, L, Peacock, M, Shi, J, Rivadeneira, F, McCarthy, MI, Anneli, P, De Boer, IH, Mangino, M, Kato, B, Smyth, DJ, Booth, SL, Jacques, PF, Burke, GL, Goodarzi, M, Cheung, CL, Wolf, M, Rice, K, Goltzman, D, Hidiroglou, N, Ladouceur, M, Wareham, NJ, Hocking, LJ, Hart, D, Arden, NK, Cooper, C, Malik, S, Fraser, WD, Hartikainen, AL, Zhai, G, Macdonald, HM, Forouhi, NG, Loos, RJF, Reid, DM, Hakim, A, Dennison, E, Liu, Y, Power, C, Stevens, HE, Jaana, L, Vasan, RS, Soranzo, N, Bojunga, J, Psaty, BM, Lorentzon, M, Foroud, T, Harris, TB, Hofman, A, Jansson, JO, Cauley, JA, Uitterlinden, AG, Gibson, Q, Järvelin, MR, Karasik, D, Siscovick, DS, Econs, MJ, Kritchevsky, SB, Florez, JC, Todd, JA, Dupuis, J, Hyppönen, E, Spector, TD, Wang, TJ, Zhang, F, Richards, JB, Kestenbaum, B, Van Meurs, JB, Berry, D, Kiel, DP, Streeten, EA, Ohlsson, C, Koller, DL, Peltonen, L, Cooper, JD, O'Reilly, PF, Houston, DK, Glazer, NL, Vandenput, L, Peacock, M, Shi, J, Rivadeneira, F, McCarthy, MI, Anneli, P, De Boer, IH, Mangino, M, Kato, B, Smyth, DJ, Booth, SL, Jacques, PF, Burke, GL, Goodarzi, M, Cheung, CL, Wolf, M, Rice, K, Goltzman, D, Hidiroglou, N, Ladouceur, M, Wareham, NJ, Hocking, LJ, Hart, D, Arden, NK, Cooper, C, Malik, S, Fraser, WD, Hartikainen, AL, Zhai, G, Macdonald, HM, Forouhi, NG, Loos, RJF, Reid, DM, Hakim, A, Dennison, E, Liu, Y, Power, C, Stevens, HE, Jaana, L, Vasan, RS, Soranzo, N, Bojunga, J, Psaty, BM, Lorentzon, M, Foroud, T, Harris, TB, Hofman, A, Jansson, JO, Cauley, JA, Uitterlinden, AG, Gibson, Q, Järvelin, MR, Karasik, D, Siscovick, DS, Econs, MJ, Kritchevsky, SB, Florez, JC, Todd, JA, Dupuis, J, Hyppönen, E, and Spector, TD

Abstract

Background Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. Methods We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Findings Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10-109 for rs2282679, in GC); 11q12 (p=2·1×10-27 for rs12785878, near DHCR7); and 11p15 (p=3·3×10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6·0×10-10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95% CI 2·20-2·78, p= 2·3×10-48) or lower than 50 nmol/L (1·92, 1·70-2·16, p=1·0×10-26) compared with those in the lowest quartile. Interpretation Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport

Published
2010

56. 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

57. Clinical and echocardiographic correlates of plasma procollagen type III amino-terminal peptide levels in the community

Author

Wang, TJ, Larsson, MG, Benjamin, EJ, Siwik, DA, Safa, R, Guo, CY, Corey, D, Sundström, Johan, Sawyer, DB, Colucci, WS, Vasan, RS, Wang, TJ, Larsson, MG, Benjamin, EJ, Siwik, DA, Safa, R, Guo, CY, Corey, D, Sundström, Johan, Sawyer, DB, Colucci, WS, and Vasan, RS

Abstract

Background Left ventricular remodeling is characterized by increased collagen deposition in the extracellular matrix. Levels of plasma procollagen type III amino-terminal peptide (PIIINP), a marker of collagen turnover, are elevated in the setting of recent myocardial infarction, heart failure, and cardiomyopathy. Whether plasma PIIINP levels are a useful indicator of subclinical left ventricular abnormalities in ambulatory individuals has not been studied. Methods We examined 967 Framingham Heart Study participants (mean age, 56 years; 60% women) who underwent routine echocardiography and measurement of plasma PIIINP levels. All participants were free of prior myocardial infarction or heart failure. Multivariable regression analyses were performed to examine the clinical and echocardiographic correlates of PIIINP levels. Results Plasma PIIINP levels increased with age and body mass index but did not significantly correlate with other cardiovascular risk factors including hypertension and diabetes. In multivariable models, there was no association between plasma PIIINP levels and left ventricular mass (P = .89), left ventricular fractional shortening (P = .15), left ventricular end-diastolic dimension (P = .51), or left atrial size (P = .68). Plasma PIIINP levels were positively correlated with tissue inhibitor of metalloproteinase-1 levels (multivariable-adjusted, P = .001). Conclusions The use of biomarkers of extracellular matrix turnover has generated recent interest, with plasma PIIINP being the most commonly studied biomarker in acute settings. However, our findings in a large, community-based cohort suggest that plasma PIIINP has limited use for the detection of structural heart disease in ambulatory individuals.

Published
2007
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61. Association of plasma B-type natriuretic peptide concentrations with longitudinal blood pressure tracking in African Americans: findings from the Jackson Heart Study.

Author

Fox ER, Musani SK, Singh P, Bidulescu A, Nagarajarao HS, Samdarshi TE, Steffes MW, Wang TJ, Taylor HA, Vasan RS, Fox, Ervin R, Musani, Solomon K, Singh, Preeti, Bidulescu, Aurelian, Nagarajarao, Harsha S, Samdarshi, Tandaw E, Steffes, Michael W, Wang, Thomas J, Taylor, Herman A, and Vasan, Ramachandran S

Abstract

Water and sodium retention precedes the development of high blood pressure (BP) and explains a compensatory rise in B-type natriuretic peptide (BNP) concentrations. It is unclear whether BNP concentrations antedate the BP progression. We hypothesized that higher BNP concentrations in our African American cohort will be associated with longitudinal increases in BP, progression of BP stage, and incident hypertension. Our study sample consisted of 888 normotensive (based on BP at examination 1 [2000-2004]) participants of the Jackson Heart Study (mean age, 47±12 years; 61% women). We examined the relation of BNP concentrations at the baseline examination to change in systolic and diastolic BPs, BP progression (an increase by 1 BP stage as defined by THE sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) and incident hypertension by examination 2 (2005-2008) adjusting for baseline BP stages, systolic and diastolic BPS, traditional risk factors, and echocardiographic left ventricular mass. Over a median follow-up period of 5.0±0.8 years, 36.9% progressed to a higher BP stage and 19.3% developed hypertension. In multivariable regression models, higher log-BNP concentrations at examination 1 were significantly and positively associated with changes in systolic and diastolic BPs (P<0.05 for both). Baseline log-BNP was significantly associated with BP progression (P=0.046). Every SD increase in baseline log BNP was associated with a 12% increased risk of BP progression. Log-BNP was not significantly associated with incident hypertension (P=0.12). In our community-based sample of African Americans, higher BNP concentrations predicted a longitudinal increase in systolic and diastolic BPs and progression of BP stage. [ABSTRACT FROM AUTHOR]

Published
2013
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62. Blood pressure tracking over the adult life course: patterns and correlates in the Framingham heart study.

Author

Cheng S, Xanthakis V, Sullivan LM, Vasan RS, Cheng, Susan, Xanthakis, Vanessa, Sullivan, Lisa M, and Vasan, Ramachandran S

Abstract

The extent to which select vascular risk factors differentially influence blood pressure (BP) is incompletely understood. Thus, we used multilevel modeling to analyze serial BP measurements using 21 732 person-observations obtained on Framingham Heart Study participants (mean age, 38 years, 52% women; 4993 unique individuals) over a 28-year period. We related longitudinal tracking of each BP measure (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) to age, sex, body mass index, smoking, diabetes mellitus, total/high-density lipoprotein cholesterol ratio, and heart rate. In multivariable-adjusted analyses, we observed that older age, male sex, greater body mass index, and higher heart rate were positively associated with increase in all BP measures (P<0.0001). Notably, higher total/high-density lipoprotein cholesterol ratio was associated with greater mean arterial pressure (P<0.01). Conversely, diabetes mellitus and smoking were associated with higher pulse pressure (P<0.01). We also observed effect modification by sex: the increase in pulse pressure with age and body mass index was more pronounced in women compared with men (P<0.0001). All BP measures tracked at higher levels in both men and women with multiple vascular risk factors. Taken together, our longitudinal observations in a large community-based sample demonstrate a greater pulsatile load in women than in men with increasing age. We also observed a differential impact of select vascular risk factors on the individual components of BP, underscoring distinct regulation of these measures over the life course. [ABSTRACT FROM AUTHOR]

Published
2012
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66. Sex hormone-binding globulin, but not testosterone, is associated prospectively and independently with incident metabolic syndrome in men: the framingham heart study.

Author

Bhasin S, Jasjua GK, Pencina M, D'Agostino R Sr, Coviello AD, Vasan RS, Travison TG, Bhasin, Shalender, Jasjua, Guneet K, Pencina, Michael, D'Agostino, Ralph Sr, Coviello, Andrea D, Vasan, Ramachandran S, and Travison, Thomas G

Subjects
METABOLIC syndrome diagnosis, GLYCOPROTEIN analysis, LIQUID chromatography, LONGITUDINAL method, MASS spectrometry, RESEARCH funding, TESTOSTERONE, LOGISTIC regression analysis, METABOLIC syndrome, PREDICTIVE tests, DISEASE incidence, CROSS-sectional method, FLUOROIMMUNOASSAY
Abstract

Objective: The association between total testosterone and metabolic syndrome has prompted speculation that low testosterone contributes to the pathophysiology of metabolic syndrome in men. We determined whether testosterone or sex hormone-binding globulin (SHBG) is independently associated with the risk of metabolic syndrome.Research Design and Methods: Cross-sectional relationships of hormone levels with metabolic syndrome were assessed in a sample of men in generation 2 of the Framingham Heart Study (FHS) who did not receive testosterone or androgen-deprivation therapy (n = 1,625) and confirmed in a validation sample of men in FHS generation 3 (n = 1,912). Hormone levels in generation 2 examination 7 were related prospectively to incident metabolic syndrome 6.6 years later at examination 8. Testosterone was measured using liquid chromatography-tandem mass spectrometry, SHBG was measured by immunofluorometric assay, and free testosterone was calculated. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS Cross-sectionally, testosterone and SHBG were more strongly associated with metabolic syndrome than free testosterone in the training sample. SHBG, but not testosterone or free testosterone, was significantly associated with metabolic syndrome after adjusting for age, smoking, BMI, and insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR]). These findings were confirmed in a validation sample. Longitudinally, SHBG at examination 7, but not testosterone or free testosterone, was associated with incident metabolic syndrome at examination 8 after adjusting for age, smoking, BMI, and HOMA-IR. Multivariable analyses suggested that age, BMI, and insulin sensitivity independently affect SHBG and testosterone levels and the risk of metabolic syndrome and its components.Conclusions: SHBG, but not testosterone, is independently associated with the risk of metabolic syndrome. These data do not reveal an independent prospective relationship between testosterone and metabolic syndrome in men. [ABSTRACT FROM AUTHOR]

Published
2011
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67. Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study.

Author

Tan ZS, Beiser AS, Fox CS, Au R, Himali JJ, Debette S, Decarli C, Vasan RS, Wolf PA, Seshadri S, Tan, Zaldy S, Beiser, Alexa S, Fox, Caroline S, Au, Rhoda, Himali, Jayandra J, Debette, Stephanie, Decarli, Charles, Vasan, Ramachandran S, Wolf, Philip A, and Seshadri, Sudha

Abstract

Objective: Diabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer's disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults.Research Design and Methods: Framingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998-2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C).Results: We observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007).Conclusions: Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort. [ABSTRACT FROM AUTHOR]

Published
2011
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69. Blood pressure and the risk of developing diabetes in african americans and whites: ARIC, CARDIA, and the framingham heart study.

Author

Wei GS, Coady SA, Goff DC Jr, Brancati FL, Levy D, Selvin E, Vasan RS, Fox CS, Wei, Gina S, Coady, Sean A, Goff, David C Jr, Brancati, Frederick L, Levy, Daniel, Selvin, Elizabeth, Vasan, Ramachandran S, and Fox, Caroline S

Abstract

Objective: We examined the association between high blood pressure and incident type 2 diabetes in African Americans and whites aged 35-54 years at baseline.Research Design and Methods: We combined data from the Atherosclerosis Risk in Communities (ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA) study, and the Framingham Heart Study offspring cohort. Overall, 10,893 participants (57% women; 23% African American) were categorized by baseline blood pressure (normal, prehypertension, hypertension) and examined for incident diabetes (median follow-up 8.9 years).Results: Overall, 14.6% of African Americans and 7.9% of whites developed diabetes. Age-adjusted incidence was increasingly higher across increasing blood pressure groups (P values for trend: <0.05 for African American men; <0.001 for other race-sex groups). After adjustment for age, sex, BMI, fasting glucose, HDL cholesterol, and triglycerides, prehypertension or hypertension (compared with normal blood pressure) was associated with greater risks of diabetes in whites (hazard ratio [HR] for prehypertension: 1.32 [95% CI 1.09-1.61]; for hypertension: 1.25 [1.03-1.53]), but not African Americans (HR for prehypertension: 0.86 [0.63-1.17]; for hypertension: 0.92 [0.70-1.21]). HRs for developing diabetes among normotensive, prehypertensive, and hypertensive African Americans versus normotensive whites were: 2.75, 2.28, and 2.36, respectively (P values <0.001).Conclusions: In African Americans, higher diabetes incidence among hypertensive individuals may be explained by BMI, fasting glucose, triglyceride, and HDL cholesterol. In whites, prehypertension and hypertension are associated with greater risk of diabetes, beyond that explained by other risk factors. African Americans, regardless of blood pressure, have greater risks of developing diabetes than whites. [ABSTRACT FROM AUTHOR]

Published
2011
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75. Relationships of BMI to cardiovascular risk factors differ by ethnicity.

Author

Taylor HA Jr, Coady SA, Levy D, Walker ER, Vasan RS, Liu J, Akylbekova EL, Garrison RJ, Fox C, Taylor, Herman A Jr, Coady, Sean A, Levy, Daniel, Walker, Evelyn R, Vasan, Ramachandran S, Liu, Jiankang, Akylbekova, Ermeg L, Garrison, Robert J, and Fox, Caroline

Abstract

The burden of cardiovascular risk associated with obesity disproportionately affects African Americans and little is known about ethnic/racial differences in the relationship of obesity to cardiometabolic risk. This report assesses whether obesity is similarly associated with cardiometabolic risk factors in African Americans and whites of European ancestry. Cross-sectional observational data from the Jackson Heart Study (JHS) and the Framingham Heart Study (FHS) were compared. This analysis uses participants aged 35-74 years with BMI >18.5 kg/m(2), and free of prevalent cardiovascular disease (CVD), from the initial JHS clinical examination (2000-2004) and the FHS Offspring (1998-2001) and Third Generation (2002-2005) cohorts. Participants were evaluated for the presence of lipid abnormalities, hypertension, and diabetes. Overall, 4,030 JHS (mean age 54 years, 64% women) and 5,245 FHS (mean age 51 years, 54% women) participants were available for analysis. The prevalence of all risk factors except high triglycerides and low high-density lipoprotein (HDL) was substantially higher in JHS (all P < 0.001) and BMI was associated with increasing prevalence of most CVD risk factors within each race. For diabetes mellitus, hypertension, and low HDL, steeper relationships to BMI were observed in FHS than in JHS (P values <0.001-0.016). There were larger proportional increases in risk factor prevalence with increasing BMI in whites than in African Americans. The higher prevalence rates of cardiometabolic risk factors at nearly all levels of BMI in African Americans, however, suggest that additional factors contribute to the burden of CVD risk in African Americans. [ABSTRACT FROM AUTHOR]

Published
2010
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79. Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging.

Author

Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S, Lieb, Wolfgang, Beiser, Alexa S, Vasan, Ramachandran S, Tan, Zaldy S, Au, Rhoda, Harris, Tamara B, Roubenoff, Ronenn, Auerbach, Sanford, and DeCarli, Charles

Abstract

Context: The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD).Objective: To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors.Design, Setting, and Participants: Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed.Main Outcome Measure: Incidence of dementia and AD during follow-up until December 31, 2007.Results: During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance.Conclusion: Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults. [ABSTRACT FROM AUTHOR]

Published
2009
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84. Association of the endogenous nitric oxide synthase inhibitor ADMA with carotid artery intimal media thickness in the Framingham Heart Study offspring cohort.

Author

Maas R, Xanthakis V, Polak JF, Schwedhelm E, Sullivan LM, Benndorf R, Schulze F, Vasan RS, Wolf PA, Böger RH, Seshadri S, Maas, Renke, Xanthakis, Vanessa, Polak, Joseph F, Schwedhelm, Edzard, Sullivan, Lisa M, Benndorf, Ralf, Schulze, Friedrich, Vasan, Ramachandran S, and Wolf, Philip A

Published
2009
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86. Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.

Author

Vasan RS, Glazer NL, Felix JF, Lieb W, Wild PS, Felix SB, Watzinger N, Larson MG, Smith NL, Dehghan A, Grosshennig A, Schillert A, Teumer A, Schmidt R, Kathiresan S, Lumley T, Aulchenko YS, König IR, Zeller T, and Homuth G

Abstract

Context: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.Objective: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.Design, Setting, and Participants: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.Main Outcome Measures: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.Results: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).Conclusions: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease. [ABSTRACT FROM AUTHOR]

Published
2009
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96. Resistin, adiponectin, and risk of heart failure the Framingham offspring study.

Author

Frankel DS, Vasan RS, D'Agostino RB Sr, Benjamin EJ, Levy D, Wang TJ, Meigs JB, Frankel, David S, Vasan, Ramachandran S, D'Agostino, Ralph B Sr, Benjamin, Emelia J, Levy, Daniel, Wang, Thomas J, and Meigs, James B

Abstract

Objectives: We tested the association of the adipokines resistin and adiponectin with incident heart failure.Background: Abnormal concentrations of adipokines may partially explain the association between obesity and heart failure.Methods: We related circulating adipokine concentrations to the incidence of heart failure in 2,739 participants in the Framingham Offspring Study.Results: During 6 years of follow-up, 58 participants developed new-onset heart failure. In proportional hazards models (adjusting for age, sex, blood pressure, antihypertensive treatment, diabetes, smoking, total/high-density lipoprotein cholesterol ratio, prevalent coronary heart disease, valvular heart disease, left ventricular hypertrophy, and estimated glomerular filtration rate) using the lowest third of the resistin distribution as the referent, the hazard ratios for heart failure in the middle and top thirds were 2.89 (95% confidence interval [CI]: 1.05 to 7.92) and 4.01 (95% CI: 1.52 to 10.57), respectively (p = 0.004 for trend). Additional adjustment for body mass index, insulin resistance (measured with the homeostasis model), C-reactive protein, and B-type natriuretic peptide did not substantively weaken this association (multivariable hazard ratios [HRs]: 2.62 and 3.74, p = 0.007). In the maximally adjusted model, each SD increment in resistin (7.45 ng/ml) was associated with a 26% increase in heart failure risk (95% CI: 1% to 60%). Concentrations of adiponectin were not associated with heart failure (multivariable HRs: 0.87 and 0.97, p = 0.9).Conclusions: Increased circulating concentrations of resistin were associated with incident heart failure, even after accounting for prevalent coronary heart disease, obesity, and measures of insulin resistance and inflammation. The findings suggest a role for resistin in human disease and a novel pathway to heart failure. [ABSTRACT FROM AUTHOR]

Published
2009
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98. Patterns of abdominal fat distribution: the Framingham Heart Study.

Author

Pou KM, Massaro JM, Hoffmann U, Lieb K, Vasan RS, O'Donnell CJ, Fox CS, Pou, Karla M, Massaro, Joseph M, Hoffmann, Udo, Lieb, Kathrin, Vasan, Ramachandran S, O'Donnell, Christopher J, and Fox, Caroline S

Abstract

Objective: The prevalence of abdominal obesity exceeds that of general obesity. We sought to determine the prevalence of abdominal subcutaneous and visceral obesity and to characterize the different patterns of fat distribution in a community-based sample.Research Design and Methods: Participants from the Framingham Heart Study (n = 3,348, 48% women, mean age 52 years) underwent multidetector computed tomography; subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were assessed. Sex-specific high SAT and VAT definitions were based on 90th percentile cut points from a healthy referent sample. Metabolic risk factors were examined in subgroups with elevated SAT and VAT.Results: The prevalence of high SAT was 30% (women) and 31% (men) and that for high VAT was 44% (women) and 42% (men). Overall, 27.8% of the sample was discordant for high SAT and high VAT: 19.9% had SAT less than but VAT equal to or greater than the 90th percentile, and 7.9% had SAT greater than but VAT less than the 90th percentile. The prevalence of metabolic syndrome was higher among women and men with SAT less than the 90th percentile and high VAT than in those with high SAT but VAT less than the 90th percentile, despite lower BMI and waist circumference. Findings were similar for hypertension, elevated triglycerides, and low HDL cholesterol.Conclusions: Nearly one-third of our sample has abdominal subcutaneous obesity, and >40% have visceral obesity. Clinical measures of BMI and waist circumference may misclassify individuals in terms of VAT and metabolic risk. [ABSTRACT FROM AUTHOR]

Published
2009
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99. Association of lifestyle factors with abdominal subcutaneous and visceral adiposity: the Framingham Heart Study.

Author

Molenaar EA, Massaro JM, Jacques PF, Pou KM, Ellison RC, Hoffmann U, Pencina K, Shadwick SD, Vasan RS, O'Donnell CJ, Fox CS, Molenaar, Esther A, Massaro, Joseph M, Jacques, Paul F, Pou, Karla M, Ellison, R Curtis, Hoffmann, Udo, Pencina, Karol, Shadwick, Steven D, and Vasan, Ramachandran S

Abstract

Objective: The purpose of this study was to assess the relationship between lifestyle factors and abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based setting.Research Design and Methods: Cross-sectional associations between lifestyle factors (dietary quality, physical activity, smoking, and alcohol consumption) and SAT and VAT volumes were examined in 2,926 Framingham Heart Study participants (48.6% women, aged 50 +/- 10 years).Results: Diets consistent with the 2005 Dietary Guidelines Adherence Index and greater physical activity were inversely associated with SAT and VAT (P < 0.0001-0.002). In men, former smoking was associated with higher SAT (2,743 +/- 56 cm(3)) compared with current smokers (2,629 +/- 88 cm(3)) or those who never smoked (2,538 +/- 44 cm(3); P = 0.02). Both former and current smoking was associated with higher VAT (P = 0.03 [women]; P = 0.005 [men]). Women with high amounts of alcohol intake (>7 drinks/week) had lower SAT (2,869 +/- 106 cm(3)) than those who consumed less alcohol (3,184 +/- 44 cm(3), P = 0.006); significant differences in VAT were not observed (P = 0.18). In men, high amounts of alcohol intake (>14 drinks/week) were associated with higher VAT (2,272 +/- 59 cm(3)) compared with intake of Conclusions: Adherence to recommended dietary guidelines and physical activity are associated with lower SAT and VAT volumes. However, both smoking and high alcohol intake are differentially associated with VAT volumes. Further research to uncover the putative mechanisms is warranted. [ABSTRACT FROM AUTHOR]

Published
2009
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