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147 results on '"Hitman, G.A."'

4. A novel TNFRSF1A splice mutation associated with increased nuclear factor kappaB (NF-[kappa]B) transcription factor activation in patients with tumour necrosis factor receptor asssociated periodic syndrome (TRAPS)

Author

Churchman, S.M., Church, L.D., Savic, S., Coulthard, L.R., Hayward, B., Nedjai, B., Turner, M.D., Mathews, R.J., Baguley, E., Hitman, G.A., Gooi, H.C., Wood, P., Emery, P., and McDermott, M.F

Subjects
Gene mutations -- Research, DNA binding proteins -- Physiological aspects, DNA binding proteins -- Research, Tumor necrosis factor -- Physiological aspects, Tumor necrosis factor -- Research, Familial Mediterranean fever -- Genetic aspects, Familial Mediterranean fever -- Research, Health
Published
2008

7. HLA-DP and coeliac disease: family and population studies

Author

Caffrey, C., Hitman, G.A., Niven, M.J., Cassell, P.G., Kumar, P., Fry, L., Mackintosh, P., Gallagher, R., Feighery, C., Weir, D., and Sachs, J.A.

Subjects
Celiac disease -- Genetic aspects, HLA class II antigens -- Health aspects, Celiac disease -- Physiological aspects, Health
Abstract

Celiac disease (CD) is an intestinal malabsorption syndrome in which diarrhea, malnutrition, and bleeding are common. CD is reversed by removal of gluten-containing cereals from the diet. CD has a genetic component that has been associated with several histocompatibility antigens. These are specific proteins present on most cells in the body. Their presence is controlled by genes that code for them, and they recognize 'self' tissues for the immune system. Thus, transplantation of foreign tissue presents new antigens to the immune system, and antibodies against the new antigens are promptly made. Human antigens are called human leukocyte (white blood cell) antigens (HLA) and different HLA subsets are associated with the occurrence of many diseases. The relationship between the subclass HLA (class II), HLA-DP, and coeliac disease, as well as the association with insulin-dependent diabetes mellitus (IDDM) and dermatitis herpetiformis (DH, another gluten-related disease), was studied in 254 subjects with these diseases or who were in a family with CD. The results confirmed previous studies which showed that people with CD frequently had an alteration in the alpha portion of the HLA-DP structure. Further, people with DH also tended to have this alteration, although less often, while people with IDDM and healthy subjects did not. An additional alteration in the beta portion of HLA-DP was found in people with CD; many of the CD patients with the alpha alteration had the beta alteration. Alterations in HLA-DP alpha structure were not associated with particular forms of two other class II HLA proteins, HLA-DR and HLA-DQ. Further, some CD patients did not possess the HLA-DP alpha alteration. The study indicates that susceptibility to CD may be related to more than one HLA characteristic, or to a complex mixture of HLA factors. (Consumer Summary produced by Reliance Medical Information, Inc.)

Published
1990

9. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a)

Author

Deshmukh, H.A., Colhoun, H.M., Johnson, T., McKeigue, P.M., Betteridge, D.J., Durrington, P.N., Fuller, J.H., Livingstone, S., Charlton-Menys, V., Neil, A., Poulter, N., Sever, P., Shields, D.C., Stanton, A.V., Chatterjee, A., Hyde, C., Calle, R.A., DeMicco, D.A., Trompet, S., Postmus, I., Ford, I., Jukema, J.W., Caulfield, M., Hitman, G.A., CARDS, ASCOT, PROSPER Investigators, and National Institute for Health Research

Subjects
Oncology, Apolipoprotein E, Male, Atorvastatin, LDL/metabolism, Genome-wide association study, 030204 cardiovascular system & hematology, 0601 Biochemistry and Cell Biology, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, lipoprotein(a), genetics, Receptors, Lysophosphatidic Acid, Randomized Controlled Trials as Topic, 0303 health sciences, biology, Lipoprotein(a), Middle Aged, 3. Good health, Treatment Outcome, 1101 Medical Biochemistry and Metabolomics, META ANALYSIS, DENSITY-LIPOPROTEIN CHOLESTEROL, CARDIOVASCULAR-DISEASE, LPA LOCUS, Glucosyltransferases, Hypertension, WHOLE-GENOME, Female, lipids (amino acids, peptides, and proteins), CARDS, ASCOT, and PROSPER Investigators, Life Sciences & Biomedicine, medicine.drug, Adult, Biochemistry & Molecular Biology, medicine.medical_specialty, Statin, Genotype, medicine.drug_class, Single-nucleotide polymorphism, QD415-436, CONTROLLED-TRIAL, Polymorphism, Single Nucleotide, statins, 03 medical and health sciences, Internal medicine, medicine, Humans, CORONARY-HEART-DISEASE, Pyrroles, Atorvastatin Calcium, 030304 developmental biology, Aged, Science & Technology, Cholesterol, business.industry, LIPID-LOWERING RESPONSE, Cell Biology, Cholesterol, LDL, PLASMA LIPOPROTEIN(A), Placebo Effect, chemistry, Diabetes Mellitus, Type 2, Heptanoic Acids, biology.protein, business, Patient-Oriented and Epidemiological Research, low density lipoprotein, Pravastatin, STATIN TREATMENT, Genome-Wide Association Study
Abstract

We carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of LDL-c response to atorvastatin that reached genome-wide significance at rs10455872 (P = 6.13 x 10(-9)) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P = 2.22 x 10(-16) and rs4420638; P = 1.01 x 10(-11)) that are proxies for the epsilon 2 and epsilon 4 variants, respectively, in APOE. The novel association with the LPA SNP was replicated in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial (P = 0.009). Using CARDS data, we further showed that atorvastatin therapy did not alter lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels. However, statin therapy had a similar effect in reducing cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P = 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response.jlr Therefore, an apparently lower LDL-c response to statin therapy may indicate a need for measurement of Lp(a). However, statin therapy seems beneficial even in those with high Lp(a).-Deshmukh, H. A., H. M. Colhoun, T. Johnson, P. M. McKeigue, D. J. Betteridge, P. N. Durrington, J. H. Fuller, S. Livingstone, V. Charlton-Menys, A. Neil, N. Poulter, P. Sever, D. C. Shields, A. V. Stanton, A. Chatterjee, C. Hyde, R. A. Calle, D. A. DeMicco, S. Trompet, I. Postmus, I. Ford, J. W. Jukema, M. Caulfield, and G. A. Hitman on behalf of the CARDS, ASCOT, and PROSPER investigators. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a). J. Lipid Res. 2012. 53: 1000-1011.

Published
2012
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10. Parental origin of sequence variants associated with complex diseases

Author

Voight, B.F., Raychaudhuri, S., Purcell, S., McCarroll, S.A., Segrè, A.V., Ardlie, K., Burtt, N.P., Crawford, G., Elliott, A.L., Green, T., Guiducci, C., Saxena, R., Daly, M.J., Florez, J.C., Altshuler, D., Meigs, J.B., Scott, L.J., Welch, R.P., Willer, C.J., Ganser, M., Jackson, A.U., Stringham, H.M., Abecasis, G.R., Boehnke, M., Steinthorsdottir, V., Thorleifsson, G., Kong, A., Walters, G.B., Thorsteinsdottir, U., Stefansson, K., Dina, C., Proença, C., Cauchi, S., Froguel, P., Zeggini, E., Bumpstead, S., Payne, F., Smith, N., Barroso, I., Ferreira, T., Elliott, K.S., Lindgren, C.M., Prokopenko, I., Rayner, N.W., Robertson, N.R., Morris, A.P., McCarthy, M.I., Huth, C., Grallert, H., Gieger, C., Klopp, N., Meitinger, T., Petersen, A.-K., Thorand, B., Wichmann, H.-E., Illig, T., Aulchenko, Y.S., Amin, N., Witteman, J., Hofman, A., Van Duijn, C.M., McCulloch, L.J., Bennett, A.J., Groves, C.J., Hassanali, N., Owen, K.R., Gloyn, A.L., Wu, G., Stein, L.D., Langenberg, C., Griffin, S., Wareham, N.J., Hoffmann, O.M., Hide, W.A., Dupuis, J., Qi, L., Kraft, P., Sun, Q., Hunter, D., Hu, F.B., Cornelis, M., VanDam, R., Van Hoek, M., Van Herpt, T., Sijbrands, E., Uitterlinden, A., Navarro, P., Balkau, B., Benediktsson, R., Sigurdsson, G., Blagieva, R., Boehm, B.O., Boerwinkle, E., Bonnycastle, L.L., Chines, P.S., Erdos, M.R., Morken, M.A., Narisu, N., Swift, A.J., Boström, K.B., Bravenboer, B., Charpentier, G., Couper, D.J., Doney, A.S.F., Morris, A.D., Palmer, C.N.A., Fox, C.S., Franklin, C.S., Rudan, I., Grarup, N., Hadjadj, S., Thomas Sparsø, [No Value], Campbell, H., Wilson, J.F., Hansen, T., Pedersen, O., Herder, C., Roden, M., Isomaa, B., Tuomi, T., Johnson, P.R.V., Jørgensen, T., Kao, W.H.L., Kuusisto, J., Laakso, M., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Nilsson, P., Groop, L., Marre, M., Midthjell, K., Platou, C., Hveem, K., Perry, J.R.B., Shields, B.M., Weedon, M.N., Frayling, T.M., Hattersley, A.T., Rathmann, W., Strassburger, K., Rocheleau, G., Sladek, R., Sampson, M.J., Shrader, P., Tichet, J., Bergman, R.N., Collins, F.S., Gyllensten, U., Hitman, G.A., Mohlke, K.L., Pramstaller, P.P., Tuomilehto, J., Walker, M., Watanabe, R.M., Pankow, J.S., and deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland. kong@decode.is

Subjects
Male, CCCTC-Binding Factor, Iceland, Mothers, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Fathers, Genomic Imprinting, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Humans, SNP, Genetic Predisposition to Disease, Allele, Alleles, 030304 developmental biology, Genetics, 0303 health sciences, Binding Sites, Multidisciplinary, Genome, Human, Chromosomes, Human, Pair 11, Haplotype, DNA Methylation, Pedigree, Repressor Proteins, Diabetes Mellitus, Type 2, Haplotypes, Carcinoma, Basal Cell, DNA methylation, Female, Human genome, Genomic imprinting, Chromosomes, Human, Pair 7, 030217 neurology & neurosurgery
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site. info:eu-repo/grantAgreement/EC/FP7/218071

Published
2009
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11. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials

Author

Mihaylova, B., Emberson, J., Blackwell, L., Keech, A., Simes, J., Barnes, E.H., Voysey, M., Gray, A., Collins, R., Baigent, C., Lemos, J. de, Braunwald, E., Blazing, M., Murphy, S., Downs, J.R., Gotto, A., Clearfield, M., Holdaas, H., Gordon, D., Davis, B., Koren, M., Dahlof, B., Poulter, N., Sever, P., Knopp, R.H., Fellstrom, B., Jardine, A., Schmieder, R., Zannad, F., Goldbourt, U., Kaplinsky, E., Colhoun, H.M., Betteridge, D.J., Durrington, P.N., Hitman, G.A., Fuller, J., Neil, A., Wanner, C., Krane, V., Sacks, F., Moye, L., Pfeffer, M., Hawkins, C.M., Kjekshus, J., Wedel, H., Wikstrand, J., Barter, P., Tavazzi, L., Maggioni, A., Marchioli, R., Tognoni, G., Franzosi, M.G., Bloomfield, H., Robins, S., Armitage, J., Parish, S., Peto, R., Sleight, P., Pedersen, T.R., Ridker, P.M., Holman, R., Meade, T., MacMahon, S., Marschner, I., Tonkin, A., Shaw, J., Serruys, P.W., Nakamura, H., Knatterud, G., Furberg, C., Byington, R., Macfarlane, P., Cobbe, S., Ford, I., Murphy, M., Blauw, G.J., Packard, C., Shepherd, J., Pedersen, T., Wilhelmsen, L., Cannon, C., Bowman, L., Landray, M., Rosa, J. la, Rossouw, J., Probstfield, J., and Cholesterol Treatment Trialists

Published
2012

12. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, R.J. Dupuis, J. Prokopenko, I. Barker, A. Ahlqvist, E. Rybin, D. Petrie, J.R. Travers, M.E. Bouatia-Naji, N. Dimas, A.S. Nica, A.C. Wheeler, E. Chen, H. Voight, B.F. Taneera, J. Kanoni, S. Peden, J.F. Turrini, F. Gustafsson, S. Zabena, C. Almgren, P. Barker, D.J.P. Barnes, D. Dennison, E.M. Eriksson, J.G. Eriksson, P. Eury, E. Folkersen, L. Fox, C.S. Frayling, T.M. Goel, A. Gu, H.F. Horikoshi, M. Isomaa, B. Jackson, A.U. Jameson, K.A. Kajantie, E. Kerr-Conte, J. Kuulasmaa, T. Kuusisto, J. Loos, R.J.F. Luan, J. Makrilakis, K. Manning, A.K. Martínez-Larrad, M.T. Narisu, N. Mannila, M.N. Öhrvik, J. Osmond, C. Pascoe, L. Payne, F. Sayer, A.A. Sennblad, B. Silveira, A. Stančcáková, A. Stirrups, K. Swift, A.J. Syvänen, A.-C. Tuomi, T. Van't Hooft, F.M. Walker, M. Weedon, M.N. Xie, W. Zethelius, B. Scott, L.J. Steinthorsdottir, V. Morris, A.P. Dina, C. Welch, R.P. Zeggini, E. Huth, C. Aulchenko, Y.S. Thorleifsson, G. Mcculloch, L.J. Ferreira, T. Grallert, H. Amin, N. Wu, G. Willer, C.J. Raychaudhuri, S. McCarroll, S.A. Hofmann, O.M. Qi, L. Segre, A.V. Van Hoek, M. Navarro, P. Ardlie, K. Balkau, B. Benediktsson, R. Bennett, A.J. Blagieva, R. Boerwinkle, E. Bonnycastle, L.L. Bostrom, K.B. Bravenboer, B. Bumpstead, S. Burtt, N.P. Charpentier, G. Chines, P.S. Cornelis, M. Couper, D.J. Crawford, G. Doney, A.S.F. Elliott, K.S. Elliott, A.L. Erdos, M.R. Franklin, C.S. Ganser, M. Gieger, C. Grarup, N. Green, T. Griffin, S. Groves, C.J. Guiducci, C. Hadjadj, S. Hassanali, N. Herder, C. Johnson, P.R.V. Jorgensen, T. Kao, W.H.L. Klopp, N. Kong, A. Kraft, P. Lauritzen, T. Li, M. Lieverse, A. Lindgren, C.M. Lyssenko, V. Marre, M. Meitinger, T. Midthjell, K. Morken, M.A. Nilsson, P. Owen, K.R. Perry, J.R.B. Petersen, A.-K. Platou, C. Proenca, C. Rathmann, W. Rayner, N.W. Robertson, N.R. Rocheleau, G. Roden, M. Sampson, M.J. Saxena, R. Shields, B.M. Shrader, P. Sigurdsson, G. Sparso, T. Strassburger, K. Stringham, H.M. Sun, Q. Thorand, B. Tichet, J. Van Dam, R.M. Van Haeften, T.W. Van Herpt, T. Van Vliet-Ostaptchouk, J.V. Walters, G.B. Wijmenga, C. Witteman, J.C.M. Bergman, R.N. Cauchi, S. Collins, F.S. Gloyn, A.L. Gyllensten, U. Hansen, T. Hide, W.A. Hitman, G.A. Hofman, A. Hunter, D.J. Hveem, K. Laakso, M. Mohlke, K.L. Morris, A.D. Palmer, C.N.A. Pramstaller, P.P. Rudan, I. Sijbrands, E. Stein, L.D. Tuomilehto, J. Uitterlinden, A.G. Wareham, N.J. Watanabe, R.M. Abecasis, G.R. Boehm, B.O. Campbell, H. Daly, M.J. Hattersley, A.T. Hu, F.B. Meigs, J.B. Pankow, J.S. Pedersen, O. Wichmann, H.-E. Barroso, I. Groop, L. Sladek, R. Thorsteinsdottir, U. Wilson, J.F. Illig, T. Froguel, P. Van Duijn, C.M. Stefansson, K. Altshuler, D. Boehnke, M. McCarthy, M.I. Speliotes, E.K. Berndt, S.I. Monda, K.L. Allen, H.L. Magi, R. Randall, J.C. Vedantam, S. Winkler, T.W. Workalemahu, T. Heid, I.M. Wood, A.R. Weyant, R.J. Estrada, K. Liang, L. Nemesh, J. Park, J.-H. Kilpelainen, T.O. Yang, J. Esko, T. Feitosa, M.F. Kutalik, Z. Mangino, M. Scherag, A. Smith, A.V. Zhao, J.H. Aben, K.K. Absher, D.M. Dixon, A.L. Fisher, E. Glazer, N.L. Goddard, M.E. Heard-Costa, N.L. Hoesel, V. Hottenga, J.-J. Johansson, A. Johnson, T. Ketkar, S. Lamina, C. Li, S. Moffatt, M.F. Myers, R.H. Peters, M.J. Preuss, M. Ripatti, S. Rivadeneira, F. Sandholt, C. Timpson, N.J. Tyrer, J.P. Van Wingerden, S. White, C.C. Wiklund, F. Barlassina, C. Chasman, D.I. Cooper, M.N. Jansson, J.-O. Lawrence, R.W. Pellikka, N. Shi, J. Thiering, E. Alavere, H. Alibrandi, M.T.S. Arnold, A.M. Aspelund, T. Atwood, L.D. Balmforth, A.J. Ben-Shlomo, Y. Bergmann, S. Biebermann, H. Blakemore, A.I.F. Boes, T. Bornstein, S.R. Brown, M.J. Buchanan, T.A. Busonero, F. Cappuccio, F.P. Cavalcanti-Proenca, C. Chen, Y.-D.I. Chen, C.-M. Clarke, R. Coin, L. Connell, J. Day, I.N.M. Den Heijer, M. Duan, J. Ebrahim, S. Elliott, P. Elosua, R. Eiriksdottir, G. Facheris, M.F. Felix, S.B. Fischer-Posovszky, P. Folsom, A.R. Friedrich, N. Freimer, N.B. Fu, M. Gaget, S. Gejman, P.V. Geus, E.J.C. Gjesing, A.P. Goyette, P. Grasler, J. Greenawalt, D.M. Gudnason, V. Hartikainen, A.-L. Hall, A.S. Havulinna, A.S. Hayward, C. Heath, A.C. Hengstenberg, C. Hicks, A.A. Hinney, A. Homuth, G. Hui, J. Igl, W. Iribarren, C. Jacobs, K.B. Jarick, I. Jewell, E. John, U. Jousilahti, P. Jula, A. Kaakinen, M. Kaplan, L.M. Kathiresan, S. Kettunen, J. Kinnunen, L. Knowles, J.W. Kolcic, I. König, I.R. Koskinen, S. Kovacs, P. Kvaloy, K. Laitinen, J. Lantieri, O. Lanzani, C. Launer, L.J. Lecoeur, C. Lehtimaki, T. Lettre, G. Liu, J. Lokki, M.-L. Lorentzon, M. Luben, R.N. Ludwig, B. Manunta, P. Marek, D. Martin, N.G. McArdle, W.L. McCarthy, A. McKnight, B. Melander, O. Meyre, D. Montgomery, G.W. Mulic, R. Ngwa, J.S. Nelis, M. Neville, M.J. Nyholt, D.R. O'Donnell, C.J. O'Rahilly, S. Ong, K.K. Oostra, B. Pare, G. Parker, A.N. Perola, M. Pichler, I. Pietilainen, K.H. Platou, C.G.P. Polasek, O. Pouta, A. Rafelt, S. Raitakari, O. Rayner, N.W. Ridderstrale, M. Rief, W. Ruokonen, A. Rzehak, P. Salomaa, V. Sanders, A.R. Sandhu, M.S. Sanna, S. Saramies, J. Savolainen, M.J. Scherag, S. Schipf, S. Schreiber, S. Schunkert, H. Silander, K. Sinisalo, J. Siscovick, D.S. Smit, J.H. Soranzo, N. Sovio, U. Stephens, J. Surakka, I. Tammesoo, M.-L. Tardif, J.-C. Teder-Laving, M. Teslovich, T.M. Thompson, J.R. Thomson, B. Tonjes, A. Van Meurs, J.B.J. Van Ommen, G.-J. Vatin, V. Viikari, J. Visvikis-Siest, S. Vitart, V. Vogel, C.I.G. Waite, L.L. Wallaschofski, H. Widen, E. Wiegand, S. Wild, S.H. Willemsen, G. Witte, D.R. Xu, J. Zhang, Q. Zgaga, L. Ziegler, A. Zitting, P. Beilby, J.P. Farooqi, I.S. Hebebrand, J. Huikuri, H.V. James, A.L. Kahonen, M. Levinson, D.F. Macciardi, F. Nieminen, M.S. Ohlsson, C. Palmer, L.J. Ridker, P.M. Stumvoll, M. Beckmann, J.S. Boeing, H. Boomsma, D.I. Caulfield, M.J. Chanock, S.J. Cupples, L.A. Smith, G.D. Erdmann, J. Gronberg, H. Hall, P. Harris, T.B. Hayes, R.B. Heinrich, J. Jarvelin, M.-R. Kaprio, J. Karpe, F. Khaw, K.-T. Kiemeney, L.A. Krude, H. Lawlor, D.A. Metspalu, A. Munroe, P.B. Ouwehand, W.H. Penninx, B.W. Peters, A. Quertermous, T. Reinehr, T. Rissanen, A. Samani, N.J. Schwarz, P.E.H. Shuldiner, A.R. Spector, T.D. Uda, M. Valle, T.T. Wabitsch, M. Waeber, G. Watkins, H. Wright, A.F. Zillikens, M.C. Chatterjee, N. Purcell, S. Schadt, E.E. Visscher, P.M. Assimes, T.L. Borecki, I.B. Deloukas, P. Haritunians, T. Kaplan, R.C. O'Connell, J.R. Peltonen, L. Schlessinger, D. Strachan, D.P. North, K.E. Hirschhorn, J.N. Ingelsson, E. Parts, L. Glass, D. Nisbet, J. Barrett, A. Sekowska, M. Potter, S. Grundberg, E. Small, K. Hedman, A.K. Bataille, V. Bell, J.T. Surdulescu, G. Ingle, C. Nestle, F.O. Di Meglio, P. Min, J.L. Wilk, A. Hammond, C.J. Yang, T.-P. Montgomery, S.B. Zondervan, K.T. Durbin, R. Ahmadi, K. Dermitzakis, E.T. Reilly, M.P. Holm, H. Stewart, A.F.R. Barbalic, M. Aherrahrou, Z. Allayee, H. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Braund, P.S. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Codd, V. Davies, R.W. Cichon, S. Dedoussis, G.V. Demissie, S. Dehghan, A. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. El Mokhtari, N.E. Ellis, S.G. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gulcher, J.R. Halperin, E. Hammond, N. Hazen, S.L. Horne, B.D. Jones, G.T. Jukema, J.W. Kaiser, M.A. Kastelein, J.J.P. Kolovou, G. Laaksonen, R. Lambrechts, D. Leander, K. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Sampietro, M.L. Sandhu, M.S. Schadt, E. Schäfer, A. Schillert, A. Schrezenmeir, J. Schwartz, S.M. Sivananthan, M. Sivapalaratnam, S. Smith, T.B. Snoep, J.D. Spertus, J.A. Stark, K. Stoll, M. Wilson Tang, W.H. Tennstedt, S. Thorgeirsson, G. Tomaszewski, M. Van Rij, A.M. Wells, G.A. Wild, P.S. Willenborg, C. Wright, B.J. Ye, S. Zeller, T. Cambien, F. Goodall, A.H. Marz, W. Blankenberg, S. Roberts, R. McPherson, R. Hopewell, J.C. Parish, S. Offer, A. Bowman, L. Sleight, P. Armitage, J. Peto, R. Collins, R. Chambers, J.C. Ahmed, N. Donnelly, P. Kooner, A.S. Scott, J. Sehmi, J. Zhang, W. Kooner, J. Sabater-Lleal, M. Mälarstig, A. Hellénius, M.-L. Olsson, G. Rust, S. Assmann, G. Seedorf, U. Barlera, S. Tognoni, G. Franzosi, M.G. Linksted, P. Ongen, H. Kyriakou, T. Green, F. Farrall, M. Saleheen, D. Rasheed, A. Zaidi, M. Shah, N. Samuel, M. Mallick, N. Azhar, M. Zaman, K. Samad, A. Ishaq, M. Gardezi, A. Memon, F.-U.-R. Frossard, P. Danesh, J. Östenson, C.-G. Lind, L. Cooper, C.C. Serrano-Ríos, M. Ferrannini, E. Forsen, T.J. Pattou, F. Langenberg, C. Hamsten, A. Florez, J.C.

Subjects
endocrine system, endocrine system diseases, nutritional and metabolic diseases
Abstract

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. © 2011 by the American Diabetes Association.

Published
2011

13. Effect of atorvastatin on C-reactive protein and benefits for cardiovascular disease in patients with type 2 diabetes: analyses from the Collaborative Atorvastatin Diabetes Trial

Author

Soedamah-Muthu, S.S., Livingstone, S.J., Charlton-Menys, V., Betteridge, D.J., Hitman, G.A., Neil, H.A.W., Bao, W., DeMicco, D.A., Preston, G.M., Fuller, J.H., Stehouwer, C.D.A., Schalkwijk, C.G., Durrington, P.N., Colhoun, H.M., Soedamah-Muthu, S.S., Livingstone, S.J., Charlton-Menys, V., Betteridge, D.J., Hitman, G.A., Neil, H.A.W., Bao, W., DeMicco, D.A., Preston, G.M., Fuller, J.H., Stehouwer, C.D.A., Schalkwijk, C.G., Durrington, P.N., and Colhoun, H.M.

Abstract

Aims/hypothesis We investigated whether atorvastatin 10 mg daily lowered C-reactive protein (CRP) and whether the effects of atorvastatin on cardiovascular disease (CVD) varied by achieved levels of CRP and LDL-cholesterol. Methods CRP levels were measured at baseline and 1 year after randomisation to atorvastatin in 2,322 patients with type 2 diabetes (40–75 years, 69% males) in a secondary analysis of the Collaborative Atorvastatin Diabetes Study, a randomised placebo-controlled trial. We used Cox regression models to test the effects on subsequent CVD events (n¿=¿147) of CRP and LDL-cholesterol lowering at 1 year. Results After 1 year, the atorvastatin arm showed a net CRP lowering of 32% (95% CI -40%, -22%) compared with placebo. The CRP response was highly variable, with 45% of those on atorvastatin having no decrease in CRP (median [interquartile range, IQR] per cent change -9.8% [-57%, 115%]). The LDL-cholesterol response was less variable, with a median (IQR) within-person per cent change of -41% (-51%, -31%). Baseline CRP did not predict CVD over 3.8 years of follow-up (HRper SD log 0.89 [95% CI 0.75, 1.06]), whereas baseline LDL-cholesterol predicted CVD (HRper SD 1.21 [95% CI 1.02, 1.44]), as did on-treatment LDL-cholesterol. There was no significant difference in the reduction in CVD by atorvastatin, with above median (HR 0.57) or below median (HR 0.52) change in CRP or change in LDL-cholesterol (HR 0.61 vs 0.50). Conclusions/interpretation CRP was not a strong predictor of CVD. Statin efficacy did not vary with achieved CRP despite considerable variability in CRP response. The use of CRP as an indicator of efficacy of statin therapy on CVD risk in patients with type 2 diabetes is not supported by these data.

Published
2015

14. Role of the mitochondrial DNA 16184-16193 poly-C tract in type 2 diabetes

Author

Chinnery, P.F., Elliott, H.R., Patel, S., Lambert, C., Keers, S.M., Durham, S.E., McCarthy, M.I., Hitman, G.A., Hattersley, A.T., and Walker, M.

Subjects
Type 2 diabetes -- Research, Type 2 diabetes -- Care and treatment, Type 2 diabetes -- Analysis, Type 2 diabetes -- Statistics
Published
2005

16. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Author

Postmus, D. (Douwe), Trompet, S. (Stella), Deshmukh, H. (Harshal), Barnes, M.J. (Michael), Li, X. (Xiaohui), Warren, H. (Helen), Chasman, D.I. (Daniel), Zhou, K. (Kaixin), Arsenault, B.J. (Benoit J.), Donnelly, L.A. (Louise), Wiggins, K.L. (Kerri), Avery, C.L., Griffin, P. (Paula), Feng, Q. (Qiping), Taylor, K.D. (Kent), Li, G. (Guo), Evans, D.S. (Daniel), Smith, A.V. (Davey), Keyser, C.E. (Catherina Elisabeth) de, Johnson, A.D. (Andrew), Craen, A.J. (Anton) de, Stott, D.J. (David. J.), Buckley, B.M. (Brendan M.), Ford, I., Westendorp, R.G.J. (Rudi), Slagboom, P.E. (Eline), Sattar, N. (Naveed), Munroe, P. (Patricia), Sever, P. (Peter), Poulter, N.R. (Neil), Stanton, A. (Alice), Shields, D.C. (Denis C.), O'Brien, E. (Eoin), Shaw-Hawkins, S. (Sue), Chen, Y.-D.I. (Ida), Nickerson, D.A. (Deborah), Smith, J.D. (Joshua D.), Dubé, G.P. (Gregory), Boekholdt, S.M. (Matthijs), Hovingh, G.K. (Kees), Kastelein, J.J.P. (John), Mckeigue, P.M. (Paul), Betteridge, J. (John), Neil, A. (Andrew), Durrington, P.N. (Paul), Doney, A.S.F. (Alex), Carr, F. (Fiona), Morris, A.D. (Andrew), McCarthy, M.I. (Mark), Groop, L. (Leif), Ahlqvist, E. (Emma), Barroso, I.E. (Inês), Blackwell, K.L. (Kimberly), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panagiotis), Duncanson, A. (Audrey), Jankowski, J.A. (Janusz Antoni), Markus, H.S. (Hugh), Mathew, C.G. (Christopher G.), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Viswanathan, A.C. (Ananth), Wood, N.W. (Nicholas), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Donnelly, P. (Peter), Langford, C. (Cordelia), Hunt, S.E. (Sarah), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, M. (Matthew), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Bis, J.C. (Joshua), Rice, K.M. (Kenneth), Smith, N.L. (Nicholas), Lumley, T. (Thomas), Whitsel, E.A. (Eric), Stürmer, T., Boerwinkle, E.A. (Eric), Ngwa, J.S., O'Donnell, C.J. (Christopher J.), Vasan, R.S. (Ramachandran Srini), Wei, W.-Q. (Wei-Qi), Wilke, R.A. (Russell A.), Liu, C.-T. (Ching-Ti), Sun, F. (Fangui), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Post, W. (Wendy), Sotoodehnia, N. (Nona), Arnold, A.M. (Alice), Stafford, J.M. (Jeanette M.), Ding, J. (Jingzhong), Herrington, D.M. (David), Kritchevsky, S.B. (Stephen), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Harris, T.B. (Tamara), Chu, A.Y. (Audrey), Giulianini, F. (Franco), MacFadyen, J.G. (Jean G.), Barratt, B.J. (Bryan J.), Nyberg, F. (Fredrik), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Emilsson, V. (Valur), Franco, O.H. (Oscar), Ridker, P.M. (Paul), Gudnason, V. (Vilmundur), Liu, Y. (YongMei), Denny, J.C. (Joshua C.), Ballantyne, C. (Christie), Rotter, J.I. (Jerome I.), Cupples, L.A. (Adrienne), Psaty, B.M. (Bruce), Tardif, J.-C. (Jean-Claude), Colhoun, H.M. (H.), Hitman, G.A. (Graham), Krauss, R.M. (Ronald), Jukema, J.W. (Jan Wouter), Caulfield, M. (Mark), Postmus, D. (Douwe), Trompet, S. (Stella), Deshmukh, H. (Harshal), Barnes, M.J. (Michael), Li, X. (Xiaohui), Warren, H. (Helen), Chasman, D.I. (Daniel), Zhou, K. (Kaixin), Arsenault, B.J. (Benoit J.), Donnelly, L.A. (Louise), Wiggins, K.L. (Kerri), Avery, C.L., Griffin, P. (Paula), Feng, Q. (Qiping), Taylor, K.D. (Kent), Li, G. (Guo), Evans, D.S. (Daniel), Smith, A.V. (Davey), Keyser, C.E. (Catherina Elisabeth) de, Johnson, A.D. (Andrew), Craen, A.J. (Anton) de, Stott, D.J. (David. J.), Buckley, B.M. (Brendan M.), Ford, I., Westendorp, R.G.J. (Rudi), Slagboom, P.E. (Eline), Sattar, N. (Naveed), Munroe, P. (Patricia), Sever, P. (Peter), Poulter, N.R. (Neil), Stanton, A. (Alice), Shields, D.C. (Denis C.), O'Brien, E. (Eoin), Shaw-Hawkins, S. (Sue), Chen, Y.-D.I. (Ida), Nickerson, D.A. (Deborah), Smith, J.D. (Joshua D.), Dubé, G.P. (Gregory), Boekholdt, S.M. (Matthijs), Hovingh, G.K. (Kees), Kastelein, J.J.P. (John), Mckeigue, P.M. (Paul), Betteridge, J. (John), Neil, A. (Andrew), Durrington, P.N. (Paul), Doney, A.S.F. (Alex), Carr, F. (Fiona), Morris, A.D. (Andrew), McCarthy, M.I. (Mark), Groop, L. (Leif), Ahlqvist, E. (Emma), Barroso, I.E. (Inês), Blackwell, K.L. (Kimberly), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panagiotis), Duncanson, A. (Audrey), Jankowski, J.A. (Janusz Antoni), Markus, H.S. (Hugh), Mathew, C.G. (Christopher G.), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Viswanathan, A.C. (Ananth), Wood, N.W. (Nicholas), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Donnelly, P. (Peter), Langford, C. (Cordelia), Hunt, S.E. (Sarah), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, M. (Matthew), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Bis, J.C. (Joshua), Rice, K.M. (Kenneth), Smith, N.L. (Nicholas), Lumley, T. (Thomas), Whitsel, E.A. (Eric), Stürmer, T., Boerwinkle, E.A. (Eric), Ngwa, J.S., O'Donnell, C.J. (Christopher J.), Vasan, R.S. (Ramachandran Srini), Wei, W.-Q. (Wei-Qi), Wilke, R.A. (Russell A.), Liu, C.-T. (Ching-Ti), Sun, F. (Fangui), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Post, W. (Wendy), Sotoodehnia, N. (Nona), Arnold, A.M. (Alice), Stafford, J.M. (Jeanette M.), Ding, J. (Jingzhong), Herrington, D.M. (David), Kritchevsky, S.B. (Stephen), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Harris, T.B. (Tamara), Chu, A.Y. (Audrey), Giulianini, F. (Franco), MacFadyen, J.G. (Jean G.), Barratt, B.J. (Bryan J.), Nyberg, F. (Fredrik), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Emilsson, V. (Valur), Franco, O.H. (Oscar), Ridker, P.M. (Paul), Gudnason, V. (Vilmundur), Liu, Y. (YongMei), Denny, J.C. (Joshua C.), Ballantyne, C. (Christie), Rotter, J.I. (Jerome I.), Cupples, L.A. (Adrienne), Psaty, B.M. (Bruce), Tardif, J.-C. (Jean-Claude), Colhoun, H.M. (H.), Hitman, G.A. (Graham), Krauss, R.M. (Ronald), Jukema, J.W. (Jan Wouter), and Caulfield, M. (Mark)

Published
2014
Full Text
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17. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Author

Albrechtsen, Anders, Grarup, Niels, Li, Y., Sparsø, Thomas Hempel, Tian, G., Cao, H., Jiang, T., Kim, S.Y., Korneliussen, Thorfinn Sand, Li, Q., Nie, C., Wu, R., Skotte, Line, Morris, A.P., Ladenvall, C., Cauchi, S., Stancáková, A., Andersen, G., Astrup, Arne, Banasik, Karina, Bennett, A.J., Bolund, Lars, Charpentier, G., Chen, Y., Dekker, J.M., Doney, A.S.F., Dorkhan, M., Forsen, T., Frayling, T.M., Groves, C.J., Gui, Y., Hallmans, G., Hattersley, A.T., He, K., Hitman, G.A., Holmkvist, J., Huang, S., Jiang, H., Jin, X., Justesen, Johanne Marie, Kristiansen, Karsten, Kuusisto, J., Lajer, M., Lantieri, O., Li, W., Liang, H., Liao, Q., Liu, X., Ma, T., Ma, X., Manijak, M.P., Marre, M., Mokrosinski, Jacek, Morris, A.D., Mu, B., Nielsen, A.A., Nijpels, G., Nilsson, P., Palmer, C.N.A., Rayner, N.W., Renström, F., Ribel-Madsen, Rasmus, Robertson, N., Rolandsson, O., Rossing, P., Schwartz, Thue W., Slagboom, P.E., Sterner, M., Tang, M., Tarnow, L., Tuomi, T., Van't Riet, E., van Leeuwen, N., Varga, T.V., Vestmar, Marie Aare, Walker, M., Wang, B., Wang, Y., Wu, H., Xi, F., Yengo, L., Yu, C., Zhang, X., Zhang, J., Zhang, Q., Zhang, W., Zheng, H., Zhou, Y., Altshuler, D., 't Hart, L.M., Franks, P.W., Balkau, B., Froguel, P., McCarthy, M.I., Laakso, M., Groop, L., Christensen, C., Brandslund, I., Lauritzen, T., Witte, D.R., Linneberg, A., Jørgensen, Torben, Hansen, Torben, Wang, Jun, Nielsen, Rasmus, Pedersen, Oluf, Albrechtsen, Anders, Grarup, Niels, Li, Y., Sparsø, Thomas Hempel, Tian, G., Cao, H., Jiang, T., Kim, S.Y., Korneliussen, Thorfinn Sand, Li, Q., Nie, C., Wu, R., Skotte, Line, Morris, A.P., Ladenvall, C., Cauchi, S., Stancáková, A., Andersen, G., Astrup, Arne, Banasik, Karina, Bennett, A.J., Bolund, Lars, Charpentier, G., Chen, Y., Dekker, J.M., Doney, A.S.F., Dorkhan, M., Forsen, T., Frayling, T.M., Groves, C.J., Gui, Y., Hallmans, G., Hattersley, A.T., He, K., Hitman, G.A., Holmkvist, J., Huang, S., Jiang, H., Jin, X., Justesen, Johanne Marie, Kristiansen, Karsten, Kuusisto, J., Lajer, M., Lantieri, O., Li, W., Liang, H., Liao, Q., Liu, X., Ma, T., Ma, X., Manijak, M.P., Marre, M., Mokrosinski, Jacek, Morris, A.D., Mu, B., Nielsen, A.A., Nijpels, G., Nilsson, P., Palmer, C.N.A., Rayner, N.W., Renström, F., Ribel-Madsen, Rasmus, Robertson, N., Rolandsson, O., Rossing, P., Schwartz, Thue W., Slagboom, P.E., Sterner, M., Tang, M., Tarnow, L., Tuomi, T., Van't Riet, E., van Leeuwen, N., Varga, T.V., Vestmar, Marie Aare, Walker, M., Wang, B., Wang, Y., Wu, H., Xi, F., Yengo, L., Yu, C., Zhang, X., Zhang, J., Zhang, Q., Zhang, W., Zheng, H., Zhou, Y., Altshuler, D., 't Hart, L.M., Franks, P.W., Balkau, B., Froguel, P., McCarthy, M.I., Laakso, M., Groop, L., Christensen, C., Brandslund, I., Lauritzen, T., Witte, D.R., Linneberg, A., Jørgensen, Torben, Hansen, Torben, Wang, Jun, Nielsen, Rasmus, and Pedersen, Oluf

Abstract

AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p¿1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p¿=¿8.5¿×¿10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p¿=¿1.2¿×¿10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p¿=¿8.2¿×¿10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

Published
2013

18. A gene variant near ATM is significantly associated with metformin treatment response In type 2 diabetes: A replication and meta-analysis of five cohorts

Author

Leeuwen, N. van, Nijpels, M.G.A.A.M. (Giel), Becker, M.L. (Matthijs), Deshmukh, H. (Harshal), Zhou, K. (K.), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Hofman, A. (Albert), Riet, E. (Esther) van 't, Palmer, C.N.A. (Colin), Guigas, B. (B.), Slagboom, P.E. (Eline), Durrington, P.N. (Paul), Calle, R.A. (R.), Neil, A. (A.), Hitman, G.A. (Graham), Livingstone, E., Colhoun, H.M. (H.), Holman, R.R. (R.), McCarthy, M.I. (Mark), Dekker, J.M. (Jacqueline), Hart, L.M. (Leen) 't, Pearson, E. (Ewan), Leeuwen, N. van, Nijpels, M.G.A.A.M. (Giel), Becker, M.L. (Matthijs), Deshmukh, H. (Harshal), Zhou, K. (K.), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Hofman, A. (Albert), Riet, E. (Esther) van 't, Palmer, C.N.A. (Colin), Guigas, B. (B.), Slagboom, P.E. (Eline), Durrington, P.N. (Paul), Calle, R.A. (R.), Neil, A. (A.), Hitman, G.A. (Graham), Livingstone, E., Colhoun, H.M. (H.), Holman, R.R. (R.), McCarthy, M.I. (Mark), Dekker, J.M. (Jacqueline), Hart, L.M. (Leen) 't, and Pearson, E. (Ewan)

Abstract

_Aims/hypothesis:_ In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. _Methods:_ Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n=929) and the Rotterdam Study (n=182) from the Netherlands, and the CARDS Trial (n=254) from the UK were genotyped for rs11212617 and tested for an association with both HbA1c reduction and treatment success, defined as the ability to reach the treatment target of an HbA1c ≤7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. _Results:_ In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p=0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p=0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p=0.016 and OR 1.25, 95% CI 1.33, 1.38, p=7.8×10-6, respectively). _ Conclusions/inter

Published
2012
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19. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

Author

DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Manning, A.K., Hivert, M.F., Scott, R.A., Grimsby, J.L., Bouatia-Naji, N., Chen, H., Rybin, D., Liu, C.T., Bielak, L.F., Barnes, D., Cadby, G., Hottenga, J.J., Ingelsson, E., Johnson, T., Kanoni, S., Ladenvall, C., Lagou, V., Lahti, J., Lecoeur, C., Liu, Y., Martinez-Larrad, M.T., Montasser, M.E., Rasmussen-Torvik, L.J., Salo, P., Sattar, N., Shungin, D., Strawbridge, R.J., Tanaka, T., An, P., de Andrade, M., Andrews, J.S., Aspelund, T., Atalay, M., Aulchenko, Y., Bandinelli, S., Beckmann, J.S., Beilby, J.P., Bellis, C., Blangero, J., Boban, M., Boomsma, D.I., Borecki, I.B., Böttcher, Y., Bouchard, C., Brunner, E., Budimir, D., Carlson, O., Clarke, R., Corbatón-Anchuelo, A., Couper, D., de Faire, U., Dedoussis, G.V., Dimitriou, M., Egan, J.M., Eiriksdottir, G., Eriksson, J.G., Eury, E., Ferrucci, L., Ford, I., Forouhi, N.G., Franzosi, M.G., Franks, P.W., Galan, P., de Geus, E., Gigante, B., Glazer, N.L., Goel, A., Gudnason, V., Hallmans, G., Hamsten, A., Hansson, O., Harris, T.B., Hayward, C., Heath, S., Hercberg, S., Hicks, A.A., Hingorani, A., Hui, J., Hung, J., Jarvelin, M.R., Jhun, M.A., Johnson, P.C., Jukema, J.W., Jula, A., Kaprio, J., Kardia, S.L., Keinanen-Kiukaanniemi, S., Kivimaki, M., Kolcic, I., Kovacs, P., Kumari, M., Kyvik, K.O., Lakka, T., Lannfelt, L., Lathrop, G.M., Launer, L.J., Leander, K., Li, G., Lind, L., Lindstrom, J., Lobbens, S., Loos, R.J., Luan, J., Mägi, R., Magnusson, P.K., Marmot, M., Meneton, P., Mooser, V., Miljkovic, I., O'Connell, J., Ong, K.K., Oostra, B.A., Palmer, L.J., Palotie, A., Peden, J.F., Pedersen, N.L., Pehlic, M., Peltonen, L., Penninx, B., Pericic, M., Perola, M., Perusse, L., Peyser, P.A., Polasek, O., Province, M.A., Räikkönen, K., Rauramaa, R., Rehnberg, E., Rice, K., Rotter, J.I., Ruokonen, A., Saaristo, T., Sabater-Lleal, M., Salomaa, V., Savage, D.B., Schwarz, P., Seedorf, U., Sennblad, B., Serrano-Rios, M., Shuldiner, A.R., Sijbrands, E.J., Siscovick, D.S., Smit, J.H., Smith, N.L., Smith, A.V., Stančáková, A., Stirrups, K., Stumvoll, M., Sun, Y.V., Tönjes, A., Trompet, S., Uitterlinden, A.G., Uusitupa, M., Vikström, M., Vitart, V., Vohl, M.C., Vollenweider, P., Waeber, G., Waterworth, D.M., Watkins, H., Wheeler, E., Widen, E., Wild, S.H., Willems, S.M., Willemsen, G., Witteman, J.C., Wright, A.F., Yaghootkar, H., Zelenika, D., Zemunik, T., Zgaga, L., DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Manning, A.K., Hivert, M.F., Scott, R.A., Grimsby, J.L., Bouatia-Naji, N., Chen, H., Rybin, D., Liu, C.T., Bielak, L.F., Barnes, D., Cadby, G., Hottenga, J.J., Ingelsson, E., Johnson, T., Kanoni, S., Ladenvall, C., Lagou, V., Lahti, J., Lecoeur, C., Liu, Y., Martinez-Larrad, M.T., Montasser, M.E., Rasmussen-Torvik, L.J., Salo, P., Sattar, N., Shungin, D., Strawbridge, R.J., Tanaka, T., An, P., de Andrade, M., Andrews, J.S., Aspelund, T., Atalay, M., Aulchenko, Y., Bandinelli, S., Beckmann, J.S., Beilby, J.P., Bellis, C., Blangero, J., Boban, M., Boomsma, D.I., Borecki, I.B., Böttcher, Y., Bouchard, C., Brunner, E., Budimir, D., Carlson, O., Clarke, R., Corbatón-Anchuelo, A., Couper, D., de Faire, U., Dedoussis, G.V., Dimitriou, M., Egan, J.M., Eiriksdottir, G., Eriksson, J.G., Eury, E., Ferrucci, L., Ford, I., Forouhi, N.G., Franzosi, M.G., Franks, P.W., Galan, P., de Geus, E., Gigante, B., Glazer, N.L., Goel, A., Gudnason, V., Hallmans, G., Hamsten, A., Hansson, O., Harris, T.B., Hayward, C., Heath, S., Hercberg, S., Hicks, A.A., Hingorani, A., Hui, J., Hung, J., Jarvelin, M.R., Jhun, M.A., Johnson, P.C., Jukema, J.W., Jula, A., Kaprio, J., Kardia, S.L., Keinanen-Kiukaanniemi, S., Kivimaki, M., Kolcic, I., Kovacs, P., Kumari, M., Kyvik, K.O., Lakka, T., Lannfelt, L., Lathrop, G.M., Launer, L.J., Leander, K., Li, G., Lind, L., Lindstrom, J., Lobbens, S., Loos, R.J., Luan, J., Mägi, R., Magnusson, P.K., Marmot, M., Meneton, P., Mooser, V., Miljkovic, I., O'Connell, J., Ong, K.K., Oostra, B.A., Palmer, L.J., Palotie, A., Peden, J.F., Pedersen, N.L., Pehlic, M., Peltonen, L., Penninx, B., Pericic, M., Perola, M., Perusse, L., Peyser, P.A., Polasek, O., Province, M.A., Räikkönen, K., Rauramaa, R., Rehnberg, E., Rice, K., Rotter, J.I., Ruokonen, A., Saaristo, T., Sabater-Lleal, M., Salomaa, V., Savage, D.B., Schwarz, P., Seedorf, U., Sennblad, B., Serrano-Rios, M., Shuldiner, A.R., Sijbrands, E.J., Siscovick, D.S., Smit, J.H., Smith, N.L., Smith, A.V., Stančáková, A., Stirrups, K., Stumvoll, M., Sun, Y.V., Tönjes, A., Trompet, S., Uitterlinden, A.G., Uusitupa, M., Vikström, M., Vitart, V., Vohl, M.C., Vollenweider, P., Waeber, G., Waterworth, D.M., Watkins, H., Wheeler, E., Widen, E., Wild, S.H., Willems, S.M., Willemsen, G., Witteman, J.C., Wright, A.F., Yaghootkar, H., Zelenika, D., Zemunik, T., and Zgaga, L.

Abstract

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-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 × 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

20. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author

DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Dastani, Z., Hivert, M.F., Timpson, N., Perry, J.R., Yuan, X., Scott, R.A., Henneman, P., Heid, I.M., Kizer, J.R., Lyytikäinen, L.P., Fuchsberger, C., Tanaka, T., Morris, A.P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, J.S., Uh, H.W., Wu, Y., Bidulescu, A., Rasmussen-Torvik, L.J., Greenwood, C.M., Ladouceur, M., Grimsby, J., Manning, A.K., Liu, C.T., Kooner, J., Mooser, V.E., Vollenweider, P., Kapur, K.A., Chambers, J., Wareham, N.J., Langenberg, C., Frants, R., Willems-Vandijk, K., Oostra, B.A., Willems, S.M., Lamina, C., Winkler, T.W., Psaty, B.M., Tracy, R.P., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, P.P., Evans, D.M., St Pourcain, B., Sattar, N., Wood, A.R., Bandinelli, S., Carlson, O.D., Egan, J.M., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, M.L., Loo, B.M., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, H.E., Deloukas, P., Katsareli, E., Couper, D.J., Duncan, B.B., Kloppenburg, M., Adair, L.S., Borja, J.B., Wilson, J.G., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, T.M., Allison, M.A., Redline, S., Buxbaum, S.G., Mohlke, K.L., Meulenbelt, I., Ballantyne, C.M., Dedoussis, G.V., Hu, F.B., Liu, Y., Paulweber, B., Spector, T.D., Slagboom, P.E., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, J.C., Salomaa, V., Eriksson, J.G., Frayling, T.M., Hicks, A.A., Lehtimäki, T., Smith, G.D., Siscovick, D.S., Kronenberg, F., van Duijn, C., Loos, R.J., Waterworth, D.M., Meigs, J.B., Dupuis, J., Richards, J.B., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Hofmann, O.M., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C.M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Morris, A.D., Palmer, C.N., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Pedersen, O., Barroso, I., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., McCarthy, M.I., Soranzo, N., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Mägi, R., Randall, J., Elliott, P., Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., 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Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., Mahley, R., Mangino, M., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Mukherjee, S., Naitza, S., Neville, M.J., Orrù, M., Pakyz, R., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Pedersen, N.L., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Province, M.A., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Seedorf, U., Sharp, S.J., Shields, B., Sigurðsson, G., Sijbrands, E.J., Silveira, A., Simpson, L., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tönjes, A., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Walley, A., Ward, K.L., Watkins, H., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., Borecki, I.B., Meneton, P., Magnusson, P.K., Nathan, D.M., 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Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Published
2012

21. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Author

Voight, B.F. (Benjamin), Scott, L.J. (Laura), Steinthorsdottir, V. (Valgerdur), Morris, A.D. (Andrew), Dina, C. (Christian), Welch, R.P. (Ryan), Zeggini, E. (Eleftheria), Huth, C. (Cornelia), Aulchenko, Y.S. (Yurii), Thorleifsson, G. (Gudmar), McCulloch, L.J. (Laura), Ferreira, T. (Teresa), Grallert, H. (Harald), Amin, N. (Najaf), Wu, G. (Guanming), Willer, C.J. (Cristen), Raychaudhuri, S. (Soumya), McCarroll, S.A. (Steven), Langenberg, C. (Claudia), Hofmann, O.M. (Oliver), Dupuis, J. (Josée), Qi, L. (Lu), Segrè, A.V. (Ayellet), Hoek, M. (Mandy) van, Navarro, P. (Pau), Ardlie, K.G. (Kristin), Balkau, B. (Beverley), Benediktsson, R. (Rafn), Bennett, A.J. (Amanda), Blagieva, R. (Roza), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Boström, K.B. (Kristina Bengtsson), Bravenboer, B. (Bert), Bumpstead, S. (Suzannah), Burtt, N.P. (Noël), Charpentier, G. (Guillaume), Chines, P.S. (Peter), Cornelis, M. (Marilyn), Couper, D.J. (David), Crawford, G. (Gabe), Doney, A.S.F. (Alex), Elliott, K.S. (Katherine), Erdos, M.R. (Michael), Fox, C.S. (Caroline), Franklin, C.S. (Christopher), Ganser, M. (Martha), Gieger, C. (Christian), Grarup, N. (Niels), Green, T. (Todd), Griffin, S. (Simon), Groves, C.J. (Christopher), Guiducci, C. (Candace), Hadjadj, S. (Samy), Hassanali, N. (Neelam), Herder, C. (Christian), Isomaa, B. (Bo), Jackson, A.U. (Anne), Johnson, P.R.V. (Paul), Jørgensen, T. (Torben), Kao, W.H.L. (Wen), Klopp, N. (Norman), Kong, A. (Augustine), Kraft, P. (Peter), Kuusisto, J. (Johanna), Lauritzen, T. (Torsten), Li, M. (Man), Lieverse, A.G. (Aloysius), Lindgren, C.M. (Cecilia), Lyssenko, V. (Valeriya), Marre, M. (Michel), Meitinger, T. (Thomas), Midthjell, K. (Kristian), Morken, M.A. (Mario), Narisu, N. (Narisu), Nilsson, P. (Peter), Owen, K.R. (Katharine), Payne, F. (Felicity), Perry, J.R.B. (John), Petersen, A.K., Platou, C. (Carl), Proença, C. (Christine), Prokopenko, I. (Inga), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Robertson, N.R. (Neil), Rocheleau, G. (Ghislain), Roden, M. (Michael), Sampson, M.J. (Michael), Saxena, R. (Richa), Shields, B.M. (Beverley), Shrader, P. (Peter), Sigurdsson, G. (Gunnar), Sparsø, T. (Thomas), Strassburger, K. (Klaus), Stringham, H.M. (Heather), Sun, Q. (Qi), Swift, A.J. (Amy), Thorand, B. (Barbara), Tichet, J. (Jean), Tuomi, T. (Tiinamaija), Dam, R.M. (Rob) van, Haeften, T.W. (Timon) van, Herpt, T.W. (Thijs) van, Vliet-Ostaptchouk, J.V. (Jana) van, Walters, G.B. (Bragi), Weedon, M.N. (Michael), Wijmenga, C. (Cisca), Witteman, J.C.M. (Jacqueline), Bergman, R.N. (Richard), Cauchi, S. (Stephane), Collins, F.S. (Francis), Gloyn, A.L. (Anna), Gyllensten, U. (Ulf), Hansen, T. (Torben), Hide, W.A. (Winston), Hitman, G.A. (Graham), Hofman, A. (Albert), Hunter, D. (David), Hveem, K. (Kristian), Laakso, M. (Markku), Mohlke, K.L. (Karen), Palmer, C.N.A. (Colin), Pramstaller, P.P. (Peter Paul), Rudan, I. (Igor), Sijbrands, E.J.G. (Eric), Stein, L.D. (Lincoln), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Walker, M. (Mark), Wareham, N.J. (Nick), Abecasis, G.R. (Gonçalo), Boehm, B.O. (Bernhard), Campbell, H. (Harry), Daly, M.J. (Mark), Hattersley, A.T. (Andrew), Hu, F.B. (Frank), Meigs, J.B. (James), Pankow, J.S. (James), Pedersen, O. (Oluf), Wichmann, H.E. (Erich), Barroso, I.E. (Inês), Florez, J.C. (Jose), Frayling, T.M. (Timothy), Groop, L. (Leif), Sladek, R. (Rob), Thorsteinsdottir, U. (Unnur), Wilson, J.F. (James), Illig, T. (Thomas), Froguel, P. (Philippe), Tikka-Kleemola, P. (Päivi), Zwart, J-A. (John-Anker), Altshuler, D. (David), Boehnke, M. (Michael), McCarthy, M.I. (Mark), Watanabe, R.M. (Richard), Voight, B.F. (Benjamin), Scott, L.J. (Laura), Steinthorsdottir, V. (Valgerdur), Morris, A.D. (Andrew), Dina, C. (Christian), Welch, R.P. (Ryan), Zeggini, E. (Eleftheria), Huth, C. (Cornelia), Aulchenko, Y.S. (Yurii), Thorleifsson, G. (Gudmar), McCulloch, L.J. (Laura), Ferreira, T. (Teresa), Grallert, H. (Harald), Amin, N. (Najaf), Wu, G. (Guanming), Willer, C.J. (Cristen), Raychaudhuri, S. (Soumya), McCarroll, S.A. (Steven), Langenberg, C. (Claudia), Hofmann, O.M. (Oliver), Dupuis, J. (Josée), Qi, L. (Lu), Segrè, A.V. (Ayellet), Hoek, M. (Mandy) van, Navarro, P. (Pau), Ardlie, K.G. (Kristin), Balkau, B. (Beverley), Benediktsson, R. (Rafn), Bennett, A.J. (Amanda), Blagieva, R. (Roza), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Boström, K.B. (Kristina Bengtsson), Bravenboer, B. (Bert), Bumpstead, S. (Suzannah), Burtt, N.P. (Noël), Charpentier, G. (Guillaume), Chines, P.S. (Peter), Cornelis, M. (Marilyn), Couper, D.J. (David), Crawford, G. (Gabe), Doney, A.S.F. (Alex), Elliott, K.S. (Katherine), Erdos, M.R. (Michael), Fox, C.S. (Caroline), Franklin, C.S. (Christopher), Ganser, M. (Martha), Gieger, C. (Christian), Grarup, N. (Niels), Green, T. (Todd), Griffin, S. (Simon), Groves, C.J. (Christopher), Guiducci, C. (Candace), Hadjadj, S. (Samy), Hassanali, N. (Neelam), Herder, C. (Christian), Isomaa, B. (Bo), Jackson, A.U. (Anne), Johnson, P.R.V. (Paul), Jørgensen, T. (Torben), Kao, W.H.L. (Wen), Klopp, N. (Norman), Kong, A. (Augustine), Kraft, P. (Peter), Kuusisto, J. (Johanna), Lauritzen, T. (Torsten), Li, M. (Man), Lieverse, A.G. (Aloysius), Lindgren, C.M. (Cecilia), Lyssenko, V. (Valeriya), Marre, M. (Michel), Meitinger, T. (Thomas), Midthjell, K. (Kristian), Morken, M.A. (Mario), Narisu, N. (Narisu), Nilsson, P. (Peter), Owen, K.R. (Katharine), Payne, F. (Felicity), Perry, J.R.B. (John), Petersen, A.K., Platou, C. (Carl), Proença, C. (Christine), Prokopenko, I. (Inga), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Robertson, N.R. (Neil), Rocheleau, G. (Ghislain), Roden, M. (Michael), Sampson, M.J. (Michael), Saxena, R. (Richa), Shields, B.M. (Beverley), Shrader, P. (Peter), Sigurdsson, G. (Gunnar), Sparsø, T. (Thomas), Strassburger, K. (Klaus), Stringham, H.M. (Heather), Sun, Q. (Qi), Swift, A.J. (Amy), Thorand, B. (Barbara), Tichet, J. (Jean), Tuomi, T. (Tiinamaija), Dam, R.M. (Rob) van, Haeften, T.W. (Timon) van, Herpt, T.W. (Thijs) van, Vliet-Ostaptchouk, J.V. (Jana) van, Walters, G.B. (Bragi), Weedon, M.N. (Michael), Wijmenga, C. (Cisca), Witteman, J.C.M. (Jacqueline), Bergman, R.N. (Richard), Cauchi, S. (Stephane), Collins, F.S. (Francis), Gloyn, A.L. (Anna), Gyllensten, U. (Ulf), Hansen, T. (Torben), Hide, W.A. (Winston), Hitman, G.A. (Graham), Hofman, A. (Albert), Hunter, D. (David), Hveem, K. (Kristian), Laakso, M. (Markku), Mohlke, K.L. (Karen), Palmer, C.N.A. (Colin), Pramstaller, P.P. (Peter Paul), Rudan, I. (Igor), Sijbrands, E.J.G. (Eric), Stein, L.D. (Lincoln), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Walker, M. (Mark), Wareham, N.J. (Nick), Abecasis, G.R. (Gonçalo), Boehm, B.O. (Bernhard), Campbell, H. (Harry), Daly, M.J. (Mark), Hattersley, A.T. (Andrew), Hu, F.B. (Frank), Meigs, J.B. (James), Pankow, J.S. (James), Pedersen, O. (Oluf), Wichmann, H.E. (Erich), Barroso, I.E. (Inês), Florez, J.C. (Jose), Frayling, T.M. (Timothy), Groop, L. (Leif), Sladek, R. (Rob), Thorsteinsdottir, U. (Unnur), Wilson, J.F. (James), Illig, T. (Thomas), Froguel, P. (Philippe), Tikka-Kleemola, P. (Päivi), Zwart, J-A. (John-Anker), Altshuler, D. (David), Boehnke, M. (Michael), McCarthy, M.I. (Mark), and Watanabe, R.M. (Richard)

Abstract

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap

Published
2010
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38. Apolipoprotein D Gene Polymorphism: A New Genetic Marker for Type 2 Diabetic Subjects in Nauru and South India

Author

Baker, W.A., primary, Hitman, G.A., additional, Hawrami, K., additional, McCarthy, M.I., additional, Riikonen, A., additional, Tuomilehto-Wolf, E., additional, Nissinen, A., additional, Tuomilehto, J., additional, Mohan, V., additional, Viswanathan, M., additional, Snehalatha, C., additional, Ramachandran, A., additional, Dowse, G.K., additional, Zimmet, P., additional, and Serjeantsona, S.W., additional

Published
1994
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45. Allelic variants in genes associated with hereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis.

Author

Aganna, E., Hawkins, P.N., Ozen, S., Pettersson, T., Bybee, A., McKee, S. A., Lachmann, H.J., Karenko, L., Ranki, A., Bakkaloglu, A., Besbas, N., Topaloglu, R., Hoffman, H.M., Hitman, G.A., Woo, P., and McDermott, M. F.

Subjects
HUMAN genetic variation, GENETIC disorders, FEVER, AMYLOIDOSIS, GENES, GENETIC mutation
Abstract

We investigated the hypothesis that low-penetrance mutations in genes (TNFRSF1A, MEFV and NALP3/CIAS1) associated with hereditary periodic fever syndromes (HPFs) might be risk factors for AA amyloidosis among patients with chronic inflammatory disorders, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), Crohn's disease, undiagnosed recurrent fevers and HPFs themselves. Four of 67 patients with RA plus amyloidosis had MEFV variants compared with none of 34 RA patients without amyloid (P value=0.03). The E148Q variant of MEFV was present in two of the three patients with TNF receptor-associated periodic syndrome (TRAPS) complicated by amyloid in two separate multiplex TRAPS families containing 5 and 16 affected members respectively, and the single patient with Muckle-Wells syndrome who had amyloidosis was homozygous for this variant. The R92Q variant of TNFRSF1A was present in two of 61 JIA patients with amyloidosis, and none of 31 nonamyloidotic JIA patients. No HPF gene mutations were found in 130 healthy control subjects. Although allelic variants in HPFs genes are not major susceptibility factors for AA amyloidosis in chronic inflammatory disease, low-penetrance variants of MEFV and TNFRSF1A may have clinically significant proinflammatory effects.Genes and Immunity (2004) 5, 289-293. doi:10.1038/sj.gene.6364070 Published online 8 April 2004 [ABSTRACT FROM AUTHOR]

Published
2004
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46. Genetic susceptibilty to fibrocalculous pancreatic diabetes in Bangladeshi subjects: a family study.

Author

Chowdhury, Z.M.d., McDermott, M.F., Davey, S., Hassan, Z., Sinnott, P.J., Hemmatpour, S.K., Sherwin, S., Ali, L., Aganna, E., Allotey, R.A., North, B.V., Cassell, P.G., Khan, A.K. Azad, and Hitman, G.A.

Subjects
GENETICS of diabetes, MAJOR histocompatibility complex, INSULIN
Abstract

Examines the association of fibrocalculous pancreatic diabetes genetic susceptibility with either the major histocompatibility complex or insulin gene loci. Genotyping; Extended transmission disequilibrium test; Genetic polymorphism.

Published
2002
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47. Diabetic hypertriglyceridaemia and related 5' flanking polymorphism of the human insulin gene.

Author

Jowett, N.I., Williams, L.G., Hitman, G.A., and Galton, D.J.

Subjects
NUCLEOTIDE sequence, TYPE 2 diabetes, DIABETES complications
Abstract

Studies the polymorphic DNA sequence on the regions of human insulin gene in relation to diabetic lipaemia. Association of non-insulin dependent diabetes with homozygous large genotype; Influence of insulin on the circulating concentrations of plasma triglyceride; Implication of diabetes and hypertriglyceridaemia in the genesis of atheroma.

Published
1984
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