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5. Genetics and cardiovascular risk (Clinical review)

Author

Day, Ian NM and Wilson, David I.

Subjects
Heart diseases -- Genetic aspects, Congenital heart disease -- Genetic aspects, Cholesterol -- Genetic aspects, Diabetes -- Genetic aspects, Smoking -- Genetic aspects, Hypertension -- Genetic aspects, Health, Genetic aspects
Abstract

Cardiovascular disease is the commonest cause of death in the Western world, and congenital heart disease affects almost 1% of liveborn infants. Both diseases have substantial genetic components. The identification [...]

Published
2001

6. Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool 'CubeX'

Author

Day Ian NM, Rodríguez Santiago, and Gaunt Tom R

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background The frequency of a haplotype comprising one allele at each of two loci can be expressed as a cubic equation (the 'Hill equation'), the solution of which gives that frequency. Most haplotype and linkage disequilibrium analysis programs use iteration-based algorithms which substitute an estimate of haplotype frequency into the equation, producing a new estimate which is repeatedly fed back into the equation until the values converge to a maximum likelihood estimate (expectation-maximisation). Results We present a program, "CubeX", which calculates the biologically possible exact solution(s) and provides estimated haplotype frequencies, D', r2 and χ2 values for each. CubeX provides a "complete" analysis of haplotype frequencies and linkage disequilibrium for a pair of biallelic markers under situations where sampling variation and genotyping errors distort sample Hardy-Weinberg equilibrium, potentially causing more than one biologically possible solution. We also present an analysis of simulations and real data using the algebraically exact solution, which indicates that under perfect sample Hardy-Weinberg equilibrium there is only one biologically possible solution, but that under other conditions there may be more. Conclusion Our analyses demonstrate that lower allele frequencies, lower sample numbers, population stratification and a possible |D'| value of 1 are particularly susceptible to distortion of sample Hardy-Weinberg equilibrium, which has significant implications for calculation of linkage disequilibrium in small sample sizes (eg HapMap) and rarer alleles (eg paucimorphisms, q < 0.05) that may have particular disease relevance and require improved approaches for meaningful evaluation.

Published
2007
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7. Refining associations between TAS2R38 diplotypes and the 6-n-propylthiouracil (PROP) taste test: findings from the Avon Longitudinal Study of Parents and Children

Author

Bartoshuk Linda M, Ring Susan M, Day Ian NM, Heron Jon, Timpson Nicholas J, Horwood Jeremy, Emmett Pauline, and Davey-Smith George

Subjects
Genetics, QH426-470
Abstract

Abstract Background Previous investigations have highlighted the importance of genetic variation in the determination of bitter tasting ability, however have left unaddressed questions as to within group variation in tasting ability or the possibility of genetic prescription of intermediate tasting ability. Our aim was to examine the relationships between bitter tasting ability and variation at the TAS2R38 locus and to assess the role of psychosocial factors in explaining residual, within group, variation in tasting ability. Results In a large sample of children from the Avon Longitudinal Study of Parents and Children, we confirmed an association between bitter compound tasting ability and TAS2R38 variation and found evidence of a genetic association with intermediate tasting ability. Antisocial behaviour, social class and depression showed no consistent relationship with the distribution of taste test scores. Conclusion Factors which could influence a child's chosen taste score, extra to taste receptor variation, appeared not to show relationships with test score. Observed spread in the distribution of the taste test scores within hypothesised taster groups, is likely to be, or at least in part, due to physiological differentiation regulated by other genetic contributors. Results confirm relationships between genetic variation and bitter compound tasting ability in a large sample, and suggest that TAS2R38 variation may also be associated with intermediate tasting ability.

Published
2007
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8. MIDAS: software for analysis and visualisation of interallelic disequilibrium between multiallelic markers

Author

Day Ian NM, Zapata Carlos, Rodriguez Santiago, and Gaunt Tom R

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Various software tools are available for the display of pairwise linkage disequilibrium across multiple single nucleotide polymorphisms. The HapMap project also presents these graphics within their website. However, these approaches are limited in their use of data from multiallelic markers and provide limited information in a graphical form. Results We have developed a software package (MIDAS – Multiallelic Interallelic Disequilibrium Analysis Software) for the estimation and graphical display of interallelic linkage disequilibrium. Linkage disequilibrium is analysed for each allelic combination (of one allele from each of two loci), between all pairwise combinations of any type of multiallelic loci in a contig (or any set) of many loci (including single nucleotide polymorphisms, microsatellites, minisatellites and haplotypes). Data are presented graphically in a novel and informative way, and can also be exported in tabular form for other analyses. This approach facilitates visualisation of patterns of linkage disequilibrium across genomic regions, analysis of the relationships between different alleles of multiallelic markers and inferences about patterns of evolution and selection. Conclusion MIDAS is a linkage disequilibrium analysis program with a comprehensive graphical user interface providing novel views of patterns of linkage disequilibrium between all types of multiallelic and biallelic markers. Availability Available from http://www.genes.org.uk/software/midas and http://www.sgel.humgen.soton.ac.uk/midas

Published
2006
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9. The association of the PON1 Q192R polymorphism with coronary heart disease: findings from the British Women's Heart and Health cohort study and a meta-analysis

Author

Kiessling Matthew, Briggs Patricia J, Hinks Lesley J, Gaunt Tom R, Day Ian NM, Lawlor Debbie A, Timpson Nick, Smith George, and Ebrahim Shah

Subjects
Genetics, QH426-470
Abstract

Abstract Background There have been inconsistent results from case-control studies assessing the association of the PON1 Q192R polymorphism with coronary heart disease (CHD). Most studies have included predominantly men and the association in women is unclear. Since lipid levels vary between the sexes the antioxidant effect of PON1 and any genes associated with it may also vary by sex. We have examined the association of the PON1 Q192R polymorphism with CHD in a large cohort of British women and combined the results from our cohort study with those from all other published studies. Results The distribution of genotypes was the same among women with CHD and those without disease. The odds ratio (95% confidence interval) of having CHD comparing those with either the QR or RR genotype to those with QQ genotype (dominant model of association) was 1.03 (0.89, 1.21) and the per allele odds ratio was 0.98 (0.95, 1.01). In a meta-analysis of this and 38 other published studies (10,738 cases and 17,068 controls) the pooled odds ratio for the dominant effect was 1.14 (1.08, 1.20) and for the per allele effect was 1.10 (1.06, 1.13). There was evidence of small study bias in the meta-analyses and the dominant effect among those studies with 500 or more cases was 1.05 (0.96, 1.15). Ethnicity and reporting of whether the genotyping was done blind to the participants clinical status also contributed to heterogeneity between studies, but there was no difference in effect between studies with 50% or more women compared to those with fewer women and no difference between studies of healthy populations compared to those at high risk (with diabetes, renal disease of familial hypercholesterolaemia). Conclusion There is no robust evidence that the PON1 Q192R polymorphism is associated with CHD risk in Caucasian women or men.

Published
2004
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10. Lipids, obesity and gallbladder disease in women:insights from genetic studies using the cardiovascular gene-centric 50K SNP array

Author

Rodriguez, Santiago, Gaunt, Tom R., Guo, Yiran, Zheng, Jie, Barnes, Michael R., Tang, Weihang, Danish, Fazal, Johnson, Andrew, Castillo, Berta A., Li, Yun R., Hakonarson, Hakon, Buxbaum, Sarah G., Palmer, Tom, Tsai, Michael Y., Lange, Leslie A., Ebrahim, Shah, Davey Smith, George, Lawlor, Debbie A., Folsom, Aaron R., Hoogeveen, Ron, Reiner, Alex, Keating, Brendan, Day, Ian Nm, Rodriguez, Santiago, Gaunt, Tom R., Guo, Yiran, Zheng, Jie, Barnes, Michael R., Tang, Weihang, Danish, Fazal, Johnson, Andrew, Castillo, Berta A., Li, Yun R., Hakonarson, Hakon, Buxbaum, Sarah G., Palmer, Tom, Tsai, Michael Y., Lange, Leslie A., Ebrahim, Shah, Davey Smith, George, Lawlor, Debbie A., Folsom, Aaron R., Hoogeveen, Ron, Reiner, Alex, Keating, Brendan, and Day, Ian Nm

Abstract

Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15 241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~53 000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P=5.88 × 10(-7), ß=-0.146) and TTC39B rs686030:C>A (P=6.95x10(-7), ß=0.271) and detect four independent SNP effects in ABCG8 rs4953023:G>A (P=7.41 × 10(-47), ß=0.734), ABCG8 rs4299376:G(>)T (P=2.40 × 10(-18), ß=0.278), ABCG5 rs6544718:T>C (P=2.08 × 10(-14), ß=0.044) and ABCG5 rs6720173:G>C (P=3.81 × 10(-12), ß(=)0.262) in conditional analyses taking genotypes of rs4953023:G>A as a covariate. We also delineate the risk effects among many genotypes known to influence lipids. These data, from the largest GBD genetic study to date, show that specific, mainly hepatocyte-centred, components of lipid metabolism are important to GBD risk in women. We discuss the potential pharmaceutical implications of our findings.European Journal of Human Genetics advance online publication, 29 April 2015; doi:10.1038/ejhg.2015.63.

Published
2016

11. Lipids, obesity and gallbladder disease in women : insights from genetic studies using the cardiovascular gene-centric 50K SNP array

Author

Rodriguez, Santiago, Gaunt, Tom R., Guo, Yiran, Zheng, Jie, Barnes, Michael R., Tang, Weihang, Danish, Fazal, Johnson, Andrew, Castillo, Berta A., Li, Yun R., Hakonarson, Hakon, Buxbaum, Sarah G., Palmer, Tom, Tsai, Michael Y., Lange, Leslie A., Ebrahim, Shah, Davey Smith, George, Lawlor, Debbie A., Folsom, Aaron R., Hoogeveen, Ron, Reiner, Alex, Keating, Brendan, Day, Ian Nm, Rodriguez, Santiago, Gaunt, Tom R., Guo, Yiran, Zheng, Jie, Barnes, Michael R., Tang, Weihang, Danish, Fazal, Johnson, Andrew, Castillo, Berta A., Li, Yun R., Hakonarson, Hakon, Buxbaum, Sarah G., Palmer, Tom, Tsai, Michael Y., Lange, Leslie A., Ebrahim, Shah, Davey Smith, George, Lawlor, Debbie A., Folsom, Aaron R., Hoogeveen, Ron, Reiner, Alex, Keating, Brendan, and Day, Ian Nm

Abstract

Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15 241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~53 000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P=5.88 × 10(-7), ß=-0.146) and TTC39B rs686030:C>A (P=6.95x10(-7), ß=0.271) and detect four independent SNP effects in ABCG8 rs4953023:G>A (P=7.41 × 10(-47), ß=0.734), ABCG8 rs4299376:G(>)T (P=2.40 × 10(-18), ß=0.278), ABCG5 rs6544718:T>C (P=2.08 × 10(-14), ß=0.044) and ABCG5 rs6720173:G>C (P=3.81 × 10(-12), ß(=)0.262) in conditional analyses taking genotypes of rs4953023:G>A as a covariate. We also delineate the risk effects among many genotypes known to influence lipids. These data, from the largest GBD genetic study to date, show that specific, mainly hepatocyte-centred, components of lipid metabolism are important to GBD risk in women. We discuss the potential pharmaceutical implications of our findings.European Journal of Human Genetics advance online publication, 29 April 2015; doi:10.1038/ejhg.2015.63.

Published
2016

12. Canonical correlation analysis for gene-based pleiotropy discovery

Author

Seoane, Jose A, Campbell, Colin, Day, Ian NM, Casas, Juan P, and Gaunt, Tom R

Subjects
lcsh:Biology (General), lcsh:QH301-705.5
Abstract

Genome-wide association studies have identified a wealth of genetic variants involved in complex traits and multifactorial diseases. There is now considerable interest in testing variants for association with multiple phenotypes (pleiotropy) and for testing multiple variants for association with a single phenotype (gene-based association tests). Such approaches can increase statistical power by combining evidence for association over multiple phenotypes or genetic variants respectively. Canonical Correlation Analysis (CCA) measures the correlation between two sets of multidimensional variables, and thus offers the potential to combine these two approaches. To apply CCA, we must restrict the number of attributes relative to the number of samples. Hence we consider modules of genetic variation that can comprise a gene, a pathway or another biologically relevant grouping, and/or a set of phenotypes. In order to do this, we use an attribute selection strategy based on a binary genetic algorithm. Applied to a UK-based prospective cohort study of 4286 women (the British Women's Heart and Health Study), we find improved statistical power in the detection of previously reported genetic associations, and identify a number of novel pleiotropic associations between genetic variants and phenotypes. New discoveries include gene-based association of NSF with triglyceride levels and several genes (ACSM3, ERI2, IL18RAP, IL23RAP and NRG1) with left ventricular hypertrophy phenotypes. In multiple-phenotype analyses we find association of NRG1 with left ventricular hypertrophy phenotypes, fibrinogen and urea and pleiotropic relationships of F7 and F10 with Factor VII, Factor IX and cholesterol levels.

Published
2014

14. Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array

Author

Rodriguez, Santiago, Gaunt, Tom R, Guo, Yiran, Zheng, Jie, Barnes, Michael R, Tang, Weihang, Danish, Fazal, Johnson, Andrew, Castillo, Berta A, Li, Yun R, Hakonarson, Hakon, Buxbaum, Sarah G, Palmer, Tom, Tsai, Michael Y, Lange, Leslie A, Ebrahim, Shah, Davey Smith, George, Lawlor, Debbie A, Folsom, Aaron R, Hoogeveen, Ron, Reiner, Alex, Keating, Brendan, and Day, Ian Nm

Subjects
Adult, Genotype, Lipoproteins, ATP Binding Cassette Transporter, Subfamily G, Member 8, Gallbladder Diseases, Middle Aged, Lipid Metabolism, Polymorphism, Single Nucleotide, humanities, Article, Body Mass Index, Phenotype, Genetic Loci, Risk Factors, Humans, ATP-Binding Cassette Transporters, Female, Obesity, ATP Binding Cassette Transporter, Subfamily G, Member 5, Lipoproteins, HDL, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study, Oligonucleotide Array Sequence Analysis
Abstract

Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15 241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~53 000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P=5.88 × 10(-7), ß=-0.146) and TTC39B rs686030:C>A (P=6.95x10(-7), ß=0.271) and detect four independent SNP effects in ABCG8 rs4953023:G>A (P=7.41 × 10(-47), ß=0.734), ABCG8 rs4299376:G(>)T (P=2.40 × 10(-18), ß=0.278), ABCG5 rs6544718:T>C (P=2.08 × 10(-14), ß=0.044) and ABCG5 rs6720173:G>C (P=3.81 × 10(-12), ß(=)0.262) in conditional analyses taking genotypes of rs4953023:G>A as a covariate. We also delineate the risk effects among many genotypes known to influence lipids. These data, from the largest GBD genetic study to date, show that specific, mainly hepatocyte-centred, components of lipid metabolism are important to GBD risk in women. We discuss the potential pharmaceutical implications of our findings.European Journal of Human Genetics advance online publication, 29 April 2015; doi:10.1038/ejhg.2015.63.

Published
2014

16. A gene-centric analysis of activated partial thromboplastin time and activated protein C resistance using the HumanCVD focused genotyping array

Author

Gaunt, Tom R, Lowe, Gordon DO, Lawlor, Debbie A, Casas, Juan-Pablo, and Day, Ian NM

Subjects
circulatory and respiratory physiology
Abstract

Activated partial thromboplastin time (aPTT) is an important routine measure of intrinsic blood coagulation. Addition of activated protein C (APC) to the aPTT test to produce a ratio, provides one measure of APC resistance. The associations of some genetic mutations (eg, factor V Leiden) with these measures are established, but associations of other genetic variations remain to be established. The objective of this work was to test for association between genetic variants and blood coagulation using a high-density genotyping array. Genetic association with aPTT and APC resistance was analysed using a focused genotyping array that tests approximately 50 000 single-nucleotide polymorphisms (SNPs) in nearly 2000 cardiovascular candidate genes, including coagulation pathway genes. Analyses were conducted on 2544 European origin women from the British Women's Heart and Health Study. We confirm associations with aPTT at the coagulation factor XII (F12)/G protein-coupled receptor kinase 6 (GRK6) and kininogen 1 (KNG1)/histidine-rich glycoprotein (HRG) loci, and identify novel SNPs at the ABO locus and novel locus kallikrein B (KLKB1)/F11. In addition, we confirm association between APC resistance and factor V Leiden mutation, and identify novel SNP associations with APC resistance in the HRG and F5/solute carrier family 19 member 2 (SLC19A2) regions. In conclusion, variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and APC resistance.

Published
2013

17. From a single whole exome read to notions of clinical screening: primary ciliary dyskinesia and RSPH9 p.Lys268del in the Arabian Peninsula

Author

AlSaadi, Muslim M, Gaunt, Tom R, Boustred, Christopher R, Guthrie, Philip AI, Liu, Xuan, Lenzi, Luca, Rainbow, Lucille, Hall, Neil, Alharbi, Khalid K, and Day, Ian NM

Subjects
Consanguinity, Cytoskeletal Proteins, Kartagener Syndrome, DNA Mutational Analysis, Mutation, otorhinolaryngologic diseases, Saudi Arabia, Humans, Exome, sense organs, Sequence Analysis, DNA, eye diseases, Article
Abstract

Primary ciliary dyskinesia (PCD) is a genetic disorder, usually autosomal recessive, causing early respiratory disease and later subfertility. Whole exome sequencing may enable efficient analysis for locus heterogeneous disorders such as PCD. We whole-exome-sequenced one consanguineous Saudi Arabian with clinically diagnosed PCD and normal laterality, to attempt ab initio molecular diagnosis. We reviewed 13 known PCD genes and potentially autozygous regions (extended homozygosity) for homozygous exon deletions, non-dbSNP codon, splice-site base variants or small indels. Homozygous non-dbSNP changes were also reviewed exome-wide. One single molecular read representing RSPH9 p.Lys268del was observed, with no wild-type reads, and a notable deficiency of mapped reads at this location. Among all observations, RSPH9 was the strongest candidate for causality. Searching unmapped reads revealed seven more mutant reads. Direct assay for p.Lys268del (MboII digest) confirmed homozygosity in the affected individual, then confirmed homozygosity in three siblings with bronchiectasis. Our finding in southwest Saudi Arabia indicates that p.Lys268del, previously observed in two Bedouin families (Israel, UAE), is geographically widespread in the Arabian Peninsula. Analogous with cystic fibrosis CFTR p.Phe508del, screening for RSPH9 p.Lys268del (which lacks sentinel dextrocardia) in those at risk would help in early diagnosis, tailored clinical management, genetic counselling and primary prevention.

Published
2012

18. A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans

Author

Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, DIAGRAM Consortium, MAGIC Investigators, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie CY, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Morris, Andrew P, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Langenberg, Claudia, Hofmann, Oliver M, Dupuis, Josée, Qi, Lu, Segrè, Ayellet V, Van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Couper, David J, Crawford, Gabe, Doney, Alex SF, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul RV, Jørgensen, Torben, Kao, Wen HL, Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R, Payne, Felicity, Perry, John RB, Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N William, Robertson, Neil R, Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J, Saxena, Richa, Shields, Beverley M, Shrader, Peter, Sigurdsson, Gunnar, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M, Sun, Qi, Swift, Amy J, Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, Van Dam, Rob M, Van Haeften, Timon W, Van Herpt, Thijs, Van Vliet-Ostaptchouk, Jana V, Walters, G Bragi, Weedon, Michael N, Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N, Cauchi, Stephane, Collins, Francis S, Gloyn, Anna L, Gyllensten, Ulf, Hansen, Torben, Hide, Winston A, Hitman, Graham A, Hofman, Albert, Hunter, David J, Hveem, Kristian, Laakso, Markku, Mohlke, Karen L, Morris, Andrew D, Palmer, Colin NA, Pramstaller, Peter P, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Hu, Frank B, Meigs, James B, Pankow, James S, Pedersen, Oluf, Wichmann, H-Erich, Barroso, Inês, Florez, Jose C, Frayling, Timothy M, Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F, Illig, Thomas, Froguel, Philippe, Van Duijn, Cornelia M, Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Johnson, Toby, Elliott, Paul, Rybin, Denis, Henneman, Peter, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Egan, Josephine M, Lajunen, Taina, Doney, Alex, Kanoni, Stavroula, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan JM, Cooper, Matthew N, Crisponi, Laura, Day, Ian NM, De Geus, Eco JC, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Frants, Rune, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hicks, Andrew A, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, Jula, Antti, Kaakinen, Marika, Kaprio, Jaakko, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Koskinen, Seppo, Kovacs, Peter, Kyvik, Kirsten Ohm, Lathrop, G Mark, Lawlor, Debbie A, Le Bacquer, Olivier, Lecoeur, Cécile, Li, Yun, Mahley, Robert, Mangino, Massimo, Manning, Alisa K, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Oostra, Ben A, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Perola, Markus, Pfeiffer, Andreas FH, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Psaty, Bruce M, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sijbrands, Eric JG, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tanaka, Toshiko, Tönjes, Anke, Uitterlinden, André G, Van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline CM, Yarnell, John WG, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, Borecki, Ingrid B, Loos, Ruth JF, Meneton, Pierre, Magnusson, Patrik KE, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Salomaa, Veikko, Smith, George Davey, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Dedoussis, George V, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, WH Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Siscovick, David S, Penninx, Brenda WJH, Boomsma, Dorret I, Deloukas, Panos, Spector, Timothy D, Ferrucci, Luigi, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Waterworth, Dawn M, Vollenweider, Peter, Peltonen, Leena, Mooser, Vincent, Sladek, Robert, Center for Liver, Digestive and Metabolic Diseases (CLDM), Palmer, Nd, Mcdonough, Cw, Hicks, Pj, Roh, Bh, Wing, Mr, An, S, Hester, Jm, Cooke, Jn, Bostrom, Ma, Rudock, Me, Talbert, Me, Lewis, Jp, Diagram, Consortium, Magic, Investigator, Ferrara, A, Lu, L, Ziegler, Jt, Sale, Mm, Divers, J, Shriner, D, Adeyemo, A, Rotimi, Cn, Ng, Mc, Langefeld, Cd, Freedman, Bi, Bowden, Dw, Voight, Bf, Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Y, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Langenberg, C, Hofmann, Om, Dupuis, J, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, P, Cornelis, M, Couper, Dj, Crawford, G, Doney, A, Elliott, K, Elliott, Al, Erdos, Mr, Fox, C, Franklin, C, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Perry, Jr, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam, Rm, van Haeften, Tw, van Herpt, T, van Vliet Ostaptchouk, Jv, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, F, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, Nj, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Meigs, Jb, Pankow, J, Pedersen, O, Wichmann, He, Barroso, I, Florez, Jc, Frayling, Tm, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn, Cm, Stefansson, K, Altshuler, D, Boehnke, M, Mccarthy, Mi, Soranzo, N, Wheeler, E, Glazer, Nl, Bouatia Naji, N, Mägi, R, Randall, J, Johnson, T, Elliott, P, Rybin, D, Henneman, P, Dehghan, A, Hottenga, Jj, Song, K, Goel, A, Egan, Jm, Lajunen, T, Kanoni, S, Cavalcanti Proença, C, Kumari, M, Timpson, Nj, Zabena, C, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, Roccasecca, Rm, Pattou, F, Sethupathy, P, Ariyurek, Y, Barter, P, Beilby, Jp, Ben Shlomo, Y, Bergmann, S, Bochud, M, Bonnefond, A, Borch Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, Sj, Chen, Yd, Clarke, R, Coin, Lj, Cooper, Mn, Crisponi, L, Day, In, de Geus, Ej, Delplanque, J, Fedson, Ac, Fischer Rosinsky, A, Forouhi, Ng, Frants, R, Franzosi, Mg, Galan, P, Goodarzi, Mo, Graessler, J, Grundy, S, Gwilliam, R, Hallmans, G, Hammond, N, Han, X, Hartikainen, Al, Hayward, C, Heath, Sc, Hercberg, S, Hicks, Aa, Hillman, Dr, Hingorani, Ad, Hui, J, Hung, J, Jula, A, Kaakinen, M, Kaprio, J, Kesaniemi, Ya, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, Ko, Lathrop, Gm, Lawlor, Da, Le Bacquer, O, Lecoeur, C, Li, Y, Mahley, R, Mangino, M, Manning, Ak, Martínez Larrad, Mt, Mcateer, Jb, Mcpherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, Bd, Mukherjee, S, Naitza, S, Neville, Mj, Oostra, Ba, Orrù, M, Pakyz, R, Paolisso, Giuseppe, Pattaro, C, Pearson, D, Peden, Jf, Pedersen, Nl, Perola, M, Pfeiffer, Af, Pichler, I, Polasek, O, Posthuma, D, Potter, Sc, Pouta, A, Province, Ma, Psaty, Bm, Rice, K, Ripatti, S, Rivadeneira, F, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, Aa, Scheet, P, Seedorf, U, Sharp, Sj, Shields, B, Sijbrands, Ej, Silveira, A, Simpson, L, Singleton, A, Smith, Nl, Sovio, U, Swift, A, Syddall, H, Syvänen, Ac, Tanaka, T, Tönjes, A, Uitterlinden, Ag, van Dijk, Kw, Varma, D, Visvikis Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Borecki, Ib, Loos, Rj, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Salomaa, V, Smith, Gd, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Dedoussis, Gv, Serrano Ríos, M, Lind, L, Palmer, Lj, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Buchanan, Ta, Valle, Tt, Rotter, Ji, Siscovick, D, Penninx, Bw, Boomsma, Di, Deloukas, P, Spector, Td, Ferrucci, L, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Waterworth, Dm, Vollenweider, P, Peltonen, L, Mooser, V, Sladek, R., Medical Research Council (MRC), Human genetics, Psychiatry, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, Langenberg, Claudia [0000-0002-5017-7344], Griffin, Simon [0000-0002-2157-4797], Wareham, Nicholas [0000-0003-1422-2993], Soranzo, Nicole [0000-0003-1095-3852], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Apollo - University of Cambridge Repository, DIAGRAM Consortium, MAGIC Investigators, Johnson, T., Bergman, S., Bochud, M., Waeber, G., and Vollenweider, P.

Subjects
Netherlands Twin Register (NTR), Male, Adult, African Americans/genetics, Aged, Case-Control Studies, Cohort Studies, Diabetes Mellitus, Type 2/ethnology, Diabetes Mellitus, Type 2/genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Validation Studies as Topic, Medicin och hälsovetenskap, Linkage disequilibrium, Genetic Screens, endocrine system diseases, lcsh:Medicine, Genome-wide association study, Medical and Health Sciences, 0302 clinical medicine, Endocrinology, Genome Sequencing, lcsh:Science, Medicine(all), Genetics, African Americans, 0303 health sciences, education.field_of_study, INSULIN-RESISTANCE, Multidisciplinary, Agricultural and Biological Sciences(all), LARGE-SCALE ASSOCIATION, STAGE RENAL-DISEASE, COMMON VARIANTS, Genomics, Medicine, Research Article, SUSCEPTIBILITY LOCI, General Science & Technology, Population, Single-nucleotide polymorphism, Biology, DIAGRAM Consortium, 03 medical and health sciences, MAGIC Investigators, SDG 3 - Good Health and Well-being, Genetic linkage, MD Multidisciplinary, Genome-Wide Association Studies, SNP, ddc:610, education, Genotyping, 030304 developmental biology, Diabetic Endocrinology, LINKAGE ANALYSIS, Biochemistry, Genetics and Molecular Biology(all), lcsh:R, TCF7L2 GENE, Case-control study, Computational Biology, nutritional and metabolic diseases, Human Genetics, Diabetes Mellitus Type 2, Stage renal-disease, large-scale association, Susceptibility loci, Insulin-resistance, Fasting glucose, Tissue factor, Homeodomain protein, Linkage analysis, Common variants, TCF7L2 gene, Black or African American, Diabetes Mellitus, Type 2, TISSUE FACTOR, Genetics of Disease, HOMEODOMAIN PROTEIN, Genetic Polymorphism, lcsh:Q, Genome Expression Analysis, 030217 neurology & neurosurgery, Population Genetics, FASTING GLUCOSE
Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

Published
2012

19. Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array

Author

Rodriguez, Santiago, primary, Gaunt, Tom R, additional, Guo, Yiran, additional, Zheng, Jie, additional, Barnes, Michael R, additional, Tang, Weihang, additional, Danish, Fazal, additional, Johnson, Andrew, additional, Castillo, Berta A, additional, Li, Yun R, additional, Hakonarson, Hakon, additional, Buxbaum, Sarah G, additional, Palmer, Tom, additional, Tsai, Michael Y, additional, Lange, Leslie A, additional, Ebrahim, Shah, additional, Davey Smith, George, additional, Lawlor, Debbie A, additional, Folsom, Aaron R, additional, Hoogeveen, Ron, additional, Reiner, Alex, additional, Keating, Brendan, additional, and Day, Ian NM, additional

Published
2015
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20. Frequency of KLK3 gene deletions in the general population.

Author

Rodriguez, Santiago, Al-Ghamdi, Osama A., Guthrie, Philip A. I., Shihab, Hashem A., McArdle, Wendy, Gaunt, Tom, Alharbi, Khalid K., Day, Ian N. M., Guthrie, Philip Ai, and Day, Ian Nm

Subjects
KALLIKREIN genetics, PROSTATE-specific antigen, PROSTATE cancer, BIOMARKERS, DELETION mutation, EARLY detection of cancer, CANCER diagnosis, BLOOD coagulation factors, DIAGNOSTIC errors, GENE expression, LONGITUDINAL method, GENETIC mutation, PATIENT monitoring, PROGNOSIS, PROSTATE tumors, RESEARCH funding, GENETIC carriers, DIAGNOSIS
Abstract

Background One of the kallikrein genes ( KLK3) encodes prostate-specific antigen, a key biomarker for prostate cancer. A number of factors, both genetic and non-genetic, determine variation of serum prostate-specific antigen concentrations in the population. We have recently found three KLK3 deletions in individuals with very low prostate-specific antigen concentrations, suggesting a link between abnormally reduced KLK3 expression and deletions of KLK3. Here, we aim to determine the frequency of kallikrein gene 3 deletions in the general population. Methods The frequency of KLK3 deletions in the general population was estimated from the 1958 Birth Cohort sample ( n = 3815) using amplification ratiometry control system. In silico analyses using PennCNV were carried out in the same cohort and in NBS-WTCCC2 in order to provide an independent estimation of the frequency of KLK3 deletions in the general population. Results Amplification ratiometry control system results from the 1958 cohort indicated a frequency of KLK3 deletions of 0.81% (3.98% following a less stringent calling criterion). From in silico analyses, we found that potential deletions harbouring the KLK3 gene occurred at rates of 2.13% (1958 Cohort, n = 2867) and 0.99% (NBS-WTCCC2, n = 2737), respectively. These results are in good agreement with our in vitro experiments. All deletions found were in heterozygosis. Conclusions We conclude that a number of individuals from the general population present KLK3 deletions in heterozygosis. Further studies are required in order to know if interpretation of low serum prostate-specific antigen concentrations in individuals with KLK3 deletions may offer false-negative assurances with consequences for prostate cancer screening, diagnosis and monitoring. [ABSTRACT FROM AUTHOR]

Published
2017
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21. The association of the PON1 Q192R polymorphism with coronary heart disease: findings from the British Women's Heart and Health cohort study and a meta-analysis

Author

Lawlor, Debbie A, Day, Ian NM, Gaunt, Tom R, Hinks, Lesley J, Briggs, Patricia J, Kiessling, Matthew, Timpson, Nick, Smith, George Davey, and Ebrahim, Shah

Abstract

BACKGROUND: There have been inconsistent results from case-control studies assessing the association of the PON1 Q192R polymorphism with coronary heart disease (CHD). Most studies have included predominantly men and the association in women is unclear. Since lipid levels vary between the sexes the antioxidant effect of PON1 and any genes associated with it may also vary by sex. We have examined the association of the PON1 Q192R polymorphism with CHD in a large cohort of British women and combined the results from our cohort study with those from all other published studies. RESULTS: The distribution of genotypes was the same among women with CHD and those without disease. The odds ratio (95% confidence interval) of having CHD comparing those with either the QR or RR genotype to those with QQ genotype (dominant model of association) was 1.03 (0.89, 1.21) and the per allele odds ratio was 0.98 (0.95, 1.01). In a meta-analysis of this and 38 other published studies (10,738 cases and 17,068 controls) the pooled odds ratio for the dominant effect was 1.14 (1.08, 1.20) and for the per allele effect was 1.10 (1.06, 1.13). There was evidence of small study bias in the meta-analyses and the dominant effect among those studies with 500 or more cases was 1.05 (0.96, 1.15). Ethnicity and reporting of whether the genotyping was done blind to the participants clinical status also contributed to heterogeneity between studies, but there was no difference in effect between studies with 50% or more women compared to those with fewer women and no difference between studies of healthy populations compared to those at high risk (with diabetes, renal disease of familial hypercholesterolaemia). CONCLUSION: There is no robust evidence that the PON1 Q192R polymorphism is associated with CHD risk in Caucasian women or men.

Published
2004

23. Very Low PSA Concentrations and Deletions of the KLK3 Gene

Author

Rodriguez, Santiago, primary, Al-Ghamdi, Osama A, primary, Burrows, Kimberley, primary, Guthrie, Philip AI, primary, Lane, J Athene, primary, Davis, Michael, primary, Marsden, Gemma, primary, Alharbi, Khalid K, primary, Cox, Angela, primary, Hamdy, Freddie C, primary, Neal, David E, primary, Donovan, Jenny L, primary, and Day, Ian NM, primary

Published
2013
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35. Independent effects of the -219?G>T and ?2/?3/?4 polymorphisms in the apolipoprotein E gene on coronary artery disease: The Southampton Atherosclerosis Study.

Author

Ye, Shu, Dunleavey, Louise, Bannister, Wendy, Day, Lorna B, Tapper, William, Collins, Andrew R, Day, Ian NM, and Simpson, Iain

Subjects
APOLIPOPROTEIN E, APOLIPOPROTEINS, GENETIC polymorphisms, POPULATION genetics, LINKAGE (Genetics), GENETICS, HEREDITY, CORONARY disease, HEART diseases
Abstract

A number of studies have shown that coronary artery disease severity is associated with the ε/ε3/ε4 polymorphism in the coding region of the apolipoprotein E gene. In this study, we investigated whether the severity of the disease was also influenced by a functional polymorphism (-219 G>T) in the promoter of the gene, and if so, whether the effects of the two polymorphisms were independent. A cohort of 1170 patients with angiographically documented coronary artery disease were genotyped for the two polymorphisms. The frequency of the ε4 allele of the ε/ε3/ε4 polymorphism increased linearly with increasing number of diseased vessels, so did the 3219T allele of the 3219 G4T polymorphism. In the sample as a whole, logistic regression analyses indicated that compared with the G/G genotype, the T/T genotype conferred an odds ratio of 1.598 (95% CI = 1.161-2.201, P = 0.004) in favor of increased disease severity, and the relationship remained significant after adjustment for ε/ε3/ε4 polymorphism genotypes, plasma cholesterol and triglyceride levels, and other risk factors. The effect of the T/T genotype on disease severity was more significant in patients who did not carry the ε4 allele (OR = 1.510, 95% CI = 1.028-2.221) than in ε4 allele carriers (OR = 1.303, 95% CI = 0.619-2.742). There was considerable linkage disequilibrium between the two polymorphisms (ρ = 0.9, P<0.001). Logistic regression analysis showed that the 3219T-ε4 haplotype conferred an odds ratio of 1.488 (95% CI = 1.133-1.954). These findings suggest that the 3219 G4T and ε2/ε3/ε4 polymorphisms, which may affect respectively the quantity and quality of apoE, have independent and possibly additive effects on coronary artery disease severity. [ABSTRACT FROM AUTHOR]

Published
2003
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36. 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

Dastani, Zari, Hivert, Marie-France, Timpson, Nicholas, Perry, John RB, Yuan, Xin, Scott, Robert A, Henneman, Peter, Heid, Iris M, Kizer, Jorge R, Lyytikäinen, Leo-Pekka, Fuchsberger, Christian, Tanaka, Toshiko, Morris, Andrew P, Small, Kerrin, Isaacs, Aaron, Beekman, Marian, Coassin, Stefan, Lohman, Kurt, Qi, Lu, Kanoni, Stavroula, Pankow, James S, Uh, Hae-Won, Wu, Ying, Bidulescu, Aurelian, Rasmussen-Torvik, Laura J, Greenwood, Celia MT, Ladouceur, Martin, Grimsby, Jonna, Manning, Alisa K, Liu, Ching-Ti, Kooner, Jaspal, Mooser, Vincent E, Vollenweider, Peter, Kapur, Karen A, Chambers, John, Wareham, Nicholas J, Langenberg, Claudia, Frants, Rune, Willems-Vandijk, Ko, Oostra, Ben A, Willems, Sara M, Lamina, Claudia, Winkler, Thomas W, Psaty, Bruce M, Tracy, Russell P, Brody, Jennifer, Chen, Ida, Viikari, Jorma, Kähönen, Mika, Pramstaller, Peter P, Evans, David M, St Pourcain, Beate, Sattar, Naveed, Wood, Andrew R, Bandinelli, Stefania, Carlson, Olga D, Egan, Josephine M, Böhringer, Stefan, Van Heemst, Diana, Kedenko, Lyudmyla, Kristiansson, Kati, Nuotio, Marja-Liisa, Loo, Britt-Marie, Harris, Tamara, Garcia, Melissa, Kanaya, Alka, Haun, Margot, Klopp, Norman, Wichmann, H-Erich, Deloukas, Panos, Katsareli, Efi, Couper, David J, Duncan, Bruce B, Kloppenburg, Margreet, Adair, Linda S, Borja, Judith B, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, Wilson, James G, Musani, Solomon, Guo, Xiuqing, Johnson, Toby, Semple, Robert, Teslovich, Tanya M, Allison, Matthew A, Redline, Susan, Buxbaum, Sarah G, Mohlke, Karen L, Meulenbelt, Ingrid, Ballantyne, Christie M, Dedoussis, George V, Hu, Frank B, Liu, Yongmei, Paulweber, Bernhard, Spector, Timothy D, Slagboom, P Eline, Ferrucci, Luigi, Jula, Antti, Perola, Markus, Raitakari, Olli, Florez, Jose C, Salomaa, Veikko, Eriksson, Johan G, Frayling, Timothy M, Hicks, Andrew A, Lehtimäki, Terho, Smith, George Davey, Siscovick, David S, Kronenberg, Florian, Van Duijn, Cornelia, Loos, Ruth JF, Waterworth, Dawn M, Meigs, James B, Dupuis, Josee, Richards, J Brent, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Hofmann, Oliver M, Segrè, Ayellet V, Van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Crawford, Gabe, Doney, Alex SF, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul RV, Jørgensen, Torben, Kao, Wen HL, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R, Payne, Felicity, Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N William, Robertson, Neil R, Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J, Saxena, Richa, Shields, Beverley M, Shrader, Peter, Sigurdsson, Gunnar, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M, Sun, Qi, Swift, Amy J, Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, Van Dam, Rob M, Van Haeften, Timon W, Van Herpt, Thijs, Van Vliet-Ostaptchouk, Jana V, Walters, G Bragi, Weedon, Michael N, Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N, Cauchi, Stephane, Collins, Francis S, Gloyn, Anna L, Gyllensten, Ulf, Hansen, Torben, Hide, Winston A, Hitman, Graham A, Hofman, Albert, Hunter, David J, Hveem, Kristian, Laakso, Markku, Morris, Andrew D, Palmer, Colin NA, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Pedersen, Oluf, Barroso, Inês, Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F, Illig, Thomas, Froguel, Philippe, Van Duijn, Cornelia M, Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Elliott, Paul, Rybin, Denis, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Lajunen, Taina, Doney, Alex, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan JM, Cooper, Matthew N, Crisponi, Laura, Day, Ian NM, De Geus, Eco JC, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, Kaakinen, Marika, Kaprio, Jaakko, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Koskinen, Seppo, Kovacs, Peter, Kyvik, Kirsten Ohm, Lathrop, G Mark, Lawlor, Debbie A, Le Bacquer, Olivier, Lecoeur, Cécile, Li, Yun, Mahley, Robert, Mangino, Massimo, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Pfeiffer, Andreas FH, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sigurðsson, Gunnar, Sijbrands, Eric JG, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tönjes, Anke, Uitterlinden, André G, Van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline CM, Yarnell, John WG, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Borecki, Ingrid B, Meneton, Pierre, Magnusson, Patrik KE, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, WH Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Procardis Consortium, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Penninx, Brenda WJH, Boomsma, Dorret I, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Peltonen, Leena, Mooser, Vincent, Sladek, Robert, MAGIC Investigators, GLGC Consortium, Musunuru, Kiran, Smith, Albert V, Edmondson, Andrew C, Stylianou, Ioannis M, Koseki, Masahiro, Pirruccello, James P, Chasman, Daniel I, Johansen, Christopher T, Fouchier, Sigrid W, Peloso, Gina M, Barbalic, Maja, Ricketts, Sally L, Bis, Joshua C, Feitosa, Mary F, Orho-Melander, Marju, Melander, Olle, Li, Xiaohui, Li, Mingyao, Cho, Yoon Shin, Go, Min Jin, Kim, Young Jin, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Ong, Rick Twee-Hee, Croteau-Chonka, Damien C, Lange, Leslie A, Smith, Joshua D, Ziegler, Andreas, Zhang, Weihua, Zee, Robert YL, Whitfield, John B, Thompson, John R, Surakka, Ida, Spector, Tim D, Smit, Johannes H, Sinisalo, Juha, Scott, James, Saharinen, Juha, Sabatti, Chiara, Rose, Lynda M, Roberts, Robert, Rieder, Mark, Parker, Alex N, Pare, Guillaume, O'Donnell, Christopher J, Nieminen, Markku S, Nickerson, Deborah A, Montgomery, Grant W, McArdle, Wendy, Masson, David, Martin, Nicholas G, Marroni, Fabio, Lucas, Gavin, Luben, Robert, Lokki, Marja-Liisa, Lettre, Guillaume, Launer, Lenore J, Lakatta, Edward G, Laaksonen, Reijo, Kyvik, Kirsten O, König, Inke R, Khaw, Kay-Tee, Kaplan, Lee M, Johansson, Åsa, Janssens, A Cecile JW, Igl, Wilmar, Hovingh, G Kees, Hengstenberg, Christian, Havulinna, Aki S, Hastie, Nicholas D, Harris, Tamara B, Haritunians, Talin, Hall, Alistair S, Groop, Leif C, Gonzalez, Elena, Freimer, Nelson B, Erdmann, Jeanette, Ejebe, Kenechi G, Döring, Angela, Dominiczak, Anna F, Demissie, Serkalem, Deloukas, Panagiotis, De Faire, Ulf, Crawford, Gabriel, Chen, Yii-Der I, Caulfield, Mark J, Boekholdt, S Matthijs, Assimes, Themistocles L, Quertermous, Thomas, Seielstad, Mark, Wong, Tien Y, Tai, E-Shyong, Feranil, Alan B, Kuzawa, Christopher W, Taylor, Herman A, Gabriel, Stacey B, Holm, Hilma, Gudnason, Vilmundur, Krauss, Ronald M, Ordovas, Jose M, Munroe, Patricia B, Kooner, Jaspal S, Tall, Alan R, Hegele, Robert A, Kastelein, John JP, Schadt, Eric E, Strachan, David P, Reilly, Muredach P, Samani, Nilesh J, Schunkert, Heribert, Cupples, L Adrienne, Sandhu, Manjinder S, Ridker, Paul M, Rader, Daniel J, and Kathiresan, Sekar

Subjects
2. Zero hunger, Male, Waist-Hip Ratio, Cholesterol, HDL, Gene Expression, Glucose Tolerance Test, Polymorphism, Single Nucleotide, White People, 3. Good health, Black or African American, Asian People, Diabetes Mellitus, Type 2, Humans, Female, Genetic Predisposition to Disease, Adiponectin, Insulin Resistance, Metabolic Networks and Pathways, Genome-Wide Association Study
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

37. Associations between APOE and low-density lipoprotein cholesterol genotypes and cognitive and physical capability: the HALCyon programme

Author

Alfred, Tamuno, Ben-Shlomo, Yoav, Cooper, Rachel, Hardy, Rebecca, Cooper, Cyrus, Deary, Ian J., Elliott, Jane, Gunnell, David, Harris, Sarah E., Kivimaki, Mika, Kumari, Meena, Martin, Richard M, Power, Chris, Sayer, Avan Aihie, Starr, John M., Kuh, Diana, and Day, Ian NM

Subjects
Adult, Male, Aging, Polymorphism, Genetic, Time Factors, Apolipoprotein E4, Enzyme-Linked Immunosorbent Assay, Cholesterol, LDL, DNA, Walking, Middle Aged, Article, Single nucleotide polymorphism, Ageing, Cognition, Phenotype, Alzheimer Disease, Humans, Female, lipids (amino acids, peptides, and proteins), Apolipoprotein E, Prospective Studies, Geriatrics and Gerontology, Follow-Up Studies
Abstract

The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90 + years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score = −0.02; 95 % CI = −0.05 to 0.02; p value = 0.3; n = 18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits. Electronic supplementary material The online version of this article (doi:10.1007/s11357-014-9673-9) contains supplementary material, which is available to authorized users.

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

Author

International Consortium For Blood Pressure Genome-Wide Association Studies, Ehret, Georg B, Munroe, Patricia B, Rice, Kenneth M, Bochud, Murielle, Johnson, Andrew D, Chasman, Daniel I, Smith, Albert V, Tobin, Martin D, Verwoert, Germaine C, Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F, Amin, Najaf, Bragg-Gresham, Jennifer L, Teumer, Alexander, Glazer, Nicole L, Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sõber, Siim, Parsa, Afshin, Luan, Jian'an, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A, Jackson, Anne U, Peden, John F, Tanaka, Toshiko, Wild, Sarah H, Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N, Fava, Cristiano, Chambers, John C, Fox, Ervin R, Kumari, Meena, Go, Min Jin, Van Der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, DG, Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H, Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Nguyen, Khanh-Dung Hoang, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R, Onland-Moret, N Charlotte, Cooper, Matthew N, Platou, Carl GP, Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S, Kuznetsova, Tatiana, Uiterwaal, Cuno SPM, Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D, CARDIoGRAM Consortium, CKDGen Consortium, KidneyGen Consortium, EchoGen Consortium, CHARGE-HF Consortium, Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C, O'Connell, Jeffrey R, Steinle, Nanette I, Grobbee, Diederick E, Arking, Dan E, Kardia, Sharon L, Morrison, Alanna C, Hernandez, Dena, Najjar, Samer, McArdle, Wendy L, Hadley, David, Brown, Morris J, Connell, John M, Hingorani, Aroon D, Day, Ian NM, Lawlor, Debbie A, Beilby, John P, Lawrence, Robert W, Clarke, Robert, Hopewell, Jemma C, Ongen, Halit, Dreisbach, Albert W, Li, Yali, Young, J Hunter, Bis, Joshua C, Kähönen, Mika, Viikari, Jorma, Adair, Linda S, Lee, Nanette R, Chen, Ming-Huei, Olden, Matthias, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M, Islam, Muhammad, Jafar, Tazeen H, Erdmann, Jeanette, Kulkarni, Smita R, Bornstein, Stefan R, Grässler, Jürgen, Groop, Leif, Voight, Benjamin F, Kettunen, Johannes, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inês, Khaw, Kay-Tee, Weder, Alan B, Hunt, Steven C, Sun, Yan V, Bergman, Richard N, Collins, Francis S, Bonnycastle, Lori L, Scott, Laura J, Stringham, Heather M, Peltonen, Leena, Perola, Markus, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A, Wang, Thomas J, Burton, Paul R, Soler Artigas, Maria, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K, Rudock, Megan E, Heckbert, Susan R, Smith, Nicholas L, Wiggins, Kerri L, Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margus, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D, Rosengren, Annika, Thelle, Dag S, Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, McKenzie, Colin A, Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thomas, Wichmann, H-Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, James, Sehmi, Joban S, Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J, Yao, Jie, Kathiresan, Sekar, O'Donnell, Christopher J, Schwartz, Stephen M, Ikram, M Arfan, Longstreth, WT, Mosley, Thomas H, Seshadri, Sudha, Shrine, Nick RG, Wain, Louise V, Morken, Mario A, Swift, Amy J, Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A, Humphries, Steve E, Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Anders, Watkins, Hugh, Bakker, Stephan JL, Van Gilst, Wiek H, Janipalli, Charles S, Mani, K Radha, Yajnik, Chittaranjan S, Hofman, Albert, Mattace-Raso, Francesco US, Oostra, Ben A, Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G, Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J, Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Ong, Rick Twee-Hee, Dörr, Marcus, Kroemer, Heyo K, Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Panos, Mangino, Massimo, Spector, Tim D, Zhai, Guangju, Meschia, James F, Nalls, Michael A, Sharma, Pankaj, Terzic, Janos, Kumar, MV Kranthi, Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E, Fowkes, F Gerald R, Charchar, Fadi J, Schwarz, Peter EH, Hayward, Caroline, Guo, Xiuqing, Rotimi, Charles, Bots, Michiel L, Brand, Eva, Samani, Nilesh J, Polasek, Ozren, Talmud, Philippa J, Nyberg, Fredrik, Kuh, Diana, Laan, Maris, Hveem, Kristian, Palmer, Lyle J, Van Der Schouw, Yvonne T, Casas, Juan P, Mohlke, Karen L, Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K, Wong, Tien Y, Tai, E Shyong, Cooper, Richard S, Laakso, Markku, Rao, Dabeeru C, Harris, Tamara B, Morris, Richard W, Dominiczak, Anna F, Kivimaki, Mika, Marmot, Michael G, Miki, Tetsuro, Saleheen, Danish, Chandak, Giriraj R, Coresh, Josef, Navis, Gerjan, Salomaa, Veikko, Han, Bok-Ghee, Zhu, Xiaofeng, Kooner, Jaspal S, Melander, Olle, Ridker, Paul M, Bandinelli, Stefania, Gyllensten, Ulf B, Wright, Alan F, Wilson, James F, Ferrucci, Luigi, Farrall, Martin, Tuomilehto, Jaakko, Pramstaller, Peter P, Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric JG, Altshuler, David, Loos, Ruth JF, Shuldiner, Alan R, Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G, Wareham, Nicholas J, Gudnason, Vilmundur, Rotter, Jerome I, Rettig, Rainer, Uda, Manuela, Strachan, David P, Witteman, Jacqueline CM, Hartikainen, Anna-Liisa, Beckmann, Jacques S, Boerwinkle, Eric, Vasan, Ramachandran S, Boehnke, Michael, Larson, Martin G, Järvelin, Marjo-Riitta, Psaty, Bruce M, Abecasis, Gonçalo R, Chakravarti, Aravinda, Elliott, Paul, Van Duijn, Cornelia M, Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J, and Johnson, Toby

Subjects
Asia, Blood Pressure, Coronary Artery Disease, Polymorphism, Single Nucleotide, 3. Good health, Europe, Stroke, Cardiovascular Diseases, Africa, Hypertension, Humans, Genetic Predisposition to Disease, Kidney Diseases, Genome-Wide Association Study
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.

39. Genetic Variants Influencing Biomarkers of Nutrition Are Not Associated with Cognitive Capability in Middle-Aged and Older Adults

Author

Yoav Ben-Shlomo, Sarah E. Harris, Tamuno Alfred, Rebecca Hardy, Diana Kuh, Mika Kivimäki, Meena Kumari, Ian N. M. Day, Jane Elliott, John M. Starr, Jane Maddock, Chris Power, Ian J. Deary, Rachel Cooper, Elina Hyppönen, Alfred, Tamuno, Ben-Shlomo, Yoav, Cooper, Rachel, Hardy, Rebecca, Deary, Ian J, Elliott, Jane, Harris, Sarah E, Hypponen, Elina, Kivimaki, Mika, Kumari, Meena, Maddock, Jane, Power, Chris, Starr, John M, Kuh, Diana, Day, Ian NM, and HALCyon Study Team

Subjects
cognition, Oncology, medicine.medical_specialty, vitamin D-binding protein, Population, Medicine (miscellaneous), vitamin D, Genome-wide association study, Biology, hemochromatosis, polymorphism, 03 medical and health sciences, iron, 0302 clinical medicine, Internal medicine, medicine, Vitamin D and neurology, 030212 general & internal medicine, Allele, education, 2. Zero hunger, Genetics, education.field_of_study, Nutrition and Dietetics, Confounding, Proteolytic enzymes, Micronutrient, nutritional status, Minor allele frequency, micronutrients, alleles, mental recall, biological markers, 030217 neurology & neurosurgery
Abstract

Several investigations have observed positive associations between good nutritional status, as indicated by micronutrients, and cognitive measures; however, these associations may not be causal. genetic polymorphisms that affect nutritional biomarkers may be useful for providing evidence for associations between micronutrients and cognitive measures. as part of the healthy ageing across the life course (HALCYON) program, men and women aged between 44 and 90 y from 6 UK cohorts were genotyped for polymorphisms associated with circulating concentrations of iron [rs4820268 transmembrane protease, serine 6 (TMPRSS6) and rs1800562 hemochromatosis (HFE)], vitamin B-12 [(rs492602 fucosyltransferase 2 (FUT2)], vitamin D ([rs2282679 group-specific component (GC)] and β-carotene ([rs6564851 beta-carotene 15,15'-monooxygenase 1 (BCMO1)]. meta-analysis was used to pool within-study effects of the associations between these polymorphisms and the followingmeasures of cognitive capability: word recall, phonemic fluency, semantic fluency, and search speed. among the several statistical tests conducted, we found little evidence for associations. we found the minor allele of rs1800562 was associated with poorer word recall scores [pooled Β on Z-score for carriers vs. noncarriers: 20.05 (95% CI: 20.09, 20.004); P = 0.03, n = 14,105] and poorer word recall scores for the vitamin D-raising allele of rs2282679 [pooled β per T allele: 20.03 (95% CI: 20.05, 20.003); P = 0.03, n = 16,527]. however, there was no evidence for other associations. our findings provide little evidence to support associations between these genotypes and cognitive capability in older adults. further investigations are required to elucidate whether the previous positive associations from observational studies between circulating measures of these micronutrients and cognitive performance are due to confounding and reverse causality. Refereed/Peer-reviewed

Published
2013

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