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15 results on '"Holm, Hilma"'

1. Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

Author

Ghouse, Jonas, Sveinbjörnsson, Gardar, Vujkovic, Marijana, Seidelin, Anne-Sofie, Gellert-Kristensen, Helene, Ahlberg, Gustav, Tragante, Vinicius, Rand, Søren, Brancale, Joseph, Vilarinho, Silvia, Lundegaard, Pia, Sørensen, Erik, Erikstrup, Christian, Bruun, Mie, Jensen, Bitten, Brunak, Søren, Banasik, Karina, Ullum, Henrik, Verweij, Niek, Lotta, Luca, Baras, Aris, Mirshahi, Tooraj, Carey, David, Kaplan, David, Lynch, Julie, Morgan, Timothy, Schwantes-An, Tae-Hwi, Dochtermann, Daniel, Pyarajan, Saiju, Tsao, Philip, Laisk, Triin, Mägi, Reedik, Kozlitina, Julia, Tybjærg-Hansen, Anne, Jones, David, Knowlton, Kirk, Nadauld, Lincoln, Ferkingstad, Egil, Björnsson, Einar, Ulfarsson, Magnus, Sturluson, Árni, Sulem, Patrick, Pedersen, Ole, Ostrowski, Sisse, Gudbjartsson, Daniel, Stefansson, Kari, Olesen, Morten, Chang, Kyong-Mi, Holm, Hilma, Bundgaard, Henning, and Stender, Stefan

Subjects
Humans, Liver Cirrhosis, Genome-Wide Association Study, Genetic Predisposition to Disease, Liver Neoplasms, Carcinoma, Hepatocellular, Alanine Transaminase, Polymorphism, Single Nucleotide, Male, Lipase, Female, gamma-Glutamyltransferase, Membrane Proteins, Cohort Studies, Case-Control Studies, Multifactorial Inheritance, Risk Factors, Genetic Variation
Abstract

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

Published
2024

2. X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

Author

Scholz, Markus, Horn, Katrin, Pott, Janne, Wuttke, Matthias, Kühnapfel, Andreas, Nasr, M, Kirsten, Holger, Li, Yong, Hoppmann, Anselm, Gorski, Mathias, Ghasemi, Sahar, Li, Man, Tin, Adrienne, Chai, Jin-Fang, Cocca, Massimiliano, Wang, Judy, Nutile, Teresa, Akiyama, Masato, Åsvold, Bjørn, Bansal, Nisha, Biggs, Mary, Boutin, Thibaud, Brenner, Hermann, Brumpton, Ben, Burkhardt, Ralph, Cai, Jianwen, Campbell, Archie, Campbell, Harry, Chalmers, John, Chasman, Daniel, Chee, Miao, Chen, Xu, Cheng, Ching-Yu, Cifkova, Renata, Daviglus, Martha, Delgado, Graciela, Dittrich, Katalin, Edwards, Todd, Endlich, Karlhans, Michael Gaziano, J, Giri, Ayush, Giulianini, Franco, Gordon, Scott, Gudbjartsson, Daniel, Hallan, Stein, Hamet, Pavel, Hartman, Catharina, Hayward, Caroline, Heid, Iris, Hellwege, Jacklyn, Holleczek, Bernd, Holm, Hilma, Hutri-Kähönen, Nina, Hveem, Kristian, Isermann, Berend, Jonas, Jost, Joshi, Peter, Kamatani, Yoichiro, Kanai, Masahiro, Kastarinen, Mika, Khor, Chiea, Kiess, Wieland, Kleber, Marcus, Körner, Antje, Kovacs, Peter, Krajcoviechova, Alena, Kramer, Holly, Krämer, Bernhard, Kuokkanen, Mikko, Kähönen, Mika, Lange, Leslie, Lash, James, Lehtimäki, Terho, Li, Hengtong, Lin, Bridget, Liu, Jianjun, Loeffler, Markus, Lyytikäinen, Leo-Pekka, Magnusson, Patrik, Martin, Nicholas, Matsuda, Koichi, Milaneschi, Yuri, Mishra, Pashupati, Mononen, Nina, Montgomery, Grant, Mook-Kanamori, Dennis, Mychaleckyj, Josyf, März, Winfried, Nauck, Matthias, Nikus, Kjell, Nolte, Ilja, Noordam, Raymond, Okada, Yukinori, Olafsson, Isleifur, Oldehinkel, Albertine, Penninx, Brenda, Perola, Markus, Pirastu, Nicola, and Polasek, Ozren

Subjects
Humans, Male, Female, Androgens, Genome-Wide Association Study, Kidney, Chromosomes, Human, X, Response Elements, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Tetraspanins
Abstract

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Published
2024

3. Genetic insights into resting heart rate and its role in cardiovascular disease.

Author

van de Vegte, Yordi, Eppinga, Ruben, van der Ende, M, Hagemeijer, Yanick, Mahendran, Yuvaraj, Salfati, Elias, Smith, Albert, Tan, Vanessa, Arking, Dan, Ntalla, Ioanna, Appel, Emil, Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing, Isaacs, Aaron, Wang, Lihua, Luan, Jianan, Hwang, Shih-Jen, Mononen, Nina, Auro, Kirsi, Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Müller-Nurasyid, Martina, Roselli, Carolina, Zhang, Weihua, Kleber, Marcus, Guo, Xiuqing, Lin, Henry, Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond, Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke, Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung, Weiss, Stefan, Sim, Xueling, Li, Hengtong, van der Most, Peter, Nolte, Ilja, Lyytikäinen, Leo-Pekka, Said, M, Witte, Daniel, Iribarren, Carlos, Launer, Lenore, Ring, Susan, de Vries, Paul, Sever, Peter, Linneberg, Allan, Bottinger, Erwin, Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Arnar, David, Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley, Silva, Claudia, Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu, Mohlke, Karen, Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari, Rao, Dabeeru, Cornelis, Marilyn, Faul, Jessica, Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie, and Sinner, Moritz

Subjects
Humans, Cardiovascular Diseases, Risk Factors, Heart Rate, Genetic Predisposition to Disease, Atrial Fibrillation, Mendelian Randomization Analysis, Genome-Wide Association Study, Polymorphism, Single Nucleotide
Abstract

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Published
2023

4. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

Author

Ramdas, Shweta, Judd, Jonathan, Graham, Sarah E, Kanoni, Stavroula, Wang, Yuxuan, Surakka, Ida, Wenz, Brandon, Clarke, Shoa L, Chesi, Alessandra, Wells, Andrew, Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Zajac, Greg JM, Wu, Kuan-Han H, Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T, Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Havulinna, Aki S, Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A, Lingren, Todd, Feng, QiPing, Kullo, Iftikhar J, Narita, Akira, Takayama, Jun, Martin, Hilary C, Hunt, Karen A, Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Rasheed, Asif, Hindy, George, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A, Yao, Jie, Manichaikul, Ani, Lee, Wen-Jane, Hsiung, Chao Agnes, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, and Sabater-Lleal, Maria

Subjects
Human Genome, Biotechnology, Genetics, 2.1 Biological and endogenous factors, Aetiology, Chromatin, Genome-Wide Association Study, Genomics, Humans, Lipids, Polymorphism, Single Nucleotide, Million Veterans Program, Global Lipids Genetics Consortium, complex traits, fine-mapping, functional genomics, lipid biology, post-GWAS, regulatory mechanism, variant prioritization, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

Published
2022

5. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, Sarah E, Clarke, Shoa L, Wu, Kuan-Han H, Kanoni, Stavroula, Zajac, Greg JM, Ramdas, Shweta, Surakka, Ida, Ntalla, Ioanna, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Hwang, Mi Yeong, Han, Sohee, Narita, Akira, Choudhury, Ananyo, Bentley, Amy R, Ekoru, Kenneth, Verma, Anurag, Trivedi, Bhavi, Martin, Hilary C, Hunt, Karen A, Hui, Qin, Klarin, Derek, Zhu, Xiang, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Ruotsalainen, Sanni E, Havulinna, Aki S, Veturi, Yogasudha, Feng, QiPing, Rosenthal, Elisabeth A, Lingren, Todd, Pacheco, Jennifer Allen, Pendergrass, Sarah A, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Hindy, George, Rasheed, Asif, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Willemsen, Gonneke, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Yao, Jie, Manichaikul, Ani, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Sidore, Carlo, Fiorillo, Edoardo, McDaid, Aaron F, Marques-Vidal, Pedro, Wielscher, Matthias, Trompet, Stella, and Sattar, Naveed

Subjects
Heart Disease, Prevention, Human Genome, Genetics, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Cardiovascular Diseases, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Population Groups, VA Million Veteran Program, Global Lipids Genetics Consortium*, General Science & Technology
Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

Published
2021

6. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Author

Teumer, Alexander, Li, Yong, Ghasemi, Sahar, Prins, Bram P, Wuttke, Matthias, Hermle, Tobias, Giri, Ayush, Sieber, Karsten B, Qiu, Chengxiang, Kirsten, Holger, Tin, Adrienne, Chu, Audrey Y, Bansal, Nisha, Feitosa, Mary F, Wang, Lihua, Chai, Jin-Fang, Cocca, Massimiliano, Fuchsberger, Christian, Gorski, Mathias, Hoppmann, Anselm, Horn, Katrin, Li, Man, Marten, Jonathan, Noce, Damia, Nutile, Teresa, Sedaghat, Sanaz, Sveinbjornsson, Gardar, Tayo, Bamidele O, van der Most, Peter J, Xu, Yizhe, Yu, Zhi, Gerstner, Lea, Ärnlöv, Johan, Bakker, Stephan JL, Baptista, Daniela, Biggs, Mary L, Boerwinkle, Eric, Brenner, Hermann, Burkhardt, Ralph, Carroll, Robert J, Chee, Miao-Li, Chee, Miao-Ling, Chen, Mengmeng, Cheng, Ching-Yu, Cook, James P, Coresh, Josef, Corre, Tanguy, Danesh, John, de Borst, Martin H, De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko PJ, Degenhardt, Frauke, Dittrich, Katalin, Divers, Jasmin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Felix, Janine F, Franco, Oscar H, Franke, Andre, Freedman, Barry I, Freitag-Wolf, Sandra, Gansevoort, Ron T, Giedraitis, Vilmantas, Gögele, Martin, Grundner-Culemann, Franziska, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hamet, Pavel, Harris, Tamara B, Hicks, Andrew A, Holm, Hilma, Foo, Valencia Hui Xian, Hwang, Shih-Jen, Ikram, M Arfan, Ingelsson, Erik, Jaddoe, Vincent WV, Jakobsdottir, Johanna, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Khor, Chiea-Chuen, Kiess, Wieland, Koenig, Wolfgang, Körner, Antje, Kovacs, Peter, Kramer, Holly, Krämer, Bernhard K, Kronenberg, Florian, Lange, Leslie A, Langefeld, Carl D, Lee, Jeannette Jen-Mai, Lehtimäki, Terho, Lieb, Wolfgang, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M, Liu, Jianjun, and Loeffler, Markus

Subjects
Animals, Humans, Drosophila melanogaster, Albuminuria, Diabetes Mellitus, Genetic Predisposition to Disease, Creatinine, Risk Factors, Chromosome Mapping, Gene Expression Regulation, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, Phenomics
Abstract

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Published
2019

7. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Teumer, Alexander, Li, Yong, Ghasemi, Sahar, Prins, Bram P, Wuttke, Matthias, Hermle, Tobias, Giri, Ayush, Sieber, Karsten B, Qiu, Chengxiang, Kirsten, Holger, Tin, Adrienne, Chu, Audrey Y, Bansal, Nisha, Feitosa, Mary F, Wang, Lihua, Chai, Jin-Fang, Cocca, Massimiliano, Fuchsberger, Christian, Gorski, Mathias, Hoppmann, Anselm, Horn, Katrin, Li, Man, Marten, Jonathan, Noce, Damia, Nutile, Teresa, Sedaghat, Sanaz, Sveinbjornsson, Gardar, Tayo, Bamidele O, van der Most, Peter J, Xu, Yizhe, Yu, Zhi, Gerstner, Lea, Ärnlöv, Johan, Bakker, Stephan JL, Baptista, Daniela, Biggs, Mary L, Boerwinkle, Eric, Brenner, Hermann, Burkhardt, Ralph, Carroll, Robert J, Chee, Miao-Li, Chee, Miao-Ling, Chen, Mengmeng, Cheng, Ching-Yu, Cook, James P, Coresh, Josef, Corre, Tanguy, Danesh, John, de Borst, Martin H, De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko PJ, Degenhardt, Frauke, Dittrich, Katalin, Divers, Jasmin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Felix, Janine F, Franco, Oscar H, Franke, Andre, Freedman, Barry I, Freitag-Wolf, Sandra, Gansevoort, Ron T, Giedraitis, Vilmantas, Gögele, Martin, Grundner-Culemann, Franziska, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hamet, Pavel, Harris, Tamara B, Hicks, Andrew A, Holm, Hilma, Foo, Valencia Hui Xian, Hwang, Shih-Jen, Ikram, M Arfan, Ingelsson, Erik, Jaddoe, Vincent WV, Jakobsdottir, Johanna, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Khor, Chiea-Chuen, Kiess, Wieland, Koenig, Wolfgang, Körner, Antje, Kovacs, Peter, Kramer, Holly, Krämer, Bernhard K, Kronenberg, Florian, Lange, Leslie A, Langefeld, Carl D, Lee, Jeannette Jen-Mai, Lehtimäki, Terho, Lieb, Wolfgang, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M, Liu, Jianjun, and Loeffler, Markus

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Kidney Disease, Cardiovascular, Renal and urogenital, Albuminuria, Animals, Chromosome Mapping, Creatinine, Diabetes Mellitus, Drosophila melanogaster, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Phenomics, Risk Factors
Abstract

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

Published
2019

8. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Author

Gusarova, Viktoria, O’Dushlaine, Colm, Teslovich, Tanya M, Benotti, Peter N, Mirshahi, Tooraj, Gottesman, Omri, Van Hout, Cristopher V, Murray, Michael F, Mahajan, Anubha, Nielsen, Jonas B, Fritsche, Lars, Wulff, Anders Berg, Gudbjartsson, Daniel F, Sjögren, Marketa, Emdin, Connor A, Scott, Robert A, Lee, Wen-Jane, Small, Aeron, Kwee, Lydia C, Dwivedi, Om Prakash, Prasad, Rashmi B, Bruse, Shannon, Lopez, Alexander E, Penn, John, Marcketta, Anthony, Leader, Joseph B, Still, Christopher D, Kirchner, H Lester, Mirshahi, Uyenlinh L, Wardeh, Amr H, Hartle, Cassandra M, Habegger, Lukas, Fetterolf, Samantha N, Tusie-Luna, Teresa, Morris, Andrew P, Holm, Hilma, Steinthorsdottir, Valgerdur, Sulem, Patrick, Thorsteinsdottir, Unnur, Rotter, Jerome I, Chuang, Lee-Ming, Damrauer, Scott, Birtwell, David, Brummett, Chad M, Khera, Amit V, Natarajan, Pradeep, Orho-Melander, Marju, Flannick, Jason, Lotta, Luca A, Willer, Cristen J, Holmen, Oddgeir L, Ritchie, Marylyn D, Ledbetter, David H, Murphy, Andrew J, Borecki, Ingrid B, Reid, Jeffrey G, Overton, John D, Hansson, Ola, Groop, Leif, Shah, Svati H, Kraus, William E, Rader, Daniel J, Chen, Yii-Der I, Hveem, Kristian, Wareham, Nicholas J, Kathiresan, Sekar, Melander, Olle, Stefansson, Kari, Nordestgaard, Børge G, Tybjærg-Hansen, Anne, Abecasis, Goncalo R, Altshuler, David, Florez, Jose C, Boehnke, Michael, McCarthy, Mark I, Yancopoulos, George D, Carey, David J, Shuldiner, Alan R, Baras, Aris, Dewey, Frederick E, and Gromada, Jesper

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Diabetes, Atherosclerosis, Cardiovascular, Metabolic and endocrine, Amino Acid Substitution, Angiopoietin-Like Protein 4, Animals, Blood Glucose, Case-Control Studies, Diabetes Mellitus, Type 2, Female, Gene Silencing, Genetic Association Studies, Genetic Variation, Heterozygote, Homeostasis, Humans, Insulin Resistance, Lipoprotein Lipase, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Risk Factors, Exome Sequencing
Abstract

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.

Published
2018

9. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Ilaria, Gandin, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth JF, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thomas, Mitchell, Braxton D, Munzel, Thomas, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcus, and Ferrucci, Luigi

Subjects
Biological Sciences, Genetics, Human Genome, Heart Disease, Biotechnology, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Atrial Function, Atrioventricular Node, Electrocardiography, Electrophysiological Phenomena, Female, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Mutation, Missense, Risk Factors
Abstract

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Published
2018

10. Discovery and refinement of loci associated with lipid levels

Author

Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Peloso, Gina M, Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L, Mora, Samia, Beckmann, Jacques S, Bragg-Gresham, Jennifer L, Chang, Hsing-Yi, Demirkan, Ayse, Den Hertog, Heleen M, Do, Ron, Donnelly, Louise A, Ehret, Georg B, Esko, Tonu, Feitosa, Mary F, Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Fraser, Ross M, Freitag, Daniel F, Gurdasani, Deepti, Heikkila, Kauko, Hyppoenen, Elina, Isaacs, Aaron, Jackson, Anne U, Johansson, Asa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E, Li, Xiaohui, Luan, Jian'an, Lyytikainen, Leo-Pekka, Magnusson, Patrik KE, Mangino, Massimo, Mihailov, Evelin, Montasser, May E, Mueller-Nurasyid, Martina, Nolte, Ilja M, O'Connell, Jeffrey R, Palmer, Cameron D, Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Service, Susan K, Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J, Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M, Thorleifsson, Gudmar, Van den Herik, Evita G, Voight, Benjamin F, Volcik, Kelly A, Waite, Lindsay L, Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Ines, Been, Latonya F, Bolton, Jennifer L, Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S, Cesana, Giancarlo, Dimitriou, Maria, Doney, Alex SF, Doering, Angela, Elliott, Paul, Epstein, Stephen E, Eyjolfsson, Gudmundur Ingi, Gigante, Bruna, Goodarzi, Mark O, Grallert, Harald, Gravito, Martha L, Groves, Christopher J, Hallmans, Goran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A, Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R, Kaleebu, Pontiano, Kastelein, John JP, Khaw, Kay-Tee, and Kim, Eric

Subjects
Cardiovascular, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Asian People, Black People, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Lipids, Triglycerides, White People, Global Lipids Genetics Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

Published
2013

11. Common variants associated with plasma triglycerides and risk for coronary artery disease

Author

Do, Ron, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Gao, Chi, Peloso, Gina M, Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L, Mora, Samia, Beckmann, Jacques S, Bragg-Gresham, Jennifer L, Chang, Hsing-Yi, Demirkan, Ayşe, Den Hertog, Heleen M, Donnelly, Louise A, Ehret, Georg B, Esko, Tõnu, Feitosa, Mary F, Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Fraser, Ross M, Freitag, Daniel F, Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U, Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E, Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik KE, Mangino, Massimo, Mihailov, Evelin, Montasser, May E, Müller-Nurasyid, Martina, Nolte, Ilja M, O'Connell, Jeffrey R, Palmer, Cameron D, Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Service, Susan K, Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J, Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M, Thorleifsson, Gudmar, Van den Herik, Evita G, Voight, Benjamin F, Volcik, Kelly A, Waite, Lindsay L, Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Been, Latonya F, Bolton, Jennifer L, Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S, Cesana, Giancarlo, Dimitriou, Maria, Doney, Alex SF, Döring, Angela, Elliott, Paul, Epstein, Stephen E, Eyjolfsson, Gudmundur Ingi, Gigante, Bruna, Goodarzi, Mark O, Grallert, Harald, Gravito, Martha L, Groves, Christopher J, Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A, Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R, Kaleebu, Pontiano, Kastelein, John JP, and Khaw, Kay-Tee

Subjects
Heart Disease - Coronary Heart Disease, Atherosclerosis, Prevention, Heart Disease, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, Biological Transport, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Humans, Polymorphism, Single Nucleotide, Risk Factors, Triglycerides, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Published
2013

12. Discovery and refinement of loci associated with lipid levels.

Author

Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Peloso, Gina M, Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L, Mora, Samia, Beckmann, Jacques S, Bragg-Gresham, Jennifer L, Chang, Hsing-Yi, Demirkan, Ayşe, Den Hertog, Heleen M, Do, Ron, Donnelly, Louise A, Ehret, Georg B, Esko, Tõnu, Feitosa, Mary F, Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Fraser, Ross M, Freitag, Daniel F, Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U, Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E, Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik KE, Mangino, Massimo, Mihailov, Evelin, Montasser, May E, Müller-Nurasyid, Martina, Nolte, Ilja M, O'Connell, Jeffrey R, Palmer, Cameron D, Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Service, Susan K, Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J, Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M, Thorleifsson, Gudmar, Van den Herik, Evita G, Voight, Benjamin F, Volcik, Kelly A, Waite, Lindsay L, Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Been, Latonya F, Bolton, Jennifer L, Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S, Cesana, Giancarlo, Dimitriou, Maria, Doney, Alex SF, Döring, Angela, Elliott, Paul, Epstein, Stephen E, Ingi Eyjolfsson, Gudmundur, Gigante, Bruna, Goodarzi, Mark O, Grallert, Harald, Gravito, Martha L, Groves, Christopher J, Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A, Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R, Kaleebu, Pontiano, Kastelein, John JP, Khaw, Kay-Tee, and Kim, Eric

Subjects
Global Lipids Genetics Consortium, Humans, Genetic Predisposition to Disease, Lipids, Triglycerides, Genotype, African Continental Ancestry Group, Asian Continental Ancestry Group, European Continental Ancestry Group, Cholesterol, LDL, Cholesterol, HDL, Coronary Artery Disease, Genome-Wide Association Study, Cardiovascular, Genetics, Heart Disease - Coronary Heart Disease, Nutrition, Atherosclerosis, Heart Disease, 2.1 Biological and endogenous factors, Metabolic and endocrine, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

Published
2013

13. Common variants associated with plasma triglycerides and risk for coronary artery disease.

Author

Do, Ron, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Gao, Chi, Peloso, Gina M, Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L, Mora, Samia, Beckmann, Jacques S, Bragg-Gresham, Jennifer L, Chang, Hsing-Yi, Demirkan, Ayşe, Den Hertog, Heleen M, Donnelly, Louise A, Ehret, Georg B, Esko, Tõnu, Feitosa, Mary F, Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Fraser, Ross M, Freitag, Daniel F, Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U, Johansson, Asa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E, Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik KE, Mangino, Massimo, Mihailov, Evelin, Montasser, May E, Müller-Nurasyid, Martina, Nolte, Ilja M, O'Connell, Jeffrey R, Palmer, Cameron D, Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Service, Susan K, Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J, Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M, Thorleifsson, Gudmar, Van den Herik, Evita G, Voight, Benjamin F, Volcik, Kelly A, Waite, Lindsay L, Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Been, Latonya F, Bolton, Jennifer L, Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S, Cesana, Giancarlo, Dimitriou, Maria, Doney, Alex SF, Döring, Angela, Elliott, Paul, Epstein, Stephen E, Eyjolfsson, Gudmundur Ingi, Gigante, Bruna, Goodarzi, Mark O, Grallert, Harald, Gravito, Martha L, Groves, Christopher J, Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A, Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R, Kaleebu, Pontiano, Kastelein, John JP, and Khaw, Kay-Tee

Subjects
Humans, Triglycerides, Risk Factors, Biological Transport, Polymorphism, Single Nucleotide, Cholesterol, LDL, Cholesterol, HDL, Coronary Artery Disease, Polymorphism, Single Nucleotide, Cholesterol, LDL, HDL, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Published
2013

14. RANTES/CCL5 and Risk for Coronary Events: Results from the MONICA/KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM Studies

Author

Herder, Christian, Peeters, Wouter, Illig, Thomas, Baumert, Jens, de Kleijn, Dominique PV, Moll, Frans L, Poschen, Ulrike, Klopp, Norman, Müller-Nurasyid, Martina, Roden, Michael, Preuss, Michael, Karakas, Mahir, Meisinger, Christa, Thorand, Barbara, Pasterkamp, Gerard, Koenig, Wolfgang, Assimes, Themistocles L, Deloukas, Panos, Erdmann, Jeanette, Holm, Hilma, Kathiresan, Sekar, König, Inke R, McPherson, Ruth, Reilly, Muredach P, Roberts, Robert, Samani, Nilesh J, Schunkert, Heribert, and Stewart, Alexandre FR

Subjects
Cardiovascular, Clinical Research, Genetics, Heart Disease - Coronary Heart Disease, Aging, Heart Disease, Atherosclerosis, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Animals, Calcinosis, Case-Control Studies, Chemokine CCL5, Cohort Studies, Coronary Disease, Female, Follow-Up Studies, Germany, Humans, Macrophages, Male, Mice, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk, CARDIoGRAM Consortium, General Science & Technology
Abstract

BackgroundThe chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events.Methods and findingsWe conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75-1.42] and 1.11 [0.81-1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years).ConclusionsHigh RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies.

Published
2011

15. RANTES/CCL5 and risk for coronary events: results from the MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies.

Author

Herder, Christian, Peeters, Wouter, Illig, Thomas, Baumert, Jens, de Kleijn, Dominique PV, Moll, Frans L, Poschen, Ulrike, Klopp, Norman, Müller-Nurasyid, Martina, Roden, Michael, Preuss, Michael, CARDIoGRAM Consortium, Karakas, Mahir, Meisinger, Christa, Thorand, Barbara, Pasterkamp, Gerard, Koenig, Wolfgang, Assimes, Themistocles L, Deloukas, Panos, Erdmann, Jeanette, Holm, Hilma, Kathiresan, Sekar, König, Inke R, McPherson, Ruth, Reilly, Muredach P, Roberts, Robert, Samani, Nilesh J, Schunkert, Heribert, and Stewart, Alexandre FR

Subjects
CARDIoGRAM Consortium, Macrophages, Animals, Humans, Mice, Coronary Disease, Calcinosis, Proportional Hazards Models, Risk, Case-Control Studies, Cohort Studies, Follow-Up Studies, Phenotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Germany, Female, Male, Atherosclerosis, Chemokine CCL5, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

BackgroundThe chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events.Methods and findingsWe conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75-1.42] and 1.11 [0.81-1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years).ConclusionsHigh RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies.

Published
2011

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