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4 results on '"Fairhurst-Hunter, Zammy"'

1. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

Author

Schmidt, Amand F., Swerdlow, Daniel I., Holmes, Michael V., Patel, Riyaz S., Fairhurst-Hunter, Zammy, Lyall, Donald M., Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hyppönen, Elina, Power, Christine, Moldovan, Max, van Iperen, Erik, Hovingh, G. Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Liu, Tian, Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F., Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G., Onland-Moret, N. Charlotte, van der Schouw, Yvonne T., Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J., Langenberg, Claudia, Scott, Robert, Luan, Jian'an, Bobak, Martin, Malyutina, Sofia, Pająk, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Husemoen, Lise Lotte Nystrup, Garup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Simonsen, Kenneth Starup, Cooper, Jackie, Humphries, Steve E., Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S., McCarty, Catherine A., Kirchner, H. Lester, Larson, Eric B., Crosslin, David R., de Andrade, Mariza, Roden, Dan M., Denny, Joshua C., Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, van der Harst, Pim, Said, M. Abdullah, Eppinga, Ruben N., Verweij, Niek, Snieder, Harold, Christen, Tim, Mook-Kanamori, Dennis O., Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Dörr, Marcus, Lerch, Markus M., Völker, Uwe, Völzke, Henry, Ward, Joey, Pell, Jill P., Smith, Daniel J., Meade, Tom, Maitland-van der Zee, Anke H., Baranova, Ekaterina V., Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L., Grobbee, Diederick E., Froguel, Philippe, Thuillier, Dorothée, Balkau, Beverley, Bonnefond, Amélie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Ridker, Paul M., Chasman, Daniel I., Reiner, Alex P., Lange, Leslie A., Ritchie, Marylyn D., Asselbergs, Folkert, Casas, Juan-Pablo, Keating, Brendan J., Preiss, David, Hingorani, Aroon D., Sattar, Naveed, LifeLines Cohort study group, UCLEB consortium, Epidemiology, and Internal Medicine

Subjects
Blood Glucose, STATIN THERAPY, Endocrinology, Diabetes and Metabolism, HEART-DISEASE, Endocrinology and Diabetes, Heart disease, Internal Medicine, Endocrinology, Medical and Health Sciences, HYPERCHOLESTEROLEMIA, Cohort Studies, Endocrinology & Metabolism, SDG 3 - Good Health and Well-being, Health Sciences, Journal Article, Diabetes Mellitus, Humans, LDL-cholesterol, Genetic Predisposition to Disease, Mendelian randomisation, COMMON, METAANALYSIS, Genetic Association Studies, Randomized Controlled Trials as Topic, ARCHITECTURE, Science & Technology, CHOLESTEROL, Diabetes, Genetic Variation, PATHWAYS, nutritional and metabolic diseases, Cholesterol, LDL, ASSOCIATION, Mendelian Randomization Analysis, UCLEB consortium, PCSK9 inhibition, Diabetes and Metabolism, INSIGHTS, Diabetes Mellitus, Type 2, Case-Control Studies, Endokrinologi och diabetes, LDL cholesterol, Proprotein Convertase 9, Blood Glucose/metabolism, Cholesterol, LDL/blood, Cholesterol, LDL/genetics, Diabetes Mellitus, Type 2/blood, Diabetes Mellitus, Type 2/diagnosis, Diabetes Mellitus, Type 2/genetics, Genetic Predisposition to Disease/genetics, Genetic Variation/genetics, Mendelian Randomization Analysis/methods, Proprotein Convertase 9/genetics, Randomized Controlled Trials as Topic/methods, Life Sciences & Biomedicine, LifeLines Cohort study group
Abstract

Background: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions\ud in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest\ud hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their\ud substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2\ud diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.\ud Methods: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials,\ud case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol,\ud fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using\ud a standardised analysis plan, meta-analyses, and weighted gene-centric scores.\ud Findings: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses\ud of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower\ud LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight\ud (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50).\ud Based on the collected data, we did not identify associations with HbA1c (0·03%, –0·01 to 0·08), fasting insulin (0·00%,\ud –0·06 to 0·07), and BMI (0·11 kg/m², –0·09 to 0·30).\ud Interpretation: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher\ud fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of\ud PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits\ud of PCSK9 inhibitor treatment, as was previously done for statins.\ud Funding: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National\ud Institute for Health Research (NIHR) Biomedical Research Centre.

Published
2017
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2. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

Author

Schmidt, Amand F., Holmes, Michael V., Preiss, David, Swerdlow, Daniel I., Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, and Steinhagen-Thiessen, Elisabeth

Subjects
TYPE 2 diabetes, BLOOD lipids, OBSTRUCTIVE lung diseases, TREATMENT effectiveness, ATRIAL fibrillation, FLUTICASONE
Abstract

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate. [ABSTRACT FROM AUTHOR]

Published
2019
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3. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Schmidt, Amand F., Holmes, Michael V., Preiss, David, Swerdlow, Daniel I., Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, Van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M., Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F., Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G., Onland-Moret, N. Charlotte, Van Der Schouw, Yvonne T., Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J., Langenberg, Claudia, Scott, Robert A., Luan, Jian’an, Bobak, Martin, Malyutina, Sofia, Pająk, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve E., Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S., McCarty, Catherine A., Lester, Kirchner H., Larson, Eric B., Crosslin, David R., De Andrade, Mariza, Roden, Dan M., Denny, Joshua C., Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O’Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, Van Der Harst, Pim, Said, M. Abdullah, Eppinga, Ruben N., Verweij, Niek, Snieder, Harold, Christen, Tim, Mook-Kanamori, D. O., Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Dörr, Marcus, Lerch, Markus M., Völker, Uwe, Völzke, Henry, Ward, Joey, Pell, Jill P., Meade, Tom, Christophersen, Ingrid E., Maitland-Van Der Zee, Anke H., Baranova, Ekaterina V., Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L., Grobbee, Diederick E., Froguel, Philippe, Thuillier, Dorothée, Roussel, Ronan, Bonnefond, Amélie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C., Seshadri, Sudha, Dale, Caroline, Costa, Rui Providencia E., Ridker, Paul M., Chasman, Daniel I., Reiner, Alex P., Ritchie, Marylyn D., Lange, Leslie A., Cornish, Alex J., Dobbins, Sara E., Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, Nilsson, Björn, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W., Patel, Riyaz S., Keating, Brendan J., Sattar, Naveed, Houlston, Richard, Casas, Juan P., and Hingorani, Aroon D.

Subjects
Genetic association studies, LDL-cholesterol, Phenome-wide association scan, Mendelian randomisation, Coronary artery disease, 3. Good health, Research Article
Abstract

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

4. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author

Schmidt, Amand F, Holmes, Michael V, Preiss, David, Swerdlow, Daniel I, Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, Van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M, Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F, Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G, Onland-Moret, N Charlotte, Van Der Schouw, Yvonne T, Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J, Langenberg, Claudia, Scott, Robert A, Luan, Jian'an, Bobak, Martin, Malyutina, Sofia, Pająk, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve E, Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S, McCarty, Catherine A, Lester, Kirchner H, Larson, Eric B, Crosslin, David R, De Andrade, Mariza, Roden, Dan M, Denny, Joshua C, Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, Van Der Harst, Pim, Said, M Abdullah, Eppinga, Ruben N, Verweij, Niek, Snieder, Harold, Lifelines Cohort Authors, Christen, Tim, Mook-Kanamori, DO, ICBP Consortium, Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Dörr, Marcus, Lerch, Markus M, Völker, Uwe, Völzke, Henry, Ward, Joey, Pell, Jill P, Meade, Tom, Christophersen, Ingrid E, Maitland-Van Der Zee, Anke H, Baranova, Ekaterina V, Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L, Grobbee, Diederick E, Froguel, Philippe, Thuillier, Dorothée, Roussel, Ronan, Bonnefond, Amélie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C, Seshadri, Sudha, METASTROKE Consortium Of The ISGC, Dale, Caroline, Costa, Rui Providencia E, Ridker, Paul M, Chasman, Daniel I, Reiner, Alex P, Ritchie, Marylyn D, Lange, Leslie A, Cornish, Alex J, Dobbins, Sara E, Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, Nilsson, Björn, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W, Patel, Riyaz S, Keating, Brendan J, Sattar, Naveed, Houlston, Richard, Casas, Juan P, and Hingorani, Aroon D

Subjects
Genetic association studies, Serine Proteinase Inhibitors, Anticholesteremic Agents, PCSK9 Inhibitors, Myocardial Infarction, Down-Regulation, Cholesterol, LDL, Polymorphism, Single Nucleotide, Risk Assessment, 3. Good health, Brain Ischemia, Stroke, Treatment Outcome, Risk Factors, LDL-cholesterol, Humans, Phenome-wide association scan, Proprotein Convertase 9, Mendelian randomisation, Biomarkers, Dyslipidemias, Genome-Wide Association Study, Randomized Controlled Trials as Topic
Abstract

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

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