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2. Secretory Phospholipase A2-IIA and Cardiovascular Disease: A Mendelian Randomization Study

Author

Holmes, Michael V., Simon, Tabassome, Exeter, Holly J., Folkersen, Lasse, Asselbergs, Folkert W., Guardiola, Montse, Cooper, Jackie A., Palmen, Jutta, Hubacek, Jaroslav A., Carruthers, Kathryn F., Horne, Benjamin D., Brunisholz, Kimberly D., Mega, Jessica L., van Iperen, Erik P.A., Li, Mingyao, Leusink, Maarten, Trompet, Stella, Verschuren, Jeffrey J.W., Hovingh, G. Kees, Dehghan, Abbas, Nelson, Christopher P., Kotti, Salma, Danchin, Nicolas, Scholz, Markus, Haase, Christiane L., Rothenbacher, Dietrich, Swerdlow, Daniel I., Kuchenbaecker, Karoline B., Staines-Urias, Eleonora, Goel, Anuj, van 't Hooft, Ferdinand, Gertow, Karl, de Faire, Ulf, Panayiotou, Andrie G., Tremoli, Elena, Baldassarre, Damiano, Veglia, Fabrizio, Holdt, Lesca M., Beutner, Frank, Gansevoort, Ron T., Navis, Gerjan J., Mateo Leach, Irene, Breitling, Lutz P., Brenner, Hermann, Thiery, Joachim, Dallmeier, Dhayana, Franco-Cereceda, Anders, Boer, Jolanda M.A., Stephens, Jeffrey W., Hofker, Marten H., Tedgui, Alain, Hofman, Albert, Uitterlinden, André G., Adamkova, Vera, Pitha, Jan, Onland-Moret, N. Charlotte, Cramer, Maarten J., Nathoe, Hendrik M., Spiering, Wilko, Klungel, Olaf H., Kumari, Meena, Whincup, Peter H., Morrow, David A., Braund, Peter S., Hall, Alistair S., Olsson, Anders G., Doevendans, Pieter A., Trip, Mieke D., Tobin, Martin D., Hamsten, Anders, Watkins, Hugh, Koenig, Wolfgang, Nicolaides, Andrew N., Teupser, Daniel, Day, Ian N.M., Carlquist, John F., Gaunt, Tom R., Ford, Ian, Sattar, Naveed, Tsimikas, Sotirios, Schwartz, Gregory G., Lawlor, Debbie A., Morris, Richard W., Sandhu, Manjinder S., Poledne, Rudolf, Maitland-van der Zee, Anke H., Khaw, Kay-Tee, Keating, Brendan J., van der Harst, Pim, Price, Jackie F., Mehta, Shamir R., Yusuf, Salim, Witteman, Jaqueline C.M., Franco, Oscar H., Jukema, J. Wouter, de Knijff, Peter, Tybjaerg-Hansen, Anne, Rader, Daniel J., Farrall, Martin, Samani, Nilesh J., Kivimaki, Mika, Fox, Keith A.A., Humphries, Steve E., Anderson, Jeffrey L., Boekholdt, S. Matthijs, Palmer, Tom M., Eriksson, Per, Paré, Guillaume, Hingorani, Aroon D., Sabatine, Marc S., Mallat, Ziad, Casas, Juan P., and Talmud, Philippa J.

Published
2013
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16. HDL Cholesterol and Risk of Type 2 Diabetes:A Mendelian Randomization Study

Author

Haase, Christiane L, Tybjærg-Hansen, Anne, Nordestgaard, Børge G, Frikke-Schmidt, Ruth, Haase, Christiane L, Tybjærg-Hansen, Anne, Nordestgaard, Børge G, and Frikke-Schmidt, Ruth

Abstract

Observationally, low levels of HDL cholesterol are consistently associated with increased risk of type 2 diabetes. Therefore, plasma HDL cholesterol increasing has been suggested as a novel therapeutic option to reduce the risk of type 2 diabetes. Whether levels of HDL cholesterol are causally associated with type 2 diabetes is unknown. In a prospective study of the general population (n = 47,627), we tested whether HDL cholesterol-related genetic variants were associated with low HDL cholesterol levels and, in turn, with an increased risk of type 2 diabetes. HDL cholesterol-decreasing gene scores and allele numbers associated with up to -13 and -20% reductions in HDL cholesterol levels. The corresponding theoretically predicted hazard ratios for type 2 diabetes were 1.44 (95% CI 1.38-1.52) and 1.77 (1.61-1.95), whereas the genetic estimates were nonsignificant. Genetic risk ratios for type 2 diabetes for a 0.2 mmol/L reduction in HDL cholesterol were 0.91 (0.75-1.09) and 0.93 (0.78-1.11) for HDL cholesterol-decreasing gene scores and allele numbers, respectively, compared with the corresponding observational hazard ratio of 1.37 (1.32-1.42). In conclusion, genetically reduced HDL cholesterol does not associate with increased risk of type 2 diabetes, suggesting that the corresponding observational association is due to confounding and/or reverse causation.

Published
2015

17. Subgroups at high risk for ischaemic heart disease:identification and validation in 67 000 individuals from the general population

Author

Frikke-Schmidt, Ruth, Tybjærg-Hansen, Anne, Dyson, Greg, Haase, Christiane L, Benn, Marianne, Nordestgaard, Børge G, Sing, Charles F, Frikke-Schmidt, Ruth, Tybjærg-Hansen, Anne, Dyson, Greg, Haase, Christiane L, Benn, Marianne, Nordestgaard, Børge G, and Sing, Charles F

Abstract

BACKGROUND: The aetiology of ischaemic heart disease (IHD) is complex and is influenced by a spectrum of environmental factors and susceptibility genes. Traditional statistical modelling considers such factors to act independently in an additive manner. The Patient Rule-Induction Method (PRIM) is a multi-model building strategy for evaluating risk attributable to context-dependent gene and environmental effects.METHODS: PRIM was applied to 9073 participants from the prospective Copenhagen City Heart Study (CCHS). Gender-specific cumulative incidences were estimated for subgroups defined by categories of age, smoking, hypertension, diabetes, body mass index, total cholesterol, high-density lipoprotein cholesterol and triglycerides and by 94 single nucleotide variants (SNVs).Cumulative incidences for subgroups were validated using an independently ascertained sample of 58 240 participants from the Copenhagen General Population Study (CGPS).RESULTS: In the CCHS the overall cumulative incidences were 0.17 in women and 0.21 in men. PRIM identified six and four mutually exclusive subgroups in women and men, respectively, with cumulative incidences of IHD ranging from 0.02 to 0.34. Cumulative incidences of IHD generated by PRIM in the CCHS were validated in four of the six subgroups of women and two of the four subgroups of men in the CGPS.CONCLUSIONS: PRIM identified high-risk subgroups characterized by specific contexts of selected values of traditional risk factors and genetic variants. These subgroups were validated in an independently ascertained cohort study. Thus, a multi-model strategy may identify groups of individuals with substantially higher risk of IHD than the overall risk for the general population.

Published
2015

18. Early Glycemic Control and Magnitude of HbA1c Reduction Predict Cardiovascular Events and Mortality: Population-Based Cohort Study of 24,752 Metformin Initiators.

Author

Svensson, Elisabeth, Baggesen, Lisbeth M., Johnsen, Søren P., Pedersen, Lars, Nørrelund, Helene, Buhl, Esben S., Haase, Christiane L., and Thomsen, Reimar W.

Subjects
GLYCEMIC control, CARDIOVASCULAR disease diagnosis, CARDIOVASCULAR disease related mortality, METFORMIN, PEOPLE with diabetes
Abstract

Objective: We investigated the association of early achieved HbA1c level and magnitude of HbA1c reduction with subsequent risk of cardiovascular events or death in patients with type 2 diabetes who initiate metformin.Research Design and Methods: This was a population-based cohort study including all metformin initiators with HbA1c tests in Northern Denmark, 2000-2012. Six months after metformin initiation, we classified patients by HbA1c achieved (<6.5% or higher) and by magnitude of HbA1c change from the pretreatment baseline. We used Cox regression to examine subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA1c and other confounding factors.Results: We included 24,752 metformin initiators (median age 62.5 years, 55% males) with a median follow-up of 2.6 years. The risk of a combined outcome event gradually increased with rising levels of HbA1c achieved compared with a target HbA1c of <6.5%: adjusted hazard ratio (HR) 1.18 (95% CI 1.07-1.30) for 6.5-6.99%, HR 1.23 (1.09-1.40) for 7.0-7.49%, HR 1.34 (1.14-1.57) for 7.5-7.99%, and HR 1.59 (1.37-1.84) for ≥8%. Results were consistent for individual outcome events and robust by age-group and other patient characteristics. A large absolute HbA1c reduction from baseline also predicted outcome: adjusted HR 0.80 (0.65-0.97) for Δ = -4, HR 0.98 (0.80-1.20) for Δ = -3, HR 0.92 (0.78-1.08) for Δ = -2, and HR 0.99 (0.89-1.10) for Δ = -1 compared with no HbA1c change (Δ = 0).Conclusions: A large initial HbA1c reduction and achievement of low HbA1c levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Published
2017
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20. Secretory phospholipase A(2)-IIA and cardiovascular disease:a mendelian randomization study

Author

Holmes, Michael V., Simon, Tabassome, Exeter, Holly J., Folkersen, Lasse, Asselbergs, Folkert W., Guardiola, Montse, Cooper, Jackie A., Palmen, Jutta, Hubacek, Jaroslav A., Carruthers, Kathryn F., Horne, Benjamin D., Brunisholz, Kimberly D., Mega, Jessica L., van Iperen, Erik P. A., Li, Mingyao, Leusink, Maarten, Trompet, Stella, Verschuren, Jeffrey J. W., Hovingh, G. Kees, Dehghan, Abbas, Nelson, Christopher P., Kotti, Salma, Danchin, Nicolas, Scholz, Markus, Haase, Christiane L., Rothenbacher, Dietrich, Swerdlow, Daniel I., Kuchenbaecker, Karoline B., Staines-Urias, Eleonora, Goel, Anuj, van 't Hooft, Ferdinand, Gertow, Karl, de Faire, Ulf, Panayiotou, Andrie G., Tremoli, Elena, Baldassarre, Damiano, Veglia, Fabrizio, Holdt, Lesca M., Beutner, Frank, Gansevoort, Ron T., Navis, Gerjan J., Mateo Leach, Irene, Breitling, Lutz P., Brenner, Hermann, Thiery, Joachim, Dallmeier, Dhayana, Franco-Cereceda, Anders, Boer, Jolanda M. A., Stephens, Jeffrey W., Hofker, Marten H., Tedgui, Alain, Hofman, Albert, Uitterlinden, André G., Adamkova, Vera, Pitha, Jan, Onland-Moret, N. Charlotte, Cramer, Maarten J., Nathoe, Hendrik M., Spiering, Wilko, Klungel, Olaf H., Kumari, Meena, Whincup, Peter H., Morrow, David A., Braund, Peter S., Hall, Alistair S., Olsson, Anders G., Doevendans, Pieter A., Trip, Mieke D., Tobin, Martin D., Hamsten, Anders, Watkins, Hugh, Koenig, Wolfgang, Nicolaides, Andrew N., Teupser, Daniel, Day, Ian N. M., Carlquist, John F., Gaunt, Tom R., Ford, Ian, Sattar, Naveed, Tsimikas, Sotirios, Schwartz, Gregory G., Lawlor, Debbie A., Morris, Richard W., Sandhu, Manjinder S., Poledne, Rudolf, Maitland-van der Zee, Anke H., Khaw, Kay-Tee, Keating, Brendan J., van der Harst, Pim, Price, Jackie F., Mehta, Shamir R., Yusuf, Salim, Witteman, Jaqueline C. M., Franco, Oscar H., Jukema, J. Wouter, de Knijff, Peter, Tybjaerg-Hansen, Anne, Rader, Daniel J., Farrall, Martin, Samani, Nilesh J., Kivimaki, Mika, Fox, Keith A. A., Humphries, Steve E., Anderson, Jeffrey L., Boekholdt, S. Matthijs, Palmer, Tom M., Eriksson, Per, Paré, Guillaume, Hingorani, Aroon D., Sabatine, Marc S., Mallat, Ziad, Casas, Juan P., Talmud, Philippa J., Holmes, Michael V., Simon, Tabassome, Exeter, Holly J., Folkersen, Lasse, Asselbergs, Folkert W., Guardiola, Montse, Cooper, Jackie A., Palmen, Jutta, Hubacek, Jaroslav A., Carruthers, Kathryn F., Horne, Benjamin D., Brunisholz, Kimberly D., Mega, Jessica L., van Iperen, Erik P. A., Li, Mingyao, Leusink, Maarten, Trompet, Stella, Verschuren, Jeffrey J. W., Hovingh, G. Kees, Dehghan, Abbas, Nelson, Christopher P., Kotti, Salma, Danchin, Nicolas, Scholz, Markus, Haase, Christiane L., Rothenbacher, Dietrich, Swerdlow, Daniel I., Kuchenbaecker, Karoline B., Staines-Urias, Eleonora, Goel, Anuj, van 't Hooft, Ferdinand, Gertow, Karl, de Faire, Ulf, Panayiotou, Andrie G., Tremoli, Elena, Baldassarre, Damiano, Veglia, Fabrizio, Holdt, Lesca M., Beutner, Frank, Gansevoort, Ron T., Navis, Gerjan J., Mateo Leach, Irene, Breitling, Lutz P., Brenner, Hermann, Thiery, Joachim, Dallmeier, Dhayana, Franco-Cereceda, Anders, Boer, Jolanda M. A., Stephens, Jeffrey W., Hofker, Marten H., Tedgui, Alain, Hofman, Albert, Uitterlinden, André G., Adamkova, Vera, Pitha, Jan, Onland-Moret, N. Charlotte, Cramer, Maarten J., Nathoe, Hendrik M., Spiering, Wilko, Klungel, Olaf H., Kumari, Meena, Whincup, Peter H., Morrow, David A., Braund, Peter S., Hall, Alistair S., Olsson, Anders G., Doevendans, Pieter A., Trip, Mieke D., Tobin, Martin D., Hamsten, Anders, Watkins, Hugh, Koenig, Wolfgang, Nicolaides, Andrew N., Teupser, Daniel, Day, Ian N. M., Carlquist, John F., Gaunt, Tom R., Ford, Ian, Sattar, Naveed, Tsimikas, Sotirios, Schwartz, Gregory G., Lawlor, Debbie A., Morris, Richard W., Sandhu, Manjinder S., Poledne, Rudolf, Maitland-van der Zee, Anke H., Khaw, Kay-Tee, Keating, Brendan J., van der Harst, Pim, Price, Jackie F., Mehta, Shamir R., Yusuf, Salim, Witteman, Jaqueline C. M., Franco, Oscar H., Jukema, J. Wouter, de Knijff, Peter, Tybjaerg-Hansen, Anne, Rader, Daniel J., Farrall, Martin, Samani, Nilesh J., Kivimaki, Mika, Fox, Keith A. A., Humphries, Steve E., Anderson, Jeffrey L., Boekholdt, S. Matthijs, Palmer, Tom M., Eriksson, Per, Paré, Guillaume, Hingorani, Aroon D., Sabatine, Marc S., Mallat, Ziad, Casas, Juan P., and Talmud, Philippa J.

Abstract

OBJECTIVES: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. BACKGROUND: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. METHODS: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. RESULTS: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. CONCLUSIONS: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

Published
2013

21. A Mendelian Randomization Study

Author

Holmes, Michael V, Simon, Tabassome, Exeter, Holly J, Folkersen, Lasse Westergaard, Asselbergs, Folkert W, Guardiola, Montse, Cooper, Jackie A, Palmen, Jutta, Hubacek, Jaroslav A, Carruthers, Kathryn F, Horne, Benjamin D, Brunisholz, Kimberly D, Mega, Jessica L, van Iperen, Erik P A, Li, Mingyao, Leusink, Maarten, Trompet, Stella, Verschuren, Jeffrey J W, Hovingh, G Kees, Dehghan, Abbas, Nelson, Christopher P, Kotti, Salma, Danchin, Nicolas, Scholz, Markus, Haase, Christiane L, Rothenbacher, Dietrich, Swerdlow, Daniel I, Kuchenbaecker, Karoline B, Staines-Urias, Eleonora, Goel, Anuj, van 't Hooft, Ferdinand, Gertow, Karl, de Faire, Ulf, Panayiotou, Andrie G, Tremoli, Elena, Baldassarre, Damiano, Veglia, Fabrizio, Holdt, Lesca M, Beutner, Frank, Gansevoort, Ron T, Navis, Gerjan J, Mateo Leach, Irene, Breitling, Lutz P, Brenner, Hermann, Thiery, Joachim, Dallmeier, Dhayana, Franco-Cereceda, Anders, Boer, Jolanda M A, Stephens, Jeffrey W, Hofker, Marten H, Tedgui, Alain, Hofman, Albert, Uitterlinden, André G, Adamkova, Vera, Pitha, Jan, Onland-Moret, N Charlotte, Cramer, Maarten J, Nathoe, Hendrik M, Spiering, Wilko, Klungel, Olaf H, Kumari, Meena, Whincup, Peter H, Morrow, David A, Braund, Peter S, Hall, Alistair S, Olsson, Anders G, Doevendans, Pieter A, Trip, Mieke D, Tobin, Martin D, Hamsten, Anders, Watkins, Hugh, Koenig, Wolfgang, Nicolaides, Andrew N, Teupser, Daniel, Day, Ian N M, Carlquist, John F, Gaunt, Tom R, Ford, Ian, Sattar, Naveed, Tsimikas, Sotirios, Schwartz, Gregory G, Lawlor, Debbie A, Morris, Richard W, Sandhu, Manjinder S, Poledne, Rudolf, Maitland-van der Zee, Anke H, Khaw, Kay-Tee, Keating, Brendan J, van der Harst, Pim, Price, Jackie F, Mehta, Shamir R, Yusuf, Salim, Witteman, Jaqueline C M, Franco, Oscar H, Jukema, J Wouter, de Knijff, Peter, Tybjaerg-Hansen, Anne, Rader, Daniel J, Farrall, Martin, Samani, Nilesh J, Kivimaki, Mika, Fox, Keith A A, Humphries, Steve E, Anderson, Jeffrey L, Boekholdt, S Matthijs, Palmer, Tom M, Eriksson, Per, Paré, Guillaume, Hingorani, Aroon D, Sabatine, Marc S, Mallat, Ziad, Casas, Juan P, Talmud, Philippa J, Holmes, Michael V, Simon, Tabassome, Exeter, Holly J, Folkersen, Lasse Westergaard, Asselbergs, Folkert W, Guardiola, Montse, Cooper, Jackie A, Palmen, Jutta, Hubacek, Jaroslav A, Carruthers, Kathryn F, Horne, Benjamin D, Brunisholz, Kimberly D, Mega, Jessica L, van Iperen, Erik P A, Li, Mingyao, Leusink, Maarten, Trompet, Stella, Verschuren, Jeffrey J W, Hovingh, G Kees, Dehghan, Abbas, Nelson, Christopher P, Kotti, Salma, Danchin, Nicolas, Scholz, Markus, Haase, Christiane L, Rothenbacher, Dietrich, Swerdlow, Daniel I, Kuchenbaecker, Karoline B, Staines-Urias, Eleonora, Goel, Anuj, van 't Hooft, Ferdinand, Gertow, Karl, de Faire, Ulf, Panayiotou, Andrie G, Tremoli, Elena, Baldassarre, Damiano, Veglia, Fabrizio, Holdt, Lesca M, Beutner, Frank, Gansevoort, Ron T, Navis, Gerjan J, Mateo Leach, Irene, Breitling, Lutz P, Brenner, Hermann, Thiery, Joachim, Dallmeier, Dhayana, Franco-Cereceda, Anders, Boer, Jolanda M A, Stephens, Jeffrey W, Hofker, Marten H, Tedgui, Alain, Hofman, Albert, Uitterlinden, André G, Adamkova, Vera, Pitha, Jan, Onland-Moret, N Charlotte, Cramer, Maarten J, Nathoe, Hendrik M, Spiering, Wilko, Klungel, Olaf H, Kumari, Meena, Whincup, Peter H, Morrow, David A, Braund, Peter S, Hall, Alistair S, Olsson, Anders G, Doevendans, Pieter A, Trip, Mieke D, Tobin, Martin D, Hamsten, Anders, Watkins, Hugh, Koenig, Wolfgang, Nicolaides, Andrew N, Teupser, Daniel, Day, Ian N M, Carlquist, John F, Gaunt, Tom R, Ford, Ian, Sattar, Naveed, Tsimikas, Sotirios, Schwartz, Gregory G, Lawlor, Debbie A, Morris, Richard W, Sandhu, Manjinder S, Poledne, Rudolf, Maitland-van der Zee, Anke H, Khaw, Kay-Tee, Keating, Brendan J, van der Harst, Pim, Price, Jackie F, Mehta, Shamir R, Yusuf, Salim, Witteman, Jaqueline C M, Franco, Oscar H, Jukema, J Wouter, de Knijff, Peter, Tybjaerg-Hansen, Anne, Rader, Daniel J, Farrall, Martin, Samani, Nilesh J, Kivimaki, Mika, Fox, Keith A A, Humphries, Steve E, Anderson, Jeffrey L, Boekholdt, S Matthijs, Palmer, Tom M, Eriksson, Per, Paré, Guillaume, Hingorani, Aroon D, Sabatine, Marc S, Mallat, Ziad, Casas, Juan P, and Talmud, Philippa J

Published
2013

22. Population-Based Resequencing of APOA1 in 10,330 Individuals:Spectrum of Genetic Variation, Phenotype, and Comparison with Extreme Phenotype Approach

Author

Haase, Christiane L, Frikke-Schmidt, Ruth, Nordestgaard, Børge G, Tybjærg-Hansen, Anne, Haase, Christiane L, Frikke-Schmidt, Ruth, Nordestgaard, Børge G, and Tybjærg-Hansen, Anne

Abstract

Rare genetic variants, identified by in-detail resequencing of loci, may contribute to complex traits. We used the apolipoprotein A-I gene (APOA1), a major high-density lipoprotein (HDL) gene, and population-based resequencing to determine the spectrum of genetic variants, the phenotypic characteristics of these variants, and how these results compared with results based on resequencing only the extremes of the apolipoprotein A-I (apoA-I) distribution. First, we resequenced APOA1 in 10,330 population-based participants in the Copenhagen City Heart Study. The spectrum and distribution of genetic variants was determined as a function of the number of individuals resequenced. Second, apoA-I and HDL cholesterol phenotypes were determined for nonsynonymous (NS) and synonymous (S) variants and were validated in the Copenhagen General Population Study (n = 45,239). Third, observed phenotypes were compared with those predicted using an extreme phenotype approach based on the apoA-I distribution. Our results are as follows: First, population-based resequencing of APOA1 identified 40 variants of which only 7 (18%) had minor allele frequencies >1%, and most were exceedingly rare. Second, 0.27% of individuals in the general population were heterozygous for NS variants which were associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L) and, surprisingly, 0.41% were heterozygous for variants predisposing to amyloidosis. NS variants associated with a hazard ratio of 1.72 (1.09-2.70) for myocardial infarction (MI), largely driven by A164S, a variant not associated with apoA-I or HDL cholesterol levels. Third, using the extreme apoA-I phenotype approach, NS variants correctly predicted the apoA-I phenotype observed in the population-based resequencing. However, using the extreme approach, between 79% (screening 0-1(st) percentile) and 21% (screening 0-20(th) percentile) of all variants were not identified; among these were varian

Published
2012

23. LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals

Author

Haase, Christiane L, Tybjærg-Hansen, Anne, Ali Qayyum, Abbas, Schou, Jesper, Nordestgaard, Børge G, Frikke-Schmidt, Ruth, Haase, Christiane L, Tybjærg-Hansen, Anne, Ali Qayyum, Abbas, Schou, Jesper, Nordestgaard, Børge G, and Frikke-Schmidt, Ruth

Abstract

Background:Epidemiologically, high-density lipoprotein (HDL) cholesterol levels associate inversely with risk of ischemic cardiovascular disease. Whether this is a causal relation is unclear.Methods:We studied 10,281 participants in the Copenhagen City Heart Study (CCHS) and 50,523 participants in the Copenhagen General Population Study (CGPS), of which 991 and 1,693 participants, respectively, had developed myocardial infarction (MI) by August 2010. Participants in the CCHS were genotyped for all six variants identified by resequencing lecithin-cholesterol acyltransferase in 380 individuals. One variant, S208T (rs4986970, allele frequency 4%), associated with HDL cholesterol levels in both the CCHS and the CGPS was used to study causality of HDL cholesterol using instrumental variable analysis.Results:Epidemiologically, in the CCHS, a 13% (0.21 mmol/liter) decrease in plasma HDL cholesterol levels was associated with an 18% increase in risk of MI. S208T associated with a 13% (0.21 mmol/liter) decrease in HDL cholesterol levels but not with increased risk of MI or other ischemic end points. The causal odds ratio for MI for a 50% reduction in plasma HDL cholesterol due to S208T genotype in both studies combined was 0.49 (0.11-2.16), whereas the hazard ratio for MI for a 50% reduction in plasma HDL cholesterol in the CCHS was 2.11 (1.70-2.62) (P(comparison) = 0.03).Conclusion:Low plasma HDL cholesterol levels robustly associated with increased risk of MI but genetically decreased HDL cholesterol did not. This may suggest that low HDL cholesterol levels per se do not cause MI.

Published
2012

24. Heterozygosity for R1141X in ABCC6 and risk of ischemic vascular disease

Author

Hornstrup, Louise S, Tybjærg-Hansen, Anne, Haase, Christiane L, Nordestgaard, Børge G, Sillesen, Henrik, Grande, Peer, Frikke-Schmidt, Ruth, Hornstrup, Louise S, Tybjærg-Hansen, Anne, Haase, Christiane L, Nordestgaard, Børge G, Sillesen, Henrik, Grande, Peer, and Frikke-Schmidt, Ruth

Abstract

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease caused by loss-of-function mutations in ABCC6 and characterized by elastic calcification leading to dermal, ocular, and ischemic vascular disease. We tested the hypothesis that heterozygosity for R1141X, the most frequent PXE-causing mutation in Caucasians, associated with risk of ischemic vascular disease, as previous studies suggested 4- to 11-fold risk of ischemic heart disease (IHD) in heterozygotes.

Published
2011

26. Heterozygosity for R1141X in ABCC6 and Risk of Ischemic Vascular Disease.

Author

Hornstrup, Louise S., Tybjaærg-Hansen, Anne, Haase, Christiane L., Nordestgaard, Børge G., Sillesen, Henrik, Grande, Peer, and Frikke-Schmidt, Ruth

Subjects
HETEROZYGOSITY, CARDIOVASCULAR diseases, ISCHEMIA, MYOCARDIAL infarction, STROKE
Abstract

The article presents a study that examined the association between heterozygosity for R1141X with risk of ischemic vascular disease (IHD). The study covered 10, 276 persons from the general population, including 1985 with IHD and 989 with ischemic cerebrovascular disease (ICVD). It downplayed the association between heterozygosity for ABCC6 R1141X and risk of IHD, myocardial infarction, ICVD, or ischemic stroke.

Published
2011
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27. Early Glycemic Control and Magnitude of HbA 1c Reduction Predict Cardiovascular Events and Mortality: Population-Based Cohort Study of 24,752 Metformin Initiators.

Author

Svensson E, Baggesen LM, Johnsen SP, Pedersen L, Nørrelund H, Buhl ES, Haase CL, and Thomsen RW

Subjects
Aged, Cardiovascular Diseases complications, Cardiovascular Diseases drug therapy, Cohort Studies, Denmark epidemiology, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Female, Follow-Up Studies, Humans, Hypoglycemic Agents therapeutic use, Male, Metformin therapeutic use, Middle Aged, Prevalence, Proportional Hazards Models, Risk Factors, Blood Glucose metabolism, Cardiovascular Diseases mortality, Diabetes Mellitus, Type 2 mortality, Glycated Hemoglobin metabolism
Abstract

Objective: We investigated the association of early achieved HbA 1c level and magnitude of HbA 1c reduction with subsequent risk of cardiovascular events or death in patients with type 2 diabetes who initiate metformin., Research Design and Methods: This was a population-based cohort study including all metformin initiators with HbA 1c tests in Northern Denmark, 2000-2012. Six months after metformin initiation, we classified patients by HbA 1c achieved (<6.5% or higher) and by magnitude of HbA 1c change from the pretreatment baseline. We used Cox regression to examine subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA 1c and other confounding factors., Results: We included 24,752 metformin initiators (median age 62.5 years, 55% males) with a median follow-up of 2.6 years. The risk of a combined outcome event gradually increased with rising levels of HbA 1c achieved compared with a target HbA 1c of <6.5%: adjusted hazard ratio (HR) 1.18 (95% CI 1.07-1.30) for 6.5-6.99%, HR 1.23 (1.09-1.40) for 7.0-7.49%, HR 1.34 (1.14-1.57) for 7.5-7.99%, and HR 1.59 (1.37-1.84) for ≥8%. Results were consistent for individual outcome events and robust by age-group and other patient characteristics. A large absolute HbA 1c reduction from baseline also predicted outcome: adjusted HR 0.80 (0.65-0.97) for Δ = -4, HR 0.98 (0.80-1.20) for Δ = -3, HR 0.92 (0.78-1.08) for Δ = -2, and HR 0.99 (0.89-1.10) for Δ = -1 compared with no HbA 1c change (Δ = 0)., Conclusions: A large initial HbA 1c reduction and achievement of low HbA 1c levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes., (© 2017 by the American Diabetes Association.)

Published
2017
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28. Subgroups at high risk for ischaemic heart disease:identification and validation in 67 000 individuals from the general population.

Author

Frikke-Schmidt R, Tybjærg-Hansen A, Dyson G, Haase CL, Benn M, Nordestgaard BG, and Sing CF

Subjects
Adult, Age Factors, Aged, Aged, 80 and over, Body Mass Index, Coronary Artery Disease epidemiology, Coronary Artery Disease genetics, Denmark epidemiology, Diabetes Mellitus epidemiology, Diabetes Mellitus genetics, Female, Humans, Hypertension epidemiology, Hypertension genetics, Lipids blood, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Sex Factors, Smoking epidemiology, Young Adult, Environment, Genetic Predisposition to Disease, Myocardial Ischemia epidemiology, Myocardial Ischemia genetics
Abstract

Background: The aetiology of ischaemic heart disease (IHD) is complex and is influenced by a spectrum of environmental factors and susceptibility genes. Traditional statistical modelling considers such factors to act independently in an additive manner. The Patient Rule-Induction Method (PRIM) is a multi-model building strategy for evaluating risk attributable to context-dependent gene and environmental effects., Methods: PRIM was applied to 9073 participants from the prospective Copenhagen City Heart Study (CCHS). Gender-specific cumulative incidences were estimated for subgroups defined by categories of age, smoking, hypertension, diabetes, body mass index, total cholesterol, high-density lipoprotein cholesterol and triglycerides and by 94 single nucleotide variants (SNVs).Cumulative incidences for subgroups were validated using an independently ascertained sample of 58 240 participants from the Copenhagen General Population Study (CGPS)., Results: In the CCHS the overall cumulative incidences were 0.17 in women and 0.21 in men. PRIM identified six and four mutually exclusive subgroups in women and men, respectively, with cumulative incidences of IHD ranging from 0.02 to 0.34. Cumulative incidences of IHD generated by PRIM in the CCHS were validated in four of the six subgroups of women and two of the four subgroups of men in the CGPS., Conclusions: PRIM identified high-risk subgroups characterized by specific contexts of selected values of traditional risk factors and genetic variants. These subgroups were validated in an independently ascertained cohort study. Thus, a multi-model strategy may identify groups of individuals with substantially higher risk of IHD than the overall risk for the general population., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Published
2015
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