28 results on '"Tybjærg-Hansen, Anne"'
Search Results
2. Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease.
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Varbo A, Benn M, Smith GD, Timpson NJ, Tybjaerg-Hansen A, and Nordestgaard BG
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- Adult, Aged, Biomarkers blood, Body Mass Index, Denmark, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Myocardial Ischemia blood, Myocardial Ischemia diagnosis, Myocardial Ischemia genetics, Myocardial Ischemia physiopathology, Obesity blood, Obesity diagnosis, Obesity genetics, Obesity physiopathology, Phenotype, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, Blood Pressure, Cholesterol blood, Cholesterol, LDL blood, Myocardial Ischemia etiology, Obesity complications
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Rationale: Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se., Objective: To test the hypothesis that the increased IHD risk because of obesity is mediated through lipoproteins, blood pressure, glucose, and C-reactive protein., Methods and Results: Approximately 90 000 participants from Copenhagen were included in a Mendelian randomization design with mediation analyses. Associations were examined using conventional measurements of body mass index and intermediate variables and using genetic variants associated with these. During ≤22 years of follow-up 13 945 participants developed IHD. The increased IHD risk caused by obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein cholesterol, through elevated blood pressure, and possibly also through elevated nonfasting glucose levels; however, reduced high-density lipoprotein cholesterol and elevated C-reactive protein levels were not mediators in genetic analyses. The 3 intermediate variables that explained the highest excess risk of IHD from genetically determined obesity were low-density lipoprotein cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional body mass index were 21%, 11%, and 20%, respectively., Conclusions: The increased IHD risk because of obesity was partly mediated through elevated levels of nonfasting remnant and low-density lipoprotein cholesterol and through elevated blood pressure. Our results suggest that there may be benefit to gain by reducing levels of these risk factors in obese individuals not able to achieve sustained weight loss., (© 2014 American Heart Association, Inc.)
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- 2015
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3. Reply to letters regarding article, "Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation".
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Varbo A, Benn M, Tybjærg-Hansen A, and Nordestgaard BG
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- Female, Humans, Male, Cholesterol metabolism, Cholesterol, LDL metabolism, Inflammation metabolism, Lipoproteins metabolism, Myocardial Ischemia metabolism, Triglycerides metabolism
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- 2014
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4. Low nonfasting triglycerides and reduced all-cause mortality: a mendelian randomization study.
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Thomsen M, Varbo A, Tybjærg-Hansen A, and Nordestgaard BG
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- Biomarkers blood, Cardiovascular Diseases blood, Cardiovascular Diseases genetics, Data Interpretation, Statistical, Denmark, Humans, Kaplan-Meier Estimate, Lipoprotein Lipase metabolism, Mortality trends, Postprandial Period, Prospective Studies, Sensitivity and Specificity, Triglycerides genetics, Cardiovascular Diseases mortality, Cholesterol blood, Lipoprotein Lipase genetics, Mendelian Randomization Analysis, Polymorphism, Genetic, Triglycerides blood
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Background: Increased nonfasting plasma triglycerides marking increased amounts of cholesterol in remnant lipoproteins are important risk factors for cardiovascular disease, but whether lifelong reduced concentrations of triglycerides on a genetic basis ultimately lead to reduced all-cause mortality is unknown. We tested this hypothesis., Methods: Using individuals from the Copenhagen City Heart Study in a mendelian randomization design, we first tested whether low concentrations of nonfasting triglycerides were associated with reduced all-cause mortality in observational analyses (n = 13 957); second, whether genetic variants in the triglyceride-degrading enzyme lipoprotein lipase, resulting in reduced nonfasting triglycerides and remnant cholesterol, were associated with reduced all-cause mortality (n = 10 208)., Results: During a median 24 and 17 years of 100% complete follow-up, 9991 and 4005 individuals died in observational and genetic analyses, respectively. In observational analyses compared to individuals with nonfasting plasma triglycerides of 266-442 mg/dL (3.00-4.99 mmol/L), multivariably adjusted hazard ratios for all-cause mortality were 0.89 (95% CI 0.78-1.02) for 177-265 mg/dL (2.00-2.99 mmol/L), 0.74 (0.65-0.84) for 89-176 mg/dL (1.00-1.99 mmol/L), and 0.59 (0.51-0.68) for individuals with nonfasting triglycerides <89 mg/dL (<1.00 mmol/L). The odds ratio for a genetically derived 89-mg/dL (1-mmol/L) lower concentration in nonfasting triglycerides was 0.50 (0.30-0.82), with a corresponding observational hazard ratio of 0.87 (0.85-0.89). Also, the odds ratio for a genetically derived 50% lower concentration in nonfasting triglycerides was 0.43 (0.23-0.80), with a corresponding observational hazard ratio of 0.73 (0.70-0.77)., Conclusions: Genetically reduced concentrations of nonfasting plasma triglycerides are associated with reduced all-cause mortality, likely through reduced amounts of cholesterol in remnant lipoproteins.
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- 2014
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5. Response: Lipoprotein subclass profiling reveals pleiotropy in the genetic variants of lipid risk factors for coronary heart disease: a note on Mendelian randomization studies.
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Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, and Nordestgaard BG
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- Female, Humans, Male, Cholesterol, Genetic Variation physiology, Lipoproteins, HDL, Myocardial Ischemia, Triglycerides
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- 2013
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6. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation.
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Varbo A, Benn M, Tybjærg-Hansen A, and Nordestgaard BG
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- Adult, C-Reactive Protein metabolism, Denmark epidemiology, Diabetes Mellitus epidemiology, Diabetes Mellitus genetics, Diabetes Mellitus metabolism, Female, Genotype, Humans, Inflammation epidemiology, Inflammation genetics, Lipoproteins genetics, Male, Middle Aged, Myocardial Ischemia epidemiology, Myocardial Ischemia genetics, Risk Factors, Cholesterol metabolism, Cholesterol, LDL metabolism, Inflammation metabolism, Lipoproteins metabolism, Myocardial Ischemia metabolism, Triglycerides metabolism
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Background: Elevated nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol are causally associated with ischemic heart disease (IHD), but whether elevated nonfasting remnant cholesterol and LDL cholesterol both cause low-grade inflammation is currently unknown., Methods and Results: We studied 60 608 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease study, of whom 10 668 had IHD diagnosed between 1977 and 2011. We genotyped for variants affecting levels of nonfasting remnant cholesterol, LDL cholesterol, C-reactive protein by CRP alleles, and C-reactive protein by IL6R alleles. Using a multidirectional mendelian randomization design, we investigated possible causal associations between the lipoproteins and C-reactive protein and between the lipoproteins and IHD. A 1-mmol/L(39 mg/dL) higher level of nonfasting remnant cholesterol was associated observationally with a 37% (95% confidence interval, 35-39) higher C-reactive protein level and causally with a 28% (95% confidence interval, 10-48) higher level. For LDL cholesterol, a 1-mmol/L (39-mg/dL) higher level was associated observationally with a 7% (95% confidence interval, 6-7) higher C-reactive protein level, but we found no causal association. Likewise, higher levels of C-reactive protein did not associate causally with elevated nonfasting remnant cholesterol or LDL cholesterol. Finally, the causal risk ratio for IHD for a 1-mmol/L (39-mg/dL) higher level was 3.3 (95% confidence interval, 2.1-5.2) for nonfasting remnant cholesterol and 1.8 (95% confidence interval, 1.5-2.2) for LDL cholesterol. The causal associations for remnant cholesterol were present even in those without diabetes mellitus and obesity., Conclusions: Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation.
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- 2013
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7. Remnant cholesterol as a causal risk factor for ischemic heart disease.
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Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, and Nordestgaard BG
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- Aged, Causality, Data Collection, Denmark epidemiology, Female, Genotype, Humans, Male, Middle Aged, Odds Ratio, Risk Factors, Time Factors, Cholesterol genetics, Cholesterol metabolism, Genetic Variation physiology, Lipoproteins, HDL genetics, Lipoproteins, HDL metabolism, Myocardial Ischemia epidemiology, Myocardial Ischemia genetics, Myocardial Ischemia metabolism, Triglycerides genetics, Triglycerides metabolism
- Abstract
Objectives: The aim of this study was to test the hypothesis that elevated nonfasting remnant cholesterol is a causal risk factor for ischemic heart disease independent of reduced high-density lipoprotein (HDL) cholesterol., Background: Elevated remnant cholesterol is associated with elevated levels of triglyceride-rich lipoproteins and with reduced HDL cholesterol, and all are associated with ischemic heart disease., Methods: A total of 73,513 subjects from Copenhagen were genotyped, of whom 11,984 had ischemic heart disease diagnosed between 1976 and 2010. Fifteen genetic variants were selected, affecting: 1) nonfasting remnant cholesterol alone; 2) nonfasting remnant cholesterol and HDL cholesterol combined; 3) HDL cholesterol alone; or 4) low-density lipoprotein (LDL) cholesterol alone as a positive control. The variants were used in a Mendelian randomization design., Results: The causal odds ratio for a 1 mmol/l (39 mg/dl) genetic increase of nonfasting remnant cholesterol was 2.8 (95% confidence interval [CI]: 1.9 to 4.2), with a corresponding observational hazard ratio of 1.4 (95% CI: 1.3 to 1.5). For the ratio of nonfasting remnant cholesterol to HDL cholesterol, corresponding values were 2.9 (95% CI: 1.9 to 4.6) causal and 1.2 (95% CI 1.2 to 1.3) observational for a 1-U increase. However, for HDL cholesterol, corresponding values were 0.7 (95% CI: 0.4 to 1.4) causal and 1.6 (95% CI: 1.4 to 1.7) observational for a 1 mmol/l (39 mg/dl) decrease. Finally, for LDL cholesterol, corresponding values were 1.5 (95% CI: 1.3 to 1.6) causal and 1.1 (95% CI: 1.1 to 1.2) observational for a 1 mmol/l (39 mg/dl) increase., Conclusions: A nonfasting remnant cholesterol increase of 1 mmol/l (39 mg/dl) is associated with a 2.8-fold causal risk for ischemic heart disease, independent of reduced HDL cholesterol. This implies that elevated cholesterol content of triglyceride-rich lipoprotein particles causes ischemic heart disease. However, because pleiotropic effects of the genetic variants studied cannot be totally excluded, these findings need to be confirmed using additional genetic variants and/or randomized intervention trials., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
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- 2013
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8. Genetic variants in the adenosine triphosphate-binding cassette transporter A1 and risk of age-related macular degeneration
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Nordestgaard, Liv Tybjærg, Christoffersen, Mette, Afzal, Shoaib, Nordestgaard, Børge Grønne, Tybjærg-Hansen, Anne, and Frikke-Schmidt, Ruth
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- 2023
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9. Women, lipids, and atherosclerotic cardiovascular disease: a call to action from the European Atherosclerosis Society.
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Lennep, Jeanine E Roeters van, Tokgözoğlu, Lale S, Badimon, Lina, Dumanski, Sandra M, Gulati, Martha, Hess, Connie N, Holven, Kirsten B, Kavousi, Maryam, Kayıkçıoğlu, Meral, Lutgens, Esther, Michos, Erin D, Prescott, Eva, Stock, Jane K, Tybjaerg-Hansen, Anne, Wermer, Marieke J H, and Benn, Marianne
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PREMATURE menopause ,CARDIOVASCULAR diseases ,POLYCYSTIC ovary syndrome ,CARDIOVASCULAR diseases risk factors ,MIDDLE-aged women ,ATHEROSCLEROSIS - Abstract
Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to identify and treat modifiable cardiovascular risk factors earlier in women, especially for those at risk due to sex-specific conditions, to reduce the unacceptably high burden of ASCVD in women. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Lipoprotein(a) Levels at Birth and in Early Childhood: The COMPARE Study.
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Strandkjær, Nina, Hansen, Malene Kongsgaard, Nielsen, Sofie Taageby, Frikke-Schmidt, Ruth, Tybjærg-Hansen, Anne, Nordestgaard, Børge G., Tabor, Ann, Bundgaard, Henning, Iversen, Kasper, and Kamstrup, Pia R.
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LIPOPROTEINS ,CARDIOVASCULAR diseases risk factors - Abstract
Background and Objective: High lipoprotein(a) is a genetically determined causal risk factor for cardiovascular disease, and 20% of the adult population has high levels (ie, >42 mg/dL, >88 nmol/L). We investigated whether early life lipoprotein(a) levels measured in cord blood may serve as a proxy for neonatal venous blood levels, whether lipoprotein(a) birth levels (ie, cord or venous) predict levels later in life, and whether early life and parental levels correlate. Methods: The Compare study is a prospective cohort study of newborns (N = 450) from Copenhagen, Denmark, including blood sampling of parents. Plasma lipoprotein(a) was measured in cord blood (N = 402), neonatal venous blood (N = 356), and at 2 (N = 320) and 15 months follow-up (N = 148) of infants, and in parents (N = 705). Results: Mean lipoprotein(a) levels were 2.2 (95% CI, 1.9-2.5), 2.4 (2.0-2.7), 4.1 (3.4-4.9), and 14.6 (11.4-17.9) mg/dL in cord, neonatal venous, and 2- and 15-month venous samples, respectively. Lipoprotein(a) levels in cord blood correlated strongly with neonatal venous blood levels (R² = 0.95, P < 0.001) and neonatal levels correlated moderately with 2- and 15-month levels (R² = 0.68 and 0.67, both P < 0.001). Birth levels ≥ 90th percentile predicted lipoprotein(a) > 42 mg/dL at 15 months with positive predictive values of 89% and 85% for neonatal venous and cord blood. Neonatal and infant levels correlated weakly with parental levels, most pronounced at 15 months (R² = 0.22, P < 0.001). Conclusions: Lipoprotein(a) levels are low in early life, cord blood may serve as a proxy for neonatal venous blood, and birth levels ≥ 90th percentile can identify newborns at risk of developing high levels. [ABSTRACT FROM AUTHOR]
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- 2022
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11. Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)
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Vallejo-Vaz, Antonio J., Marco, Martina De, Stevens, Christophe A. T., Akram, Asif, Freiberger, Tomas, Hovingh, G. Kees, Kastelein, John J. P., Mata, Pedro, Raal, Frederick J., Santos, Raul D., Soran, Handrean, Watts, Gerald F., Abifadel, Marianne, Aguilar-Salinas, Carlos A., Al-Khnifsawi, Mutaz, Alkindi, Fahad A., Alnouri, Fahad, Alonso, Rodrigo, Al-Rasadi, Khalid, Al-Sarraf, Ahmad, Ashavaid, Tester F., Binder, Christoph J., Bogsrud, Martin P., Bourbon, Mafalda, Bruckert, Eric, Chlebus, Krzysztof, Corral, Pablo, Descamps, Olivier, Durst, Ronen, Ezhov, Marat, Fras, Zlatko, Genest, Jacques, Groselj, Urh, Harada-Shiba, Mariko, Kayikcioglu, Meral, Lalic, Katarina, Lam, Carolyn S. P., Latkovskis, Gustavs, Laufs, Ulrich, Liberopoulos, Evangelos, Lin, Jie, Maher, Vincent, Majano, Nelson, Marais, A. David, März, Winfried, Mirrakhimov, Erkin, Miserez, André R., Mitchenko, Olena, Nawawi, Hapizah M., Nordestgaard, B. rge G., Paragh, György, Petrulioniene, Zaneta, Pojskic, Belma, Postadzhiyan, Arman, Reda, Ashraf, Reiner, Željko, Sadoh, Wilson E., Sahebkar, Amirhossein, Shehab, Abdullah, Shek, Aleksander B., Stoll, Mario, Su, Ta-Chen, Subramaniam, Tavintharan, Susekov, Andrey V., Symeonides, Phivos, Tilney, Myra, Tomlinson, Brian, Truong, Thanh-Huong, Tselepis, Alexandros D., Tybjærg-Hansen, Anne, Vázquez-Cárdenas, Alejandra, Viigimaa, Margus, Vohnout, Branislav, Widén, Elisabeth, Yamashita, Shizuya, Banach, Maciej, Gaita, Dan, Jiang, Lixin, Nilsson, Lennart, Santos, Lourdes E., Schunkert, Heribert, Tokgözoğlu, Lale, Car, Josip, Catapano, Alberico L., Ray, Kausik K., Schreier, Laura, Pang, Jing, Dieplinger, Hans, Hanauer-Mader, Gabriele, Desutter, Johan, Langlois, Michel, Mertens, Ann, Rietzschel, Ernst, Wallemacq, Caroline, Isakovic, Dzenana, Dzankovic, Amra M., Obralija, Jasna, Pojskic, Lamija, Sisic, Ibrahim, Stimjanin, Ena, Torlak, Vildana A., Jannes, Cinthia E., Krieger, Jose E., Pereira, Alexandre C., Ruel, Isabelle, Asenjo, Sylvia, Cuevas, Ada, Pećin, Ivan, Miltiadous, George, Panayiotou, Andrie G., Vrablik, Michal, Benn, Marianne, Heinsar, Silver, Béliard, S., Gouni-Berthold, Ioanna, Hengstenberg, Wibke, Julius, Ulrich, Kassner, Ursula, Klose, Gerald, König, Christel, König, Wolfgang, Otte, Britta, Parhofer, Klaus, Schatz, Ulrike, Schmidt, Nina, Steinhagen-Thiessen, Elisabeth, Vogt, Anja, Antza, Christina, Athyros, Vasilios, Bilianou, Eleni, Boufidou, Amalia, Chrousos, George, Elisaf, Moses, Garoufi, Anastasia, Katsiki, Niki, Kolovou, Genovefa, Kotsis, Vasilios, Rallidis, Loukianos, Rizos, Christos, Skalidis, Emmanouel, Skoumas, Ioannis, Tziomalos, Kostantinos, Shawney, J. P. S., Abbaszadegan, Mohammad R., Aminzadeh, Majid, Hosseini, Sousan, Mobini, Moein, Vakili, Rahim, Zaeri, Hossein, Agar, Ruth, Boran, Gerard, Colwell, Nial, Crowley, Vivion, Durkin, Maeve, Griffin, Damian, Kelly, Michael, Rakovac-Tisdall, Ana, Bitzur, Rafael, Cohen, Hofit, Eliav, Osnat, Ellis, Avishay, Gavish, Dov, Harats, Dror, Henkin, Yaacov, Knobler, Hila, Leavit, Leah, Leitersdorf, Eran, Rubinstein, Ardon, Schurr, Daniel, Shpitzen, Shoshi, Szalat, Auryan, Arca, Marcello, Averna, Maurizio, Bertolini, Stefano, Calandra, Sebastiano, Tarugi, Patrizia, Erglis, Andrejs, Gilis, Dainus, Nesterovics, Georgijs, Saripo, Vita, Upena-Roze, Arta, Elbitar, Sandy, Jambart, S. lim, Khoury, Petra El, Gargalskaite, Urte, Kutkiene, Sandra, Al-Khateeb, Alyaa, An, Chua Y., Ismail, Zaliha, Kasim, Sazzli, Ibrahim, Khairul S., Radzi, Ahmad B. M., Kasim, Noor A., Nor, Noor S. M., Ramli, Anis S., Razak, Suraya A., Muid, Suhaila, Rosman, Azhari, Sanusi, Abd R., Razman, Aimi Z., Nazli, Sukma A., Kek, Teh L., Azzopardi, Conrad, Aguilar Salinas, Carlos A., Vázquez-Cárdenas, N. Alejandra, Galán, Gabriela, Magaña-Torres, M. T., Martagon, Alexandro, Mehta, Roopa, Wittekoek, M. E., Isara, Alphonsus R., Obaseki, Darlington E., Ohenhen, Oluwatoyin A., Holven, Kirsten B., Gruchała, Marcin, Baranowska, Marlena, Borowiec-Wolny, Justyna, Gilis-Malinowska, Natasza, Michalska-Grzonkowska, Aleksandra, Pajkowski, Marcin, Parczewska, Aleksandra, Romanowska-Kocejko, Marzena, Stróżyk, Aneta, Żarczyńska-Buchowiecka, Marta, Kleinschmidt, Mariola, Alves, Ana C., Medeiros, Ana M., Ershova, Alexandra, Korneva, Victoria, Kuznetsova, Tatiana, Malyshev, Pavel, Meshkov, Alexey, Rozhkova, Tatiana, Rajkovic, Natasa, Popovic, Ljiljana, Lukac, Sandra S., Stosic, Ljubica, Rasulic, Iva, Lalic, Nebojsa M., Chua, Terrance S. J., Ting, Sharon P. L., Raslova, Katarina, Battelino, Tadej, Cevc, Matija, Jug, Borut, Kovac, Jernej, Podkrajsek, Katarina T., Sustar, Ursa, Trontelj, Katja J., Marais, David, Isla, Leopoldo Perez de, Martin, François J., Charng, Ming-Ji, Chen, Pei-Lung, Kayikçioglu, Meral, Dell’oca, Nicolás, Fernández, Graciela, Ressia, Andrés, Reyes, Ximena, Zelarayan, Mario, Alieva, Rano B., Hoshimov, Shavkat U., Kurbanov, Ravshanbek D., Nizamov, Ulugbek I., Lima-Martínez, Marcos M., Nguyen, Mai-Ngoc Thi, Do, Doan-Loi, Kim, Ngoc-Thanh, le, Hong-An, le, Thanh-Tung, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Institute for Molecular Medicine Finland, University of Helsinki, Genomic Discoveries and Clinical Translation, Kardiyoloji, Lee Kong Chian School of Medicine (LKCMedicine), Pfizer Incorporated, European Atherosclerosis Society, ACS - Atherosclerosis & ischemic syndromes, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, and Ege Üniversitesi
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International Cooperation ,MÉTODOS EPIDEMIOLÓGICOS ,030204 cardiovascular system & hematology ,Nationwide survey ,Global Health ,Health Services Accessibility ,Doenças Cardio e Cérebro-vasculares ,MOLECULAR-GENETICS ,0302 clinical medicine ,Risk Factors ,Prevalence ,CARDIOVASCULAR RISK-FACTORS ,030212 general & internal medicine ,Cooperative Behavior ,DEFECTIVE APOLIPOPROTEIN B-100 ,GENERAL-POPULATION ,education.field_of_study ,medicine.diagnostic_test ,Anticholesteremic Agents ,Familial hypercholesterolaemia ,FHSC ,Primary dyslipidaemia ,Biomarkers ,Cholesterol, LDL ,Genetic Predisposition to Disease ,Health Care Surveys ,Healthcare Disparities ,Humans ,Hyperlipoproteinemia Type II ,Phenotype ,Predictive Value of Tests ,Treatment Outcome ,Blood Component Removal ,EAS Familial Hypercholesterolaemia Studies Collaboration ,3. Good health ,PREVALENCE ,Cholesterol ,CORONARY-ARTERY-DISEASE ,NATIONWIDE SURVEY ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Cardiovascular risk factors ,Population ,LDL-RECEPTOR ,1102 Cardiovascular Medicine And Haematology ,LDL ,03 medical and health sciences ,medicine ,Medicine [Science] ,fhsc ,familial hypercholesterolaemia ,primary dyslipidaemia ,education ,Genetic testing ,Government ,Public health ,EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC) Investigators ,SAFEHEART REGISTRY ,1103 Clinical Sciences ,Cardiovascular System & Hematology ,Family medicine ,3121 General medicine, internal medicine and other clinical medicine ,Cardiovascular System & Cardiology ,Business ,FOLLOW-UP - Abstract
PubMed: 30270054, 2-s2.0-85053666909, Background and aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ?2/3 countries. Lipoprotein-apheresis is offered in ?60% countries, although access is limited. Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed. © 2018 Elsevier B.V., Universidade de São Paulo, USP European Atherosclerosis Society, EAS Amgen Merck Sharp and Dohme, MSD, The ELSA Study suggests heterozygous FH (HeFH) may affect 1:263 Brazilians (?766,000 individuals). Currently, the only active genetic cascade screening program in Brazil is Hipercol Brasil in Sao Paulo (genetic testing for adults with low-density lipoprotein cholesterol (LDL-C) ?230?mg/dL, to maximise cost-effectiveness), with 1719 heterozygotes, 25 homozygotes, 13 compound-heterozygotes and one double-heterozygote identified by March 2018. To date, 4340 individuals from 440 families were screened. Genetic testing is funded by a government tax reduction programme (PROADI-SUS), and cascade screening by partnering between Samaritano Hospital and Heart Institute (InCor) University of Sao Paulo. Most FH patients are under non-specialist care and currently under-treated., Prevalence is unknown but assumed at 1:250. There is no state programme and few patients were diagnosed before the Latvian FH Registry was established in 2015. To date, the Registry has identified 181 cases (2.3% of 7876 estimated HeFH cases; no HoFH). Cascade screening is performed in first-degree relatives of index cases with probable/definite FH. Genetic testing is not reimbursed but has been funded by research grants for a few patients/relatives. About 5% of patients had LDL-C at target before inclusion in the Registry [ 61 ]. Statins are reimbursed 50% in primary prevention; statins and ezetimibe, 75–100% in secondary prevention; PCSK9i are available, but not reimbursed., Estimated prevalence is 1:250 (based on a meta-analysis of 6 observational studies) or 136,300 adults (only 2% diagnosed) [ 69 , 70 ]. Based on LIPIDOGRAM studies (2004–2015, ?50,000 participants), prevalence might be?1:200 [ 71 , 72 ]. Five HoFH cases are described [ 73 , 74 ]. Patients with DLCN ?3 are referred for genetic testing, funded by the National Health Program. The National Centre for FH at University Clinical Hospital, Medical University of Gdansk, was established in 2017, financed by the Ministry of Health. From August 2017, 345 patients underwent genetic testing (153 positive, including 46 relatives; 1 HoFH). Since 1999, 1884 patients (562 families) have undergone genetic testing and cascade diagnosis (data from the National Polish FH Registry, Medical University of Gdansk, established in 2000). PCSK9i are not reimbursed (under discussion with the Ministry of Health)., The EAS FHSC project has received support from a Pfizer Independent Grant for Learning & Change 2014 (No: 16157823 ) and from investigator-initiated unrestricted research grants to the European Atherosclerosis Society from Amgen , MSD , and Sanofi-Aventis .
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- 2018
12. Elevated Apolipoprotein A1 and HDL Cholesterol Associated with Age-related Macular Degeneration: 2 Population Cohorts.
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Nordestgaard, Liv Tybjærg, Tybjærg-Hansen, Anne, Frikke-Schmidt, Ruth, and Nordestgaard, Børge Grønne
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HDL cholesterol ,HIGH density lipoproteins ,MACULAR degeneration ,LDL cholesterol ,BLOOD lipoproteins ,RESEARCH ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,APOLIPOPROTEINS ,PROPORTIONAL hazards models - Abstract
Context: To enable prevention and treatment of age-related macular degeneration (AMD), understanding risk factors for AMD is important.Objective: We tested the hypotheses that elevated plasma apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol and low levels of low-density lipoprotein (LDL) cholesterol are associated with increased risk of AMD.Methods: From the Danish general population, we studied 106 703 and 16 032 individuals in the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS) with median follow-up of 9 and 32 years, respectively.The main outcome measures were 1787 AMD in CGPS and 206 in CCHS.Results: Higher concentrations of plasma apolipoprotein A1 and HDL cholesterol, and lower concentrations of LDL cholesterol, were associated with higher risk of AMD in CGPS. After multifactorial adjustment, individuals in the highest versus lowest quartile of plasma apolipoprotein A1 and HDL cholesterol had hazard ratios for AMD of 1.40 (95% CI: 1.20-1.63) and 1.22 (1.03-1.45). Corresponding hazard ratios for individuals in the lowest versus highest quartile of LDL cholesterol were 1.18 (1.02-1.37). Per 100 mg/dL higher plasma apolipoprotein A1, 1 mmol/L (39 mg/dL) higher HDL, and 1 mmol/L (39 mmol/L) lower LDL cholesterol, the hazard ratios for AMD were 1.53(1.31-1.80), 1.19 (1.07-1.32), and 1.05 (1.00-1.11), respectively, with similar results across strata of different risk factors. Higher concentrations of HDL cholesterol were also associated with higher risk of AMD in the CCHS.Conclusion: Elevated plasma apolipoprotein A1 and HDL cholesterol and lower LDL cholesterol are associated with increased risk of AMD. [ABSTRACT FROM AUTHOR]- Published
- 2021
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13. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials
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Swerdlow, Daniel I., Preiss, David, Kuchenbaecker, Karoline B., Holmes, Michael V., Engmann, Jorgen E. L., Shah, Tina, Sofat, Reecha, Stender, Stefan, Johnson, Paul C. D., Scott, Robert A., Leusink, Maarten, Verweij, Niek, Sharp, Stephen J., Guo, Yiran, Giambartolomei, Claudia, Chung, Christina, Peasey, Anne, Amuzu, Antoinette, Li, KaWah, Palmen, Jutta, Howard, Philip, Cooper, Jackie A., Drenos, Fotios, Lowe, Gordon, Gallacher, John, Stewart, Marlene C. W., Tzoulaki, Ioanna, Buxbaum, Sarah G., van der A, Daphne L., Forouhi, Nita G., Onland-Moret, N. Charlotte, van der Schouw, Yvonne T., Hubacek, Jaroslav A., Kubinova, Ruzena, Baceviciene, Migle, Tamosiunas, Abdonas, Pajak, Andrzej, Topor-Madry, Roman, Stepaniak, Urszula, Malyutina, Sofia, Baldassarre, Damiano, Sennblad, Bengt, Tremoli, Elena, de Faire, Ulf, Veglia, Fabrizio, Ford, Ian, Wouter Jukema, J., Westendorp, Rudi G. J., de Borst, Gert Jan, de Jong, Pim A., Algra, Ale, Spiering, Wilko, H Maitland-van der Zee, Anke H., Klungel, Olaf H., de Boer, Anthonius, Doevendans, Pieter A., Eaton, Charles B., Robinson, Jennifer G., Duggan, David, DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium, Kjekshus, John, Downs, John R., Gotto, Antonio M., Keech, Anthony C., Marchioli, Roberto, Tognoni, Gianni, Sever, Peter S., Poulter, Neil R., Waters, David D., Pedersen, Terje R., Amarenco, Pierre, Nakamura, Haruo, McMurray, John J. V., Lewsey, James D., Chasman, Daniel I., Ridker, Paul M., Maggioni, Aldo P., Tavazzi, Luigi, Ray, Kausik K., Kondapally Seshasai, Sreenivasa Rao, Manson, JoAnn E., Price, Jackie F., Whincup, Peter H., Morris, Richard W., Lawlor, Debbie A., Smith, George Davey, Ben-Shlomo, Yoav, Schreiner, Pamela J., Fornage, Myriam, Siscovick, David S., Cushman, Mary, Kumari, Meena, Wareham, Nick J., Verschuren, W. M. Monique, Redline, Susan, Patel, Sanjay R., Whittaker, John C., Hamsten, Anders, Delaney, Joseph A., Dale, Caroline, Gaunt, Tom R., Wong, Andrew, Kuh, Diana, Hardy, Rebecca, Kathiresan, Sekar, Castillo, Berta A., van der Harst, Pim, Brunner, Eric J., Tybjaerg-Hansen, Anne, Marmot, Michael G., Krauss, Ronald M., Tsai, Michael, Coresh, Josef, Hoogeveen, Ronald C., Psaty, Bruce M., Lange, Leslie A., Hakonarson, Hakon, Dudbridge, Frank, Humphries, Steve E., Talmud, Philippa J., Kivimäki, Mika, Timpson, Nicholas J., Langenberg, Claudia, Asselbergs, Folkert W., Voevoda, Mikhail, Bobak, Martin, Pikhart, Hynek, Wilson, James G., Reiner, Alex P., Keating, Brendan J., Hingorani, Aroon D., Sattar, Naveed, Li, Yun R., Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Sharp, Stephen [0000-0003-2375-1440], Forouhi, Nita [0000-0002-5041-248X], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
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Male ,STATIN THERAPY ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Gastroenterology ,DISEASE ,Body Mass Index ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Medicine ,HIGH-DOSE ATORVASTATIN ,Randomized Controlled Trials as Topic ,RISK ,0303 health sciences ,MAGIC Consortium ,Articles ,11 Medical And Health Sciences ,General Medicine ,Middle Aged ,3. Good health ,MENDELIAN RANDOMIZATION ,Female ,Life Sciences & Biomedicine ,medicine.medical_specialty ,Statin ,medicine.drug_class ,DIAGRAM Consortium ,Placebo ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Medicine, General & Internal ,General & Internal Medicine ,Internal medicine ,Diabetes mellitus ,Humans ,Genetic Testing ,METAANALYSIS ,Aged ,030304 developmental biology ,Science & Technology ,business.industry ,Cholesterol ,Body Weight ,Cholesterol, HDL ,Type 2 Diabetes Mellitus ,Cholesterol, LDL ,Odds ratio ,InterAct Consortium ,medicine.disease ,R1 ,PREVENTION ,BODY-MASS INDEX ,Endocrinology ,Diabetes Mellitus, Type 2 ,chemistry ,Hydroxymethylglutaryl CoA Reductases ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,LDL CHOLESTEROL ,business ,ASSOCIATION ANALYSES ,Body mass index - Abstract
Background: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.Methods: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.Findings: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).Interpretation: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.Funding: The funding sources are cited at the end of the paper.
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- 2015
14. Association ofLPAVariants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies
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Burgess, Stephen, Ference, Brian A., Staley, James R., Freitag, Daniel F., Mason, Amy M., Nielsen, Sune F., Willeit, Peter, Young, Robin, Surendran, Praveen, Karthikeyan, Savita, Bolton, Thomas R., Peters, James E., Kamstrup, Pia, Tybjærg-Hansen, Anne, Benn, Marianne, Langsted, Anne, Schnohr, Peter, Vedel-Krogh, Signe, Kobylecki, Camilla J., Ford, Ian, Packard, Chris, Trompet, Stella, Jukema, J. Wouter, Sattar, Naveed, Di Angelantonio, Emanuele, Saleheen, Danish, Howson, Joanna M.M., Nordestgaard, Børge G., Butterworth, Adam S., Danesh, John, Bargess, Stephen, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Matullo, Giuseppe, Boer, Jolanda, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Wareham, Nicholas J., Key, Timothy J., Riboli, Elio, Burgess, Stephen [0000-0001-5365-8760], Mason, Amy [0000-0002-8019-0777], Surendran, Praveen [0000-0002-4911-6077], Karthikeyan, Savita [0000-0002-4798-5746], Di Angelantonio, Emanuele [0000-0001-8776-6719], Howson, Joanna [0000-0001-7618-0050], Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository
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Male ,medicine.medical_specialty ,Population ,Coronary Disease ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Polymorphism, Single Nucleotide ,Article ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Randomized controlled trial ,Ezetimibe ,Risk Factors ,law ,Internal medicine ,medicine ,Humans ,Prospective Studies ,030212 general & internal medicine ,Precision Medicine ,Prospective cohort study ,education ,Hypolipidemic Agents ,education.field_of_study ,biology ,Cholesterol ,business.industry ,Genetic Variation ,Mendelian Randomization Analysis ,Cholesterol, LDL ,Lipoprotein(a) ,Odds ratio ,Middle Aged ,Prognosis ,Phenotype ,chemistry ,biology.protein ,Female ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Follow-Up Studies ,medicine.drug - Abstract
Importance: Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.Objective: To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD.Design, Setting, and Participants: A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.Exposures: Genetic LPA score and plasma Lp(a) mass concentration.Main Outcomes and Measures: Coronary heart disease.Results: Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk.Conclusions and Relevance: The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).
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- 2018
15. Genetic variation in the cholesterol transporter NPC1L1, ischaemic vascular disease, and gallstone disease.
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Lauridsen, Bo Kobberø, Stender, Stefan, Frikke-Schmidt, Ruth, Nordestgaard, Børge G., and Tybjærg-Hansen, Anne
- Abstract
Aims Ezetimibe reduces plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting Niemann-Pick C1-Like protein 1 (NPC1L1), the transporter responsible for cholesterol uptake fromthe intestine into enterocytes and fromthe bile into hepatocytes. We tested the hypothesis that genetic variation in NPC1L1, mimicking the effect of ezetimibe, was associated with reduced risk of ischaemic vascular disease (IVD) and with increased risk of symptomatic gallstone disease. METHODS AND RESULTS We included 67 385 individuals from the general population. Of these, 5255 and 3886 individuals developed IVD or symptomatic gallstone disease, respectively, during follow-up from 1977 to 2013. We genotyped four common NPC1L1 variants, previously associated with reduced LDL cholesterol levels, thus mimicking the effect of ezetimibe, and calculated a weighted genotype score. With increasing genotype score, LDL cholesterol decreased stepwise up to 3.5% (0.12 mmol/L) and total cholesterol up to 1.9% (0.11 mmol/L) (P-trend: 2 × 10(-12) and 2 × 10(-9)). The cumulative incidence by age of IVD decreased, while that of symptomatic gallstone disease increased as a function of increasing genotype score (P-trend: 0.005 and 0.01). Hazard ratios for genotype scores = 5.0 vs. <2.0 were 0.82 (95% confidence interval: 0.70-0.95) for IVD and 1.22 (0.99-1.49) for gallstone disease (P-trend across genotype scores: 0.004 and 0.01). Conclusion Genetic variation in NPC1L1 is associated with a reduction in risk of IVD, with a corresponding reduction in LDL cholesterol, but with a concomitant increased risk of gallstone disease. These data support the hypothesis that treatment with ezetimibe protects againstIVD but raise the question whether long-term treatment increases the risk of gallstone disease. [ABSTRACT FROM AUTHOR]
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- 2015
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16. Population-Based Resequencing of APOA1 in 10,330 Individuals: Spectrum of Genetic Variation, Phenotype, and Comparison with Extreme Phenotype Approach.
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Haase, Christiane L., Frikke-Schmidt, Ruth, Nordestgaard, Børge G., and Tybjærg-Hansen, Anne
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APOLIPOPROTEINS ,HUMAN genetic variation ,GENOTYPE-environment interaction ,CHOLESTEROL ,AMYLOIDOSIS ,NUCLEOTIDE sequence - 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 0-1st percentile) and 21% (screening 0-20th percentile) of all variants were not identified; among these were variants previously associated with amyloidosis. Population-based resequencing of APOA1 identified a majority of rare NS variants associated with reduced apoA-1 and HDL cholesterol levels and/or predisposing to amyloidosis. In addition, NS variants associated with increased risk of MI. [ABSTRACT FROM AUTHOR]
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- 2012
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17. Lipoprotein distribution and serum concentrations of 7α-hydroxy-4-cholesten-3-one and bile acids: effects of monogenic disturbances in high-density lipoprotein metabolism.
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STEINER, Carine, HOLLEBOOM, Adriaan G., KARUNA, Ratna, MOTAZACKER, Mohammad M., KUIVENHOVEN, Jan Albert, FRIKKE-SCHMIDT, Ruth, TYBJAERG-HANSEN, Anne, ROHRER, Lucia, RENTSCH, Katharina M., and VON ECKARDSTEIN, Arnold
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BILE acids ,HIGH density lipoproteins ,HYDROXY acids ,LOW density lipoproteins ,CHOLESTEROL ,LECITHIN ,CHOLESTERYL ester transfer protein - Abstract
BA (bile acid) formation is considered an important final step in RCT (reverse cholesterol transport). HDL (high-density lipoprotein) has been reported to transport BAs. We therefore investigated the effects of monogenic disturbances in human HDL metabolism on serum concentrations and lipoprotein distributions of the major 15 BA species and their precursor C4 (7a-hydroxy-4-cholesten-3-one). In normolipidaemic plasma, approximately 84%, 11% and 5% of BAs were recovered in the LPDS (lipoprotein-depleted serum), HDL and the combined LDL (low-density lipoprotein)/VLDL (very-low-density lipoproteins) fraction respectively. Conjugated BAs were slightly over-represented in HDL. For C4, the respective percentages were 23%, 21% and 56% (41% in LDL and 15% in VLDL) respectively. Compared with unaffected family members, neither HDL-C (HDL-cholesterol)-decreasing mutations in the genes APOA1 [encoding ApoA-I (apolipoprotein A-I], ABCA1 (ATP-binding cassette transporter A1) or LCAT (lecithin:cholesterol acyltransferase) nor HDL-C-increasing mutations in the genes CETP (cholesteryl ester transfer protein) or LIPC (hepatic lipase) were associated with significantly different serum concentrations of BA and C4. Plasma concentrations of conjugated and secondary BAs differed between heterozygous carriers of SCARB1 (scavenger receptor class B1) mutations and unaffected individuals (P<0.05), but this difference was not significant after correction for multiple testing. Moreover, no differences in the lipoprotein distribution of BAs in the LPDS and HDL fractions from SCARB1 heterozygotes were observed. In conclusion, despite significant recoveries of BAs and C4 in HDL and despite the metabolic relationships between RCT and BA formation, monogenic disorders of HDL metabolism do not lead to altered serum concentrations of BAs and C4. [ABSTRACT FROM AUTHOR]
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- 2012
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18. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.
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Chapman, M. John, Ginsberg, Henry N., Amarenco, Pierre, Andreotti, Felicita, Borén, Jan, Catapano, Alberico L., Descamps, Olivier S., Fisher, Edward, Kovanen, Petri T., Kuivenhoven, Jan Albert, Lesnik, Philippe, Masana, Luis, Nordestgaard, Børge G., Ray, Kausik K., Reiner, Zeljko, Taskinen, Marja-Riitta, Tokgözoglu, Lale, Tybjærg-Hansen, Anne, and Watts, Gerald F.
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Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal. [ABSTRACT FROM PUBLISHER]
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- 2011
19. Nonfasting triglycerides, cholesterol, and ischemic stroke in the general population.
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Varbo, Anette, Nordestgaard, Børge G., Tybjærg?Hansen, Anne, Schnohr, Peter, Jensen, Gorm B., and Benn, Marianne
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ISCHEMIA ,ISOPENTENOIDS ,TRIGLYCERIDES ,CHOLESTEROL ,CORONARY disease - Abstract
The article focuses on the study conducted to examine the nonfasting triglycerides, cholesterol, and ischemic stroke. It compares the compare the increasing levels of nonfasting triglycerides and cholesterol for their association with risk of ischemic stroke in the general population. It concludes that the increasing levels of nonfasting triglycerides in women were associated with increasing risk of ischemic stroke.
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- 2011
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20. Low-Density Lipoprotein Cholesterol and the Risk of Cancer: A Mendelian Randomization Study.
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Benn, Marianne, Tybjærg-Hansen, Anne, Stender, Stefan, Frikke-Schmidt, Ruth, and Nordestgaard, Børge G.
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CANCER risk factors , *LOW density lipoproteins , *CHOLESTEROL , *ETIOLOGY of diseases , *CLINICAL medicine - Abstract
Background Low plasma levels of low-density lipoprotein (LDL) cholesterol are associated with an increased risk of cancer, but whether this association is causal is unclear. Methods We studied 10 613 participants in the Copenhagen City Heart Study (CCHS) and 59 566 participants in the Copenhagen General Population Study, 6816 of whom had developed cancer by May 2009. Individuals were genotyped for PCSK9 R46L (rs11591147), ABCG8 D19H (rs11887534), and APOE R112C (rs429358) and R158C (rs7412) polymorphisms, all of which are associated with lifelong reduced plasma LDL cholesterol levels. Plasma LDL cholesterol was calculated using the Friedewald equation in samples in which the triglyceride level was less than 354 mg/dL and measured directly by colorimetry for samples with higher triglyceride levels. Risk of cancer was estimated prospectively using Cox proportional hazards regression analyses and cross-sectionally by logistic regression analyses. Causality was studied using instrumental variable analysis. All statistical tests were two-sided. Results In the CCHS, compared with plasma LDL cholesterol levels greater than the 66th percentile (>158 mg/dL), those lower than the 10th percentile (<87 mg/dL) were associated with a 43% increase (95% confidence interval [CI] = 15% to 79% increase) in the risk of cancer. The polymorphisms were associated with up to a 38% reduction (95% CI = 36% to 41% reduction) in LDL cholesterol levels but not with increased risk of cancer. The causal odds ratio for cancer for a 50% reduction in plasma LDL cholesterol level due to all the genotypes in both studies combined was 0.96 (95% CI = 0.87 to 1.05), whereas the hazard ratio of cancer for a 50% reduction in plasma LDL cholesterol level in the CCHS was 1.10 (95% CI = 1.01 to 1.21) (P for causal odds ratio vs observed hazard ratio = .03). Conclusion Low plasma LDL cholesterol levels were robustly associated with an increased risk of cancer, but genetically decreased LDL cholesterol was not. This finding suggests that low LDL cholesterol levels per se do not cause cancer. [ABSTRACT FROM PUBLISHER]
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- 2011
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21. Common clinical practice versus new PRIM score in predicting coronary heart disease risk
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Frikke-Schmidt, Ruth, Tybjærg-Hansen, Anne, Schnohr, Peter, Jensen, Gorm B., and Nordestgaard, Børge G.
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CORONARY heart disease risk factors , *HIGH density lipoproteins , *CHOLESTEROL , *BLOOD pressure , *DIABETES , *DISEASES in women , *HYPERTENSION - Abstract
Abstract: Objectives: To compare the new Patient Rule Induction Method (PRIM) Score and common clinical practice with the Framingham Point Score for classification of individuals with respect to coronary heart disease (CHD) risk. Methods and results: PRIM Score and the Framingham Point Score were estimated for 11,444 participants from the Copenhagen City Heart Study. Gender specific cumulative incidences and 10 year absolute CHD risks were estimated for subsets defined by age, total cholesterol, high-density lipoprotein (HDL) cholesterol, blood pressure, diabetes and smoking categories. PRIM defined seven mutually exclusive subsets in women and men, with cumulative incidences of CHD from 0.01 to 0.22 in women, and from 0.03 to 0.26 in men. PRIM versus Framingham Point Score found 11% versus 4% of all women, and 31% versus 35% of all men to have 10 year CHD risks>20%. Among women≥65 years with hypertension and/or with diabetes, 10 year CHD risk>20% was found for 100% with PRIM scoring but for only 18% with the Framingham Point Score. Conclusion: Compared to the PRIM Score, common clinical practice with the Framingham Point Score underestimates CHD risk in women, especially in women≥65 years with hypertension and/or with diabetes. [ABSTRACT FROM AUTHOR]
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- 2010
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22. PCSK9R46L, Low-Density Lipoprotein Cholesterol Levels, and Risk of Ischemic Heart Disease 3 Independent Studies and Meta-Analyses
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Benn, Marianne, Nordestgaard, Børge G., Grande, Peer, Schnohr, Peter, and Tybjærg-Hansen, Anne
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lipids ,PCSK9 ,genetics of cardiovascular disease ,LDL cholesterol ,cholesterol ,epidemiology - Abstract
ObjectivesThe aim of this study was to examine the effect of PCSK9R46L on low-density lipoprotein cholesterol (LDL-C), risk of ischemic heart disease (IHD), and mortality.BackgroundThe 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies.MethodsWe determined the association of R46L genotype with LDL-C, risk of IHD, myocardial infarction (MI), and mortality in the prospective CCHS (Copenhagen City Heart Study) (n = 10,032) and validated the results in: 1) the cross-sectional CGPS (Copenhagen General Population Study) (n = 26,013); and 2) the case-control CIHDS (Copenhagen Ischemic Heart Disease Study) (n = 9,654). We also performed meta-analyses of present and previous studies (n = 66,698).ResultsIn carriers (2.6%) versus noncarriers, the 46L allele was associated with reductions in LDL-C of 0.35 to 0.55 mmol/l (11% to 16%) from 20 to 80+ years in the general population (CCHS and CGPS; p values
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23. ABCA1 Gene Mutations, HDL Cholesterol Levels, and Risk of Ischemic Heart Disease.
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Tybjærg-Hansen, Anne, Nordestgaard, Børge G., and Frikke-Schmidt, Ruth
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LETTERS to the editor , *CHOLESTEROL - Abstract
Anne Tybjaerg-Hansen, Borge G. Nordestgaard and Ruth Frikke-Schmidt respond to a letter to the editor about their article "Association of Loss of Function Mutations in the ABC1 Gene With High Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease" in a previous issue.
- Published
- 2008
24. The ABCG5/8 Cholesterol Transporter and Myocardial Infarction Versus Gallstone Disease.
- Author
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Stender, Stefan, Frikke-Schmidt, Ruth, Nordestgaard, Børge G., and Tybjærg-Hansen, Anne
- Subjects
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CHOLESTEROL in the body , *ATP-binding cassette transporters , *MYOCARDIAL infarction , *GALLSTONES , *GENETIC polymorphisms , *MYOCARDIAL infarction risk factors - Abstract
Objectives: The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions. Background: High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation. Methods: A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated. Results: Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score ≥8.0 (prevalence = 11%) versus <2.0 (prevalence = 9%; p for trend across 5 groups = 2 × 10E-35). The cumulative incidences of MI and gallstone disease as a function of age and increasing genotype score were decreased and increased (log-rank ps for trend: 6 × 10E-4 and 9 × 10E-45), respectively. The multifactorially adjusted odds ratios were 0.83 (95% confidence interval: 0.73 to 0.94) for MI and 2.85 (95% confidence interval: 2.39 to 3.39) for symptomatic gallstone disease for individuals with a genotype score ≥8.0 versus <2.0. Conclusions: Genetic variation in ABCG5/8, which associates with decreased levels of plasma LDL cholesterol protects against MI, but increases the risk of symptomatic gallstone disease. These results suggest that MI and gallstones, 2 seemingly unrelated diseases, are intrinsically linked via the function of the ABCG5/8 cholesterol transporter. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
25. Low-density lipoprotein cholesterol and risk of gallstone disease: A Mendelian randomization study and meta-analyses
- Author
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Stender, Stefan, Frikke-Schmidt, Ruth, Benn, Marianne, Nordestgaard, Børge G., and Tybjærg-Hansen, Anne
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- *
LOW density lipoproteins , *CHOLESTEROL , *GALLSTONES , *RANDOMIZATION (Statistics) , *META-analysis , *HUMAN genetic variation , *DISEASES - Abstract
Background & Aims: Drugs which reduce plasma low-density lipoprotein cholesterol (LDL-C) may protect against gallstone disease. Whether plasma levels of LDL-C per se predict risk of gallstone disease remains unclear. We tested the hypothesis that elevated LDL-C is a causal risk factor for symptomatic gallstone disease. Methods: We used a Mendelian randomization approach and genotyped 63,051 individuals from a prospective cohort study of the general Danish population, including 3323 subjects with symptomatic gallstones. We selected eight genetic variants in APOE, APOB, LDLR, and PCSK9 affecting LDL-C. Furthermore, studies of APOE rs429358/rs7412 (defining ε2/ε3/ε4 alleles; 12 studies) and APOB rs693 (eight studies) were included in meta-analyses. Results: The observational hazard ratio (HR) for symptomatic gallstone disease for the fifth versus first quintile of LDL-C was 0.94 (95% confidence interval: 0.76–1.17), despite a corresponding 134% increase in LDL-C. Furthermore, although individual genetic variants in APOE, APOB, LDLR, and PCSK9 associated with stepwise increases/decreases in LDL-C of up to +59% compared with non-carriers (p <0.001), none predicted the risk of symptomatic gallstone disease. Combining all variants into 10 genotypes, carriers of 9 versus ⩽3 LDL-C increasing alleles associated with 41% increased LDL-C (p <0.001), but predicted a HR for symptomatic gallstone disease of 1.09 (0.70–1.69). Finally, in meta-analyses, random effects odds ratios for gallstone disease were 0.91 (0.78–1.06) for carriers of APOE ε4 versus non-carriers, and 1.25 (0.95–1.63) for APOB rs693 CT+TT versus CC. Conclusions: Results from the observational study, genetic studies, and meta-analyses suggest that elevated plasma levels of LDL-C are not causally associated with increased risk of symptomatic gallstone disease. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
26. Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism
- Author
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Karuna, Ratna, Holleboom, Adriaan G., Motazacker, Mohammad M., Kuivenhoven, Jan Albert, Frikke-Schmidt, Ruth, Tybjaerg-Hansen, Anne, Georgopoulos, Spiros, van Eck, Miranda, van Berkel, Theo J.C., von Eckardstein, Arnold, and Rentsch, Katharina M.
- Subjects
- *
CHOLESTEROL , *BLOOD plasma , *HIGH density lipoproteins , *MASS spectrometry , *OXYSTEROLS , *ACYLTRANSFERASES , *LABORATORY mice ,BLOOD lipoprotein metabolism - Abstract
Abstract: Secretion of 27-hydroxycholesterol (27OHC) from macrophages is considered as an alternative to HDL-mediated reverse transport of excess cholesterol. We investigated 27OHC-concentrations in plasma of humans and mice with monogenic disorders of HDL metabolism. As compared to family controls mutations in the genes for apolipoprotein A-I, ATP binding cassette transporter (ABC) A1 and lecithin:cholesterol acylstransferase (LCAT) were associated with reduced concentrations of both HDL-cholesterol and HDL-27OHC whereas mutations in the genes for cholesterylester transfer protein (CETP), scavenger receptor type BI and hepatic lipase were associated with elevated HDL concentrations of either sterol. Compared to family controls and relative to the concentrations of total 27OHC and cholesterol, lower 27OHC-ester but normal cholesterylester levels were found in HDL of heterozygous LCAT mutation carriers and nonHDL of heterozygous CETP mutation carriers. In family controls, LCAT activity and CETP mass were more strongly correlated with 27OHC-ester than cholesterylester concentrations in HDL and nonHDL, respectively. These findings suggest that the formation and transfer of 27OHC-esters are more sensitive to reduced activities of LCAT and CETP, respectively, than the formation and transfer of cholesterylesters. 27OHC plasma levels were also decreased in apoA-I-, ABCA1- or LCAT-knockout mice but increased in SR-BI-knockout mice. Transplantation of ABCA1- and/or ABCG1-deficient bone marrow into LDL receptor deficient mice decreased plasma levels of 27OHC. In conclusion, mutations or absence of HDL genes lead to distinct alterations in the quantity, esterification or lipoprotein distribution of 27OHC. These findings argue against the earlier suggestion that 27OHC-metabolism in plasma occurs independently of HDL. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
27. PCSK9 R46L, Low-Density Lipoprotein Cholesterol Levels, and Risk of Ischemic Heart Disease: 3 Independent Studies and Meta-Analyses
- Author
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Benn, Marianne, Nordestgaard, Børge G., Grande, Peer, Schnohr, Peter, and Tybjærg-Hansen, Anne
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- *
LOW density lipoproteins , *CHOLESTEROL , *CORONARY heart disease risk factors , *ISCHEMIA , *META-analysis , *HEART disease related mortality , *CONFIDENCE intervals , *DISEASE risk factors ,HEART disease epidemiology - Abstract
Objectives: The aim of this study was to examine the effect of PCSK9 R46L on low-density lipoprotein cholesterol (LDL-C), risk of ischemic heart disease (IHD), and mortality. Background: The 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies. Methods: We determined the association of R46L genotype with LDL-C, risk of IHD, myocardial infarction (MI), and mortality in the prospective CCHS (Copenhagen City Heart Study) (n = 10,032) and validated the results in: 1) the cross-sectional CGPS (Copenhagen General Population Study) (n = 26,013); and 2) the case-control CIHDS (Copenhagen Ischemic Heart Disease Study) (n = 9,654). We also performed meta-analyses of present and previous studies (n = 66,698). Results: In carriers (2.6%) versus noncarriers, the 46L allele was associated with reductions in LDL-C of 0.35 to 0.55 mmol/l (11% to 16%) from 20 to 80+ years in the general population (CCHS and CGPS; p values <0.0001). Observed risk reductions for IHD in 46L allele carriers were: 6% in the CCHS study (hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.68 to 1.31), 46% in the CGPS study (odds ratio [OR]: 0.54; 95% CI: 0.39 to 0.77), 18% in the CIHDS study (OR: 0.82; 95% CI: 0.55 to 1.21), and 30% in the studies combined (OR: 0.70; 95% CI: 0.58 to 0.86). In the CCHS study, HR for mortality was 1.18 (95% CI: 0.93 to 1.50). In meta-analyses, 46L allele carriers had a 12% (0.43 mmol/l) reduction in LDL-C and a 28% reduction in risk of IHD (HR: 0.72; 95% CI: 0.62 to 0.84), similar to results in the CCHS, CGPS, and CIHDS studies combined. However, the observed 12% (0.43 mmol/l) reduction in LDL-C theoretically predicted an only 5% reduction in risk of IHD (HR: 0.95; 95% CI: 0.92 to 0.97). Conclusions: The PCSK9 46L allele was associated with reductions in LDL-C from 20 to 80+ years in the general population. The reduction in risk of IHD was larger than predicted by the observed reduction in LDL-C alone. This could be because genotype is a better predictor of lifelong exposure to LDL-C than LDL-C measured in adult life. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
28. Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population.
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Frikke-Schmidt, Ruth, Nordestgaard, Borge G., Jensen, Gorm B., Tybaerg-Hansen, Anne, Nordestgaard, Børge G, and Tybjaerg-Hansen, Anne
- Subjects
- *
PATHOLOGY , *HYPOLIPOPROTEINEMIA , *GENETIC research , *BLOOD lipoprotein metabolism disorders , *CHOLESTEROL , *DIAGNOSIS , *ALLELES , *AMINO acids , *BIOLOGICAL models , *CARRIER proteins , *COMPARATIVE studies , *DOCUMENTATION , *GENES , *GENETIC polymorphisms , *GENETICS , *HIGH density lipoproteins , *RESEARCH methodology , *MEDICAL cooperation , *GENETIC mutation , *PROTEINS , *RESEARCH , *RNA , *EVALUATION research , *GENETIC carriers , *HAPLOTYPES , *GENOTYPES - Abstract
Homozygosity for mutations in ABC transporter A1 (ABCA1) causes Tangier disease, a rare HDL-deficiency syndrome. Whether heterozygosity for genetic variation in ABCA1 also contributes to HDL cholesterol (HDL-C) levels in the general population is presently unclear. We determined whether mutations or single-nucleotide polymorphisms (SNPs) in ABCA1 were overrepresented in individuals with the lowest 1% (n=95) or highest 1% (n=95) HDL-C levels in the general population by screening the core promoter and coding region of ABCA1. For all nonsynonymous SNPs identified, we determined the effect of genotype on lipid traits in 9,259 individuals from the general population. Heterozygosity for ABCA1 mutations was identified in 10% of individuals with low HDL-C only. Three of 6 nonsynonymous SNPs (V771M, V825I, and R1587K) were associated with increases or decreases in HDL-C in women in the general population and some with consistent trends in men, determined as isolated single-site effects varying only at the relevant SNP. Finally, these results were consistent over time. In conclusion, we show that at least 10% of individuals with low HDL-C in the general population are heterozygous for mutations in ABCA1 and that both mutations and SNPs in ABCA1 contribute to HDL-C levels in the general population. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
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