Anne Tybjaerg-Hansen

Publications (102)916.62 Total impact

• Article: Exploring causal associations between alcohol and coronary heart disease risk factors: findings from a Mendelian randomization study in the Copenhagen General Population Study.

  Debbie A Lawlor, Børge G Nordestgaard, Marianne Benn, Luisa Zuccolo, Anne Tybjaerg-Hansen, George Davey Smith
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  ABSTRACT: AimsTo explore the causal effect of long-term alcohol consumption on coronary heart disease risk factors.Methods and resultsWe used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on body mass index (BMI), blood pressure (BP), lipids, fibrinogen, and glucose. Analyses were undertaken in 54 604 Danes (mean age 56 years). Both confounder-adjusted multivariable and IV analyses suggested that a greater alcohol consumption among those who drank any alcohol resulted in a higher BP [mean difference in SBP per doubling of alcohol consumption among drinkers: 0.76 mmHg (95% CI: 0.63, 0.90) from multivariable analyses and 0.94 mmHg (-3.03, 4.69) from IV analyses; P-value for difference in these results = 0.95]. The positive association of alcohol with HDLc in the multivariable analyses [4.9% (4.7, 5.1)] appeared stronger than in the IV analyses [1.5% (-4.5, 7.4)], and the weak inverse association with fibrinogen in the multivariable analysis [-2.0% (-2.1, -1.8)] was not present in the IV analyses [0.6% (-3.8, 5.0)], but statistically the results for both of these could not be reliably distinguished from each other (P-values 0.21 and 0.32, respectively). The weak inverse association of alcohol with BMI [-0.13 kg/m(2) (-0.16, -0.10)] and with triglycerides [-0.4% (-0.7, 0.4)] in multivariable analyses were in contrast to the strong positive association of alcohol with BMI [1.37 kg/m(2) (0.59, 2.15)] and the strong inverse association with triglycerides [-14.9% (-25.6, -4.3)] in IV analyses; P = 0.006 and 0.01, respectively, for difference between the two. Alcohol was not associated with non-HDLc or glucose.Conclusion Our results show adverse effects of long-term alcohol consumption on BP and BMI. We also found novel evidence for a potentially beneficial effect on triglyceride levels, which needs further replication.
  European Heart Journal 03/2013; · 10.48 Impact Factor
• Article: European Lipoprotein Club: Report of the 35th ELC Annual Conference (Tutzing, 10th-13th September 2012).

  Philippe Costet, Ewa Ehrenborg, Rachel Fisher, Barbara Fielding, Albert Groen, Dimitris Kardassis, Ernst Malle, Monique Mulder, Andreas Niemeier, Giuseppe Danilo Norata, Anne Tybjaerg Hansen, Arnold von Eckardstein
  Atherosclerosis 12/2012; · 3.79 Impact Factor
• Article: Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication.

  Marianne Benn, Gerald F Watts, Anne Tybjaerg-Hansen, Børge G Nordestgaard
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  ABSTRACT: Context:The diagnosis of familial hypercholesterolemia (FH) can be made using the Dutch Lipid Clinic Network criteria. This employs the personal and family history of premature coronary artery disease and hypercholesterolemia and the presence of a pathogenic mutation in the low-density lipoprotein receptor (LDLR) and apolipoprotein B (APOB) genes.Objective:We employed this tool to investigate the prevalence of FH and the associations between FH and coronary artery disease and cholesterol-lowering medication in the Copenhagen General Population Study.Setting:The study was of an unselected, community-based population comprising 69,016 participants.Main Outcome Measures:FH (definite/probable) was defined as a Dutch Lipid Clinic Network score higher than 5. Coronary artery disease was myocardial infarction or angina pectoris.Results:The prevalence of FH was 0.73% (one in 137). Of participants with FH, 20% had an LDLR or APOB mutation. The prevalence of coronary artery disease among FH participants was 33%. Only 48% of subjects with FH admitted to taking cholesterol-lowering medication. The odds ratio for coronary artery disease off cholesterol-lowering medication was 13.2 (10.0-17.4) in definite/probable FH compared with non-FH subjects, after adjusting for age, gender, body mass index, hypertension, metabolic syndrome and diabetes, and smoking. The corresponding adjusted odds ratio for coronary artery disease in FH subjects on cholesterol-lowering medication was 10.3 (7.8-13.8).Conclusion:The prevalence of FH appears to be higher than commonly perceived in a general population of white Danish individuals, with at least half of affected subjects not receiving cholesterol-lowering medication. The very high risk of coronary artery disease irrespective of use of medication reflects the extent of underdiagnosis and undertreatment of FH in the community and primary care.
  The Journal of clinical endocrinology and metabolism 08/2012; · 6.50 Impact Factor
• Article: The plasma concentration of HDL-associated apoM is influenced by LDL receptor-mediated clearance of apoB-containing particles.

  Christina Christoffersen, Marianne Benn, Pernille M Christensen, Philip L S M Gordts, Anton J M Roebroek, Ruth Frikke-Schmidt, Anne Tybjaerg-Hansen, Björn Dahlbäck, Lars B Nielsen
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  ABSTRACT: ApoM is mainly associated with HDL. Nevertheless, we have consistently observed positive correlations of apoM with plasma LDL cholesterol in humans. Moreover, LDL receptor deficiency is associated with increased plasma apoM in mice. Here, we tested the idea that plasma apoM concentrations are affected by the rate of LDL receptor-mediated clearance of apoB-containing particles. We measured apoM in humans each carrying one of three different LDL receptor mutations (n = 9) or the apoB3500 mutation (n = 12). These carriers had increased plasma apoM (1.34 ± 0.13 µM, P = 0.003, and 1.23 ± 0.10 µM, P = 0.02, respectively) as compared with noncarriers (0.93 ± 0.04 µM). When we injected human apoM-containing HDL into Wt (n = 6) or LDL receptor-deficient mice (n = 6), the removal of HDL-associated human apoM was delayed in the LDL receptor-deficient mice. After 2 h, 54 ± 5% versus 90 ± 8% (P < 0.005) of the initial amounts of human apoM remained in the plasma of Wt and LDL receptor-deficient mice, respectively. Finally, we compared the turnover of radio-iodinated LDL and plasma apoM concentrations in 45 normocholesterolemic humans. There was a negative correlation between plasma apoM and the fractional catabolic rate of LDL (r = -0.38, P = 0.009). These data suggest that the plasma clearance of apoM, despite apoM primarily being associated with HDL, is influenced by LDL receptor-mediated clearance of apoB-containing particles.
  The Journal of Lipid Research 07/2012; 53(10):2198-204. · 5.56 Impact Factor
• Article: Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis.

  S Stender, R Frikke-Schmidt, B G Nordestgaard, P Grande, A Tybjaerg-Hansen
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  ABSTRACT: BACKGROUND: Elevated plasma levels of bilirubin, an endogenous antioxidant, have been associated with reduced risk of ischaemic heart disease (IHD) and myocardial infarction (MI). Whether this is a causal relationship remains unclear. OBJECTIVE: We tested the hypothesis that elevated plasma bilirubin is causally related to decreased risk of IHD and MI. DESIGN: We used a Mendelian randomization approach and three independent studies from Copenhagen, Denmark. We measured bilirubin in 43 708 white individuals from the general population, and genotyped rs6742078 G>T in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in 67 068 individuals, of whom 11 686 had IHD. RESULTS: Third versus first tertile of baseline bilirubin levels was associated with 134% increased bilirubin levels, with sex- and age-adjusted hazard ratios (HRs) of 0.86 [95% confidence interval (CI), 0.76-0.98; P = 0.02] for IHD and 0.81 (95% CI, 0.66-0.99; P = 0.04) for MI, but with corresponding multifactorially adjusted HRs of 0.93 (95% CI, 0.82-1.06; P = 0.29) and 0.90 (95% CI, 0.73-1.12; P = 0.35). UGT1A1 rs6742078 TT versus GG genotype was associated with 95% increased bilirubin levels (P < 0.001); TT versus GG genotype was associated with odds ratios (ORs) of 1.03 (95% CI, 0.96-1.11; P = 0.73) for IHD and 1.01 (95% CI, 0.92-1.12; P = 0.68) for MI. Finally, in a meta-analysis of the present three studies and eight previous studies including a total of 14 711 cases and 60 324 controls, the random effects OR for ischaemic cardiovascular disease for genotypes with approximately 100% increased bilirubin levels versus reference genotypes was 1.01 (95% CI, 0.88-1.16). CONCLUSION: These data suggest that plasma bilirubin is not causally associated with risk of IHD.
  Journal of Internal Medicine 07/2012; · 5.48 Impact Factor
• Article: Lipoprotein distribution and serum concentrations of 7α-hydroxy-4-cholesten-3-one and bile acids: effects of monogenic disturbances in high-density lipoprotein metabolism.

  Carine Steiner, Adriaan G Holleboom, Ratna Karuna, Mohammad M Motazacker, Jan Albert Kuivenhoven, Ruth Frikke-Schmidt, Anne Tybjaerg-Hansen, Lucia Rohrer, Katharina M Rentsch, Arnold von Eckardstein
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  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 (7α-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.
  Clinical Science 04/2012; 122(8):385-96. · 4.61 Impact Factor
• Article: European Lipoprotein Club: Report of the 34th ELC annual conference, Tutzing, 5-8 September 2011.

  Franco Bernini, Philippe Costet, Ewa Ehrenborg, Rachel Fisher, Barbara Fielding, Dilys Freeman, Albert Groen, Ernst Malle, Monique Mulder, Andreas Niemeier, Anne Tybjaerg Hansen, Arnold von Eckardstein
  Atherosclerosis 12/2011; 221(1):287-93. · 3.79 Impact Factor
• Article: β2 -adrenergic receptor Thr164IIe polymorphism, blood pressure and ischaemic heart disease in 66 750 individuals.

  M Thomsen, M Dahl, A Tybjaerg-Hansen, B G Nordestgaard
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  ABSTRACT: The β(2) -adrenergic receptor (ADRB2) is located on smooth muscle cells and is an important regulator of smooth muscle tone. The Thr164Ile polymorphism (rs1800888) in the ADRB2 gene is rare but has profound functional consequences on receptor function and could cause lifelong elevated smooth muscle tone. We tested the hypothesis that Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of cardiovascular disease (CVD). A total of 66 750 individuals from two large Danish general population studies were genotyped, and 1943 Thr164Ile heterozygotes and 16 homozygotes were identified. Thr164Ile genotype was associated with increased systolic and diastolic blood pressure in women (trend: P = 0.04 and 0.02): systolic and diastolic blood pressure increased by 5% and 2%, respectively, in female homozygotes compared with female noncarriers. All female Thr164Ile homozygotes had hypertension compared with 58% of female heterozygotes and 54% of female noncarriers (chi-square: P = 0.001). Female Thr164Ile homozygotes and heterozygotes had odds ratios for ischaemic heart disease (IHD) of 2.93 (0.56-15.5) and 1.28 (1.03-1.61), respectively, compared with female noncarriers (trend: P = 0.007). These differences were not observed in men. Furthermore, Gly16Arg (rs1042713) and Gln27Glu (rs1042714) in the ADRB2 gene were not associated with blood pressure, hypertension or CVD either in the population overall or in women and men separately. ADRB2 Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of IHD amongst women in the general population. These findings, particularly for homozygotes, are novel.
  Journal of Internal Medicine 08/2011; 271(3):305-14. · 5.48 Impact Factor
• Article: Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels.

  C L Haase, R Frikke-Schmidt, B G Nordestgaard, A K Kateifides, D Kardassis, L B Nielsen, C B Andersen, L Køber, A H Johnsen, P Grande, V I Zannis, A Tybjaerg-Hansen
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  ABSTRACT: To determine whether mutations in APOA1 affect levels of high-density lipoprotein (HDL) cholesterol and to predict risk of ischaemic heart disease (IHD) and total mortality in the general population. Epidemiologically, risk of IHD is inversely related to HDL cholesterol levels. Mutations in apolipoprotein (apo) A-I, the major protein constituent of HDL, might be associated with low HDL cholesterol and predispose to IHD and early death. We resequenced APOA1 in 190 individuals and examined the effect of mutations on HDL cholesterol, risk of IHD, myocardial infarction (MI) and mortality in 10 440 individuals in the prospective Copenhagen City Heart Study followed for 31 years. Results were validated in an independent case-control study (n = 16 035). Additionally, we determined plasma ratios of mutant to wildtype (WT) apoA-I in human heterozygotes and functional effects of mutations in adenovirus-transfected mice. We identified a new mutation, A164S (1 : 500 in the general population), which predicted hazard ratios for IHD, MI and total mortality of 3.2 [95% confidence interval (CI): 1.6-6.5], 5.5 (95% CI: 2.6-11.7) and 2.5 (95% CI: 1.3-4.8), respectively, in heterozygotes compared with noncarriers. Mean reduction in survival time in heterozygotes was 10 years (P < 0.0001). Results for IHD and MI were confirmed in the case-control study. Furthermore, the ratio of mutant S164 to WT A164 apoA-I in plasma of heterozygotes was reduced. In addition, A164S heterozygotes had normal plasma lipid and lipoprotein levels, including HDL cholesterol and apoA-I, and this finding was confirmed in adenovirus-transfected mice. A164S is the first mutation in APOA1 to be described that predicts an increased risk of IHD, MI and total mortality without low HDL cholesterol levels.
  Journal of Internal Medicine 03/2011; 270(2):136-46. · 5.48 Impact Factor
• Article: Sterol transporter adenosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62,000 individuals from the general population.

  Stefan Stender, Ruth Frikke-Schmidt, Børge G Nordestgaard, Anne Tybjaerg-Hansen
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  ABSTRACT: Gallstone disease, a risk factor for biliary cancer, has a strong heritable component, but the underlying genes are largely unknown. To test the hypothesis that ABCG8 (adenosine triphosphate-binding cassette transporter G8) Asp19His (D19H) genotype predicted risk of gallstones and biliary cancer in the general population, we studied 62,279 white individuals from The Copenhagen City Heart Study and The Copenhagen General Population Study, randomly selected to reflect the adult Danish population aged 20 to 80+ years. Endpoints were recorded from January 1976 through May 2009. During a mean follow-up of, respectively, 31 and 4.4 years, 3124 participants developed symptomatic gallstone disease and 30 developed biliary cancer. The multifactorially adjusted hazard ratio for symptomatic gallstone disease was 1.9 (95% confidence interval, 1.7-2.1) in DH heterozygotes (prevalence, 12%), and 3.3 (2.3-4.6) in HH homozygotes (0.4%) versus noncarriers (P for trend <0.001). Mean age at onset of symptomatic gallstone disease was 56 years for noncarriers, 54 for DH heterozygotes, and 52 for HH homozygotes (P for trend <0.001). The fraction of all gallstones attributed to D19H was 11%. The multifactorially adjusted hazard ratio for biliary cancer was 4.0 (1.9-8.4) in DH heterozygotes and HH homozygotes combined versus noncarriers (P < 0.001). The fraction of all biliary cancers attributed to the D19H genotype was 27%. Finally, D19H genotype associated with stepwise increases in plasma levels of alanine aminotransferase and gamma glutamyltransferase of up to 14% and 25% in HH homozygotes, and with corresponding stepwise reductions in plasma levels of total and low-density lipoprotein cholesterol of up to 5% versus noncarriers (all comparisons, P for trend <0.001). CONCLUSION: In this general population cohort, ABCG8 D19H genotype was an important predictor of both symptomatic gallstone disease and biliary cancer.
  Hepatology 02/2011; 53(2):640-8. · 11.66 Impact Factor
• Article: Nonfasting triglycerides, cholesterol, and ischemic stroke in the general population.

  Anette Varbo, Børge G Nordestgaard, Anne Tybjaerg-Hansen, Peter Schnohr, Gorm B Jensen, Marianne Benn
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  ABSTRACT: Current guidelines on stroke prevention have recommendations on desirable cholesterol levels, but not on nonfasting triglycerides. We compared stepwise increasing levels of nonfasting triglycerides and cholesterol for their association with risk of ischemic stroke in the general population. A total of 7,579 women and 6,372 men from the Copenhagen City Heart Study with measurements of nonfasting triglycerides and cholesterol at baseline in 1976-1978 were followed for up to 33 years; of these, 837 women and 837 men developed ischemic stroke during follow-up, which was 100% complete. The fluctuation of nonfasting triglycerides and cholesterol over 15 years was similar. In both women and men, stepwise increasing levels of nonfasting triglycerides were associated with increased risk of ischemic stroke. Compared to women with triglycerides <1 mmol/liter, multivariate adjusted hazard ratios ranged from 1.2 (95% confidence interval [CI], 0.9-1.7) for triglyceride levels of 1.00-1.99 mmol/liter to 3.9 (95%CI, 1.3-11.1) for triglyceride levels ≥ 5 mmol/liter (trend: p < 0.001); corresponding hazard ratios in men ranged from 1.2 (95%CI, 0.8-1.7) to 2.3 (95%CI, 1.2-4.3) (p = 0.001). Increasing cholesterol levels were not associated with risk of ischemic stroke except in men with cholesterol levels ≥ 9.00 mmol/liter vs < 5.00 mmol/liter, with a hazard ratio of 4.4 (95%CI, 1.9-10.6). In women, stepwise increasing levels of nonfasting triglycerides were associated with increasing risk of ischemic stroke while increasing cholesterol levels were not. In men, these results were similar except that cholesterol ≥ 9.00 mmol/liter was associated with increased risk of ischemic stroke.
  Annals of Neurology 02/2011; 69(4):628-34. · 11.09 Impact Factor
• Source

  Available from: Miranda Van Eck

  Article: Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism.

  Ratna Karuna, Adriaan G Holleboom, Mohammad M Motazacker, Jan Albert Kuivenhoven, Ruth Frikke-Schmidt, Anne Tybjaerg-Hansen, Spiros Georgopoulos, Miranda van Eck, Theo J C van Berkel, Arnold von Eckardstein, Katharina M Rentsch
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  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.
  Atherosclerosis 02/2011; 214(2):448-55. · 3.79 Impact Factor
• Article: Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults.

  Debbie A Lawlor, Roger M Harbord, Anne Tybjaerg-Hansen, Tom M Palmer, Jeppe Zacho, Marianne Benn, Nicholas J Timpson, George Davey Smith, Børge G Nordestgaard
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  ABSTRACT: We used genetic variants that are robustly associated with adiposity to examine the causal association of adiposity with psychological distress. We examined the association of adiposity with psychological distress in a large (N = 53,221) general population cohort of 20- to 99-year-old adults from Copenhagen, Denmark. Psychological distress was assessed using four questions that asked about: feeling stressed; not accomplishing very much; wanting to give up; and regular use of antidepressants/sedatives. We used the genetic loci FTO rs9939609 and MC4R rs17782313 as instrumental variables for adiposity quantified by body mass index (BMI) and waist to hip ratio (WHR). In conventional multivariable analyses, BMI and WHR were positively associated with distress. For example, the odds ratio of reporting not accomplishing for each additional standard deviation increase for BMI was 1.11 (95% CI: 1.09, 1.13) and for WHR was 1.10 (95% CI: 1.08, 1.13) in the fully adjusted analyses. In contrast, instrumental variable analyses showed an inverse association of adiposity on distress; corresponding odds ratio in instrumental variable analyses was 0.64 (95% CI: 0.46, 0.89) for BMI and 0.49 (95% CI: 0.25, 0.94) for WHR (P-values for difference between the two approaches both = 0.001). The inverse associations of adiposity and psychological distress when genetic variants are used as instrumental variables could be explained by biological pathways linking adiposity and distress. The positive associations of adiposity with distress in multivariable analyses might be explained by residual confounding or reverse causality.
  Journal of Internal Medicine 01/2011; 269(5):525-37. · 5.48 Impact Factor
• Source

  Available from: W Scott Argraves

  Article: S1P, dihydro-S1P and C24:1-ceramide levels in the HDL-containing fraction of serum inversely correlate with occurrence of ischemic heart disease.

  Kelley M Argraves, Amar A Sethi, Patrick J Gazzolo, Brent A Wilkerson, Alan T Remaley, Anne Tybjaerg-Hansen, Børge G Nordestgaard, Sharon D Yeatts, Katherine S Nicholas, Jeremy L Barth, W Scott Argraves
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  ABSTRACT: The lysosphingolipid sphingosine 1-phosphate (S1P) is carried in the blood in association with lipoproteins, predominantly high density lipoproteins (HDL). Emerging evidence suggests that many of the effects of HDL on cardiovascular function may be attributable to its S1P cargo. Here we have evaluated how levels of S1P and related sphingolipids in an HDL-containing fraction of human serum correlate with occurrence of ischemic heart disease (IHD). To accomplish this we used liquid chromatography-mass spectrometry to measure S1P levels in the HDL-containing fraction of serum (depleted of LDL and VLDL) from 204 subjects in the Copenhagen City Heart Study (CCHS). The study group consisted of individuals having high serum HDL cholesterol (HDL-C) (females:≥ 73.5 mg/dL; males:≥ 61.9 mg/dL) and verified IHD; subjects with high HDL-C and no IHD; individuals with low HDL-C (females:≤ 38.7 mg/dL; males:≤ 34.1 mg/dL) and IHD, and subjects with low HDL-C and no IHD. The results show a highly significant inverse relationship between the level of S1P in the HDL-containing fraction of serum and the occurrence of IHD. Furthermore, an inverse relationship with IHD was also observed for two other sphingolipids, dihydro-S1P and C24:1-ceramide, in the HDL-containing fraction of serum. Additionally, we demonstrated that the amount of S1P on HDL correlates with the magnitude of HDL-induced endothelial cell barrier signaling. These findings indicate that compositional differences of sphingolipids in the HDL-containing fraction of human serum are related to the occurrence of IHD, and may contribute to the putative protective role of HDL in IHD.
  Lipids in Health and Disease 01/2011; 10:70. · 2.17 Impact Factor
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  Available from: ludesign.nl

  Article: Report of the 33rd annual conference of the European Lipoprotein Club, Tutzing, 6-9 September 2010.

  Franco Bernini, Rachel Fisher, Dilys Freeman, Albert Groen, Athina Kalopissis, Ernst Malle, Monique Mulder, Andreas Niemeier, Paolo Parini, Anne Tybjaerg Hansen, Arnold von Eckardstein
  Atherosclerosis 12/2010; 215(1):249-55. · 3.79 Impact Factor
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  Available from: clinchem.org

  Article: Plasma YKL-40 and total and disease-specific mortality in the general population.

  Julia S Johansen, Stig E Bojesen, Anne Tybjaerg-Hansen, Anne K Mylin, Paul A Price, Børge G Nordestgaard
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  ABSTRACT: Increased plasma YKL-40 is associated with short-term survival in patients with cardiovascular disease and cancer. We tested the hypothesis that increased plasma YKL-40 is associated with total and disease-specific mortality in the general population. We measured plasma YKL-40 in 8899 study participants, aged 20-95 years, in the Copenhagen City Heart Study from the Danish general population who were followed for 16 years: 3059 died, 2158 had ischemic cardiovascular disease, 2271 had cancer, and 2820 had other diseases associated with increased YKL-40. Hazard ratios for early death and absolute 10-year mortality rates were calculated according to plasma YKL-40 percentile groupings computed within sex and age decade: 0%-33%, 34%-66%, 67%-90%, 91%-95%, and 96%-100%. Median survival age decreased from 83 years for participants with plasma YKL-40 in category 0%-33% to 69 years in category 96%-100% (trend, P < 0.0001). Risk of early death was increased (multifactorially adjusted hazard ratios) by 10% for YKL-40 category 34%-66%, by 30% for 67%-90%, by 70% for 91%-95%, and by 90% for 96%-100% vs YKL-40 category 0%-33% (trend, P < 0.0001). Corresponding increases in participants with ischemic cardiovascular disease were 10%, 20%, 80%, and 60% (P < 0.0001); in those with cancer were 10%, 20%, 50%, and 70% (P < 0.0001); and in those with other diseases were 10%, 20%, 40%, and 60% (P < 0.0001). Highest absolute 10-year mortality rates were 78% and 90% in women and men, respectively, who were >70 years old, smoked, and were in YKL-40 category 96%-100%. Increased plasma YKL-40 is associated with risk of early death from cardiovascular disease, cancer, and other diseases in the general population.
  Clinical Chemistry 10/2010; 56(10):1580-91. · 7.91 Impact Factor
• Article: Does elevated C-reactive protein increase atrial fibrillation risk? A Mendelian randomization of 47,000 individuals from the general population.

  Sarah C W Marott, Børge G Nordestgaard, Jeppe Zacho, Jens Friberg, Gorm B Jensen, Anne Tybjaerg-Hansen, Marianne Benn
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  ABSTRACT: The purpose of this study was to test whether the association of C-reactive protein (CRP) with increased risk of atrial fibrillation is a robust and perhaps even causal association. Elevated levels of CRP previously have been associated with increased risk of atrial fibrillation. We studied 10,276 individuals from the prospective Copenhagen City Heart Study, including 771 individuals who had atrial fibrillation during follow-up, and another 36,600 persons from the cross-sectional Copenhagen General Population Study, including 1,340 cases with atrial fibrillation. Individuals were genotyped for 4 CRP gene polymorphisms and had high-sensitivity CRP levels measured. A CRP level in the upper versus lower quintile associated with a 2.19-fold (95% confidence interval [CI]: 1.54- to 3.10-fold) increased risk of atrial fibrillation. Risk estimates attenuated slightly after multifactorial adjustment to 1.77 (95% CI: 1.22 to 2.55), and after additional adjustment for heart failure and plasma fibrinogen level to 1.47 (95% CI: 1.02 to 2.13) and 1.63 (95% CI: 1.21 to 2.20), respectively. Genotype combinations of the 4 CRP polymorphisms associated with up to a 63% increase in plasma CRP levels (p < 0.001), but not with increased risk of atrial fibrillation. The estimated causal odds ratio for atrial fibrillation by instrumental variable analysis for a doubling in genetically elevated CRP levels was lower than the odds ratio for atrial fibrillation observed for a doubling in plasma CRP on logistic regression (0.94 [95% CI: 0.70 to 1.27] vs. 1.36 [95% CI: 1.30 to 1.44]; p < 0.001). Elevated plasma CRP robustly associated with increased risk of atrial fibrillation; however, genetically elevated CRP levels did not. This suggests that elevated plasma CRP per se does not increase atrial fibrillation risk.
  Journal of the American College of Cardiology 08/2010; 56(10):789-95. · 14.16 Impact Factor
• Article: C-reactive protein and all-cause mortality--the Copenhagen City Heart Study.

  Jeppe Zacho, Anne Tybjaerg-Hansen, Børge G Nordestgaard
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  ABSTRACT: We tested whether elevated levels of C-reactive protein is robustly and causally associated with all-cause mortality. We studied 10 388 white persons from the general population. During 16 years 3124 persons died. We measured baseline high-sensitivity C-reactive protein and fibrinogen levels and genotyped for four C-reactive protein polymorphisms and two apolipoprotein E polymorphisms. Levels of C-reactive protein >3 mg/L vs. <1 mg/L associated with a multi-factorially adjusted two-fold increased risk of all-cause mortality. Stratifying C-reactive protein into tertiles, quintiles, or octiles resulted in step-by-step increased risk of all-cause mortality, even after fibrinogen adjustment. Finally, genetically elevated C-reactive protein levels associated with a causal hazard ratio of 0.94 (95% CI: 0.64-1.39) for all-cause mortality per doubling of C-reactive protein levels on instrumental variable analysis, for which the corresponding hazard ratio on Cox regression for a doubling in measured plasma C-reactive protein levels was 1.25 (1.21-1.29). As a positive control, a doubling in genetically elevated cholesterol levels via apolipoprotein E associated with a hazard ratio of 6.3 (1.8-22) for all-cause mortality. A single C-reactive protein measurement robustly associates with increased risk of all-cause mortality; however, this does not appear to be a causal association. Therefore, elevated C-reactive protein levels more likely are a marker of hidden, potentially fatal inflammatory disease.
  European Heart Journal 07/2010; 31(13):1624-32. · 10.48 Impact Factor
• Article: High pre-beta1 HDL concentrations and low lecithin: cholesterol acyltransferase activities are strong positive risk markers for ischemic heart disease and independent of HDL-cholesterol.

  Amar A Sethi, Maureen Sampson, Russell Warnick, Nehemias Muniz, Boris Vaisman, Børge G Nordestgaard, Anne Tybjaerg-Hansen, Alan T Remaley
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  ABSTRACT: We hypothesized that patients with high HDL-cholesterol (HDL-C) and ischemic heart disease (IHD) may have dysfunctional HDL or unrecognized nonconventional risk factors. Individuals with IHD (Copenhagen University Hospital) and either high HDL-C (n = 53; women >or=735 mg/L; men >or=619 mg/L) or low HDL-C (n = 42; women <or=387 mg/L; men <or=341 mg/L) were compared with individuals without IHD (Copenhagen City Heart Study) matched by age, sex, and HDL-C concentrations (n = 110). All participants had concentrations within reference intervals for LDL-C (<1600 mg/L) and triglyceride (<1500 mg/L), and none were treated with lipid-lowering medications. Pre-beta(1) HDL and phospholipid transfer protein concentrations were measured by using commercial kits and lecithin:cholesterol acyltransferase (LCAT) activity by using a proteoliposome cholesterol esterification assay. Pre-beta(1) HDL concentrations were 2-fold higher in individuals with IHD vs no IHD in both the high [63 (5.7) vs 35 (2.3) mg/L; P < 0.0001] and low HDL-C [49 (5.0) vs 27 (1.5) mg/L; P = 0.001] groups. Low LCAT activity was also associated with IHD in the high [95.2 (6.7) vs 123.0 (5.3) micromol x L(-1) x h(-1); P = 0.002] and low [93.4 (8.3) vs 113.5 (4.9) micromol x L(-1) . h(-1); P = 0.03] HDL-C groups. ROC curves for pre-beta(1) HDL in the high-HDL-C groups yielded an area under the curve of 0.71 (95% CI: 0.61-0.81) for predicting IHD, which increased to 0.92 (0.87-0.97) when LCAT was included. Similar results were obtained for low HDL-C groups. An inverse correlation between LCAT activity and pre-beta(1) HDL was observed (r(2) = 0.30; P < 0.0001) in IHD participants, which was stronger in the low HDL-C group (r(2) = 0.56; P < 0.0001). IHD was associated with high pre-beta(1) HDL concentrations and low LCAT levels, yielding correct classification in more than 90% of the IHD cases for which both were measured, thus making pre-beta(1) HDL concentration and LCAT activity level potentially useful diagnostic markers for cardiovascular disease.
  Clinical Chemistry 07/2010; 56(7):1128-37. · 7.91 Impact Factor
• Article: PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses.

  Marianne Benn, Børge G Nordestgaard, Peer Grande, Peter Schnohr, Anne Tybjaerg-Hansen
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  ABSTRACT: 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. The 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies. 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). 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). 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.
  Journal of the American College of Cardiology 06/2010; 55(25):2833-42. · 14.16 Impact Factor