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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 1 A1 ( 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. [ABSTRACT FROM AUTHOR]

Glutathione-S-transferase T1 (GSTT1) and GSTM1 detoxify carcinogens and thus potentially contribute to inter-individual susceptibility to cancer. We determined the ability of GST copy number variation (CNV) to predict the risk of cancer in the general population. Exact copy numbers of GSTT1 and GSTM1 were measured by real-time PCR in 10 247 individuals, of whom 2090 had cancer. In men, the cumulative incidence of prostate cancer increased and the cumulative 5-year survival decreased with decreasing GSTT1 copy numbers (trends=0.02). The hazard ratios (HRs) (95% CIs) for prostate cancer and for death after prostate cancer diagnosis were, respectively, 1.2 (0.8-1.8) and 1.2 (0.6-2.1) for GSTT1*1/0, and 1.8 (1.1-3.0) and 2.2 (1.1-4.4) for GSTT1*0/0 versus GSTT1*1/1. In women, the cumulative incidence of corpus uteri cancer increased with decreasing GSTT1 copy numbers (trend=0.04). The HRs for corpus uteri cancer were, respectively, 1.8 (1.0-3.2) and 2.2 (1.0-4.6) for GSTT1*1/0 and GSTT1*0/0 versus GSTT1*1/1. Finally, the cumulative incidence of bladder cancer increased, and the cumulative 5-year survival decreased, with decreasing GSTM1 copy numbers (P=0.03-0.05). The HRs for bladder cancer were, respectively, 1.5 (0.7-3.2) and 2.0 (0.9-4.3) for GSTM1*1/0 and GSTM1*0/0 versus GSTM1*1/1. The HR for death after bladder cancer diagnosis was 1.9 (1.0-3.7) for GSTM1*0/0 versus GSTM1*1/0. In conclusion, exact CNV in GSTT1 and GSTM1 predict incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer. [ABSTRACT FROM AUTHOR]

Objectives. To determine whether mutations in APOA1 affect levels of high-density lipoprotein (HDL) cholesterol and to predict risk of ischaemic heart disease (IHD) andtotal mortality in the general population. Background. 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 IHDandearlydeath. Design. 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. Results. 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 lipo protein levels, including HDL cholesterol and apoA-I, and this finding was confirmed in adenovirus- transfectedmice. Conclusions. 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. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate whether an increased hazard of developing ischemic heart disease (IHD) is associated with any of the three genotypes A560T832/A560T832, A560T832/A560G832 and A560T832/T560T832, defined by variations in two non-coding SNPs in the 5′ promoter region of the apolipoprotein E ( APOE) gene. These genotypes were selected because they distinguished between high and low levels of HDL-C, TG and/or T-C in our earlier study of multiple samples defined by gender and population. We found a significant increase (p<0.05) in the hazard of IHD in females with the A560T832/T560T832 genotype that remained significant after fitting the effects of dyslipidemia, other established risk factors, and the structural isoform variations of the ApoE molecule. We discuss why this statistically significant genetic predictor may not be an appropriate screening test for IHD in the Danish population at large. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (APOE) plays a pivotal role in the catabolism of triglyceride-rich lipoproteins by serving as a ligand for lipoprotein receptors. The common three-allele (ε2/ε3/ε4) variation in the APOE gene is the most studied susceptibility polymorphism to date, identified in more than 50 different populations worldwide. Differences in the associations between APOE genotype and lipids, lipoproteins, and risk of ischemic heart disease between and within studies have raised the possibility that this gene is expressed in a context-dependent rather than invariant manner. The objective of this review was to focus on studies that in particular yield information about such context-dependent associations of the APOE polymorphism. The well-documented pattern of increasing cholesterol levels from ε2 to ε3 to ε4 seems invariant across different populations; however, the magnitude of this association appears to be modifiable by gender, exogenous estrogens, diet and perhaps by body size. The less pronounced associations between the APOE polymorphism and high-density lipoprotein (HDL) cholesterol and triglycerides appear to differ by gender, to be enhanced by hyperglycemia and alcohol consumption, and abolished by exogenous estrogens in women, thus suggesting strong context dependency. The APOE polymorphism explains more of the variation in levels of cholesterol and apolipoprotein B (APOB) in women than in men, whereas a larger fraction of the variation in triglycerides is explained by the APOE polymorphism in men than in women. Finally, relative to ε33 individuals, ε32 women may be protected while ε43 and ε44 men may be particularly susceptible to ischemic heart disease. In conclusion, differences in magnitude or presence of APOE gene associations across studies or across subgroups within studies appear to be due to the influence of gender, exogenous estrogens, diet, hyperglycemia, alcohol consumption and perhaps body size. Consequently, these contexts should be considered when APOE polymorphism is studied. [ABSTRACT FROM AUTHOR]

Presents summaries of the Astrup Competition in Scandinavia. Effects of apolipoprotein E Genotype; Treatment of hydrophobic membranes with cationic detergents; Regulation of the human complement system through a cluster of charged amino acids.

Objectives: B‐cell dysfunction and activation are thought to contribute to lymphoma development in HIV‐positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B‐cell dysfunction [free light chain (FLC)‐κ, FLC‐λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV‐positive people. Methods: A nested matched case–control study was carried out within the EuroSIDA cohort, including 73 HIV‐positive people with lymphoma and 143 HIV‐positive lymphoma‐free controls. Markers of B‐cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. Results: Two‐fold higher levels of FLC‐κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC‐λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC‐λ emerging as the strongest candidate with a c‐statistic of 0.67 (95% CI 0.58, 0.76). Conclusions: FLC‐κ, FLC‐λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B‐cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention. [ABSTRACT FROM AUTHOR]

Objective: Alterations of pancreatic β-cell cholesterol content may contribute to β-cell dysfunction. Two important determinants of intracellular cholesterol content are the ATP-binding cassette (ABC) transporters A1 (ABCA1) and -G1 (ABCG1). Whether genetic variation in ABCA1 and ABCG1 predicts risk of type 2 diabetes in the general population is unknown.Research Design and Methods: We tested whether genetic variation in the promoter and coding regions of ABCA1 and ABCG1 predicted risk of type 2 diabetes in the general population. Twenty-seven variants, identified by previous resequencing of both genes, were genotyped in the Copenhagen City Heart Study (CCHS) (n = 10,185). Two loss-of-function mutations (ABCA1 N1800H and ABCG1 g.-376C>T) (n = 322) and a common variant (ABCG1 g.-530A>G) were further genotyped in the Copenhagen General Population Study (CGPS) (n = 30,415).Results: Only one of the variants examined, ABCG1 g.-530A>G, predicted a decreased risk of type 2 diabetes in the CCHS (P for trend = 0.05). Furthermore, when validated in the CGPS or in the CCHS and CGPS combined (n = 40,600), neither the two loss-of-function mutations (ABCA1 N1800H, ABCG1 g.-376C>T) nor ABCG1 g.-530A>G were associated with type 2 diabetes (P values >0.57 and >0.30, respectively).Conclusions: Genetic variations in ABCA1 and ABCG1 were not associated with increased risk of type 2 diabetes in the general population. These data were obtained in general population samples harboring the largest number of heterozygotes for loss-of-function mutations in ABCA1 and ABCG1. [ABSTRACT FROM AUTHOR]