Milk intake and incident stroke and CHD in populations of European descent: a Mendelian randomisation study.

Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (ß = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.

Measurement and initial characterization of leukocyte telomere length in 474,074 participants in UK Biobank.

Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in 'biological age' than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL.

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Dietary fibre intake and ischaemic heart disease mortality: the European Prospective Investigation into Cancer and Nutrition-Heart study.

BACKGROUND/OBJECTIVES: Evidence from prospective studies is consistent in showing an inverse association between dietary fibre intake and risk of ischaemic heart disease (IHD), but whether dietary fibre from various food sources differ in their effect on IHD risk is less clear. The objective of this study was to assess the associations of total and food sources of dietary fibre with IHD mortality in the European Prospective Investigation into Cancer and Nutrition-Heart study. SUBJECTS/METHODS: Participants were 306,331 men and women from eight European countries. Dietary fibre intake was assessed using centre or country-specific diet questionnaires and calibrated using a 24-h diet recall. RESULTS: After an average follow-up of 11.5 years, there were 2381 IHD deaths among participants without cardiovascular disease at baseline. The calibrated intake of dietary fibre was inversely related with IHD mortality; each 10 g/day was associated with a 15% lower risk (relative risk (RR) 0.85; 95% confidence interval (CI): 0.73-0.99, P=0.031). There was no difference in the associations of the individual food sources of dietary fibre with the risk of IHD mortality; RR for each 5 g/day higher cereal fibre intake was 0.91 (CI: 0.82-1.01), RR for each 2.5 g/day fruit fibre intake was 0.94 (CI: 0.88-1.01) and RR for each 2.5 g/day vegetable fibre intake was 0.90 (95% CI: 0.76-1.07). CONCLUSION: A higher consumption of dietary fibre is associated with a lower risk of fatal IHD with no clear difference in the association with IHD for fibre from cereals, fruits or vegetables.

Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.

BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.

C-reactive protein and coronary heart disease: a critical review.

Modestly elevated baseline concentrations of C-reactive protein (CRP), the classical acute phase protein, are associated with the long-term risk of coronary heart disease in general populations, whilst the major acute phase response of CRP following myocardial infarction is associated with death and cardiac complications. The pathogenic and clinical significance of these associations is controversial. Here we critically review the evidence and describe large-scale epidemiological studies, novel experiments and possible specific therapies which will rigorously inform the debate. We distinguish between the potential pathogenicity of high acute phase circulating CRP concentrations in individuals with substantial tissue damage and modest but persistent increases in baseline values in generally healthy subjects.

The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases.

Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.

Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration.

Long-term increases in plasma fibrinogen levels of 1 g/liter are associated with an approximate doubling of risk of major cardiovascular disease outcomes, but causality remains uncertain. To quantify cross-sectional associations of fibrinogen levels with established risk factors and other characteristics, the investigators combined individual data on 154,211 apparently healthy adults from 31 prospective studies conducted between 1967 and 2003, using a linear mixed model that included random effects at the cohort level. Fibrinogen levels increased with age and showed continuous, approximately linear relations with several risk markers and slightly curvilinear associations with log triglycerides, albumin, and tobacco and alcohol consumption. Female sex, Black ethnicity, lower socioeconomic status, and alcohol abstinence were each associated with modestly higher fibrinogen levels. Approximately one third of the variation in fibrinogen levels was explained by cohort, age, and sex. An additional 7% was explained by established risk factors (notably, positive associations with smoking and body mass index and an inverse association with high density lipoprotein cholesterol), and a further 10% was explained by inflammatory markers (notably, a positive association with C-reactive protein). The association with body mass index was twice as strong in women as in men, whereas the association with smoking was much stronger in men. These findings substantially advance understanding of the correlates and possible determinants of fibrinogen levels.

Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases.

BACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors. OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic 'meta-analysis', with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes. METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.

Associations between apolipoprotein B, apolipoprotein AI, the apolipoprotein B/AI ratio and coronary heart disease: a literature-based meta-analysis of prospective studies.

OBJECTIVES: To assess associations of circulating levels of apolipoprotein (apo) AI, apoB and the apoB/AI ratio (apoB/A) with risk of incident coronary heart disease (CHD). DESIGN: Literature-based meta-analysis of prospective studies. DATA SOURCES: Prospective studies in essentially general populations that reported on associations between apoAI, apoB or apoB/A and first incident CHD outcomes. Studies were identified by computer-based searches and by manual searches of the relevant literature. RESULTS: Data from 23 relevant studies were identified. For apoAI, with 6333 CHD cases in 21 studies, comparison of individuals in the bottom third with those in the top third of baseline values yielded a combined relative risk of 1.62 (95% confidence interval: 1.43-1.83), i.e. an inverse association. For apoB, a combined analysis of 6320 CHD cases from 19 studies gave a relative risk of 1.99 (1.65-2.39) for a comparison of individuals in the top third versus those in the bottom third of baseline values. For apoB/A, with 3730 CHD cases from seven studies, a comparison of individuals in the top third versus the bottom third of baseline values gave a combined relative risk of 1.86 (1.55-2.22). These associations were somewhat stronger following correction for within-person variations in apolipoprotein levels. There was evidence of heterogeneity amongst the published studies, but it was only partly explained by available study-level characteristics. CONCLUSIONS: The present quantitative review suggests the existence of moderately strong associations between baseline levels of each of apoAI, apoB, and apoB/A and risk of CHD. More detailed analysis, perhaps based on individual participant data from prospective studies, could help to overcome several limitations in the present review and to clarify any relevance of these apolipoproteins to disease prediction and aetiology.

Tissue plasminogen activator antigen and coronary heart disease. Prospective study and meta-analysis.

AIMS: To determine whether circulating tissue plasminogen activator (t-PA) antigen concentrations are prospectively related to risk of coronary heart disease (CHD) in the general population. METHODS AND RESULTS: We measured baseline concentrations of t-PA antigen in the stored serum samples of 606 CHD cases and 1227 controls 'nested' in a prospective cohort of 5661 men monitored for 16 years, and conducted a meta-analysis of previous relevant studies to place our findings in context. Tissue plasminogen activator antigen values were strongly correlated with several vascular risk factors, including serum lipids, body mass index, alcohol consumption, and markers of systemic inflammation. In a comparison of men in the top third compared with those in the bottom third of baseline t-PA antigen values, the odds ratio for CHD was 2.20 (95% confidence interval (CI) 1.70-2.85) after adjustment for age and town only, but this fell to 1.48 (1.09-2.01) after further adjustment. Analysis of t-PA as a continuous variable gave similar results. Similarly, when published information on all seven available prospective cohort studies in general populations (2119 cases and 8832 controls in total) was synthesized, the combined odds ratio was 2.18 (1.77-2.69) after adjustment for age and sex only, and this fell to 1.47 (1.19-1.81) after further adjustment. CONCLUSION: Although there is a statistically significant association between circulating concentrations of t-PA antigen and subsequent CHD, additional studies are needed to determine to what extent this is independent from more established risk factors.

von Willebrand factor and coronary heart disease: prospective study and meta-analysis.

AIMS: To determine whether circulating von Willebrand factor concentrations are prospectively related to risk of coronary heart disease in the general population. METHODS AND RESULTS: We measured baseline von Willebrand factor values in the stored serum samples of 625 men with major coronary events and in 1266 controls 'nested' in a prospective study of 5661 men aged 40-59 years, recruited from general practices in 18 British towns in 1978-1980 and followed up for 16 years for fatal coronary heart disease and non-fatal myocardial infarction. We conducted a meta-analysis of previous relevant studies to place our results in context. Men in the top third of baseline von Willebrand factor values (tertile cutoff >126 IU.dl(-1)) had an odds ratio for coronary heart disease of 1.83 (95% confidence interval 1.43-2.35; 2P <0.0001) compared with those in the bottom third (tertile cutoff <90 IU.dl(-1)), after adjustments for age and town. The odds ratio was little changed after further adjustment for risk factors (1.82, 95% CI 1.37-2.41), and was not significantly different in an analysis restricted to the 404 cases and 1007 controls without baseline evidence of coronary heart disease (odds ratio 1.53, 95% CI 1.10-2.12). A meta-analysis of all relevant population-based prospective studies (including the present study) yielded a combined odds ratio of 1.5 (95% CI 1.1-2.0). von Willebrand factor values were strongly correlated with Helicobacter pylori seropositivity and circulating concentrations of C-reactive protein (2 P<0.0001 for each), but not with smoking, blood lipids, or most other measured risk factors. CONCLUSION: Though circulating von Willebrand factor concentrations may be associated with incident coronary heart disease, further studies are needed to determine the extent to which this is causal.

Chlamydia pneumoniae IgA titres and coronary heart disease; prospective study and meta-analysis.

AIMS: To examine associations between Chlamydia pneumoniae IgA titres and incident coronary heart disease, and to compare them with associations previously reported between C. pneumoniae IgG titres and coronary heart disease. METHODS AND RESULTS: We measured serum concentrations of C. pneumoniae IgA antibodies in 502 coronary heart disease cases and in 1005 age- and town-matched controls 'nested' in a community-based prospective study of 5661 British men (mean follow-up in controls, 16 years), and conducted a meta-analysis of published prospective studies to place our findings in context. Two hundred and twenty-one (44%) of the cases were in the top third of C. pneumoniae IgA titres compared with 336 (33%) of the controls, yielding an odds ratio for coronary heart disease of 1.84 (95% confidence interval 1.40-2.43) which was largely unchanged after adjustment. In aggregate, the present study and nine previously reported prospective studies of C. pneumoniae IgA titres involved 2283 cases, yielding a combined odds ratio for coronary heart disease of 1.25 (1.03-1.53), with no significant heterogeneity among the ten studies (chi(2)9=7.8; P>0.1). This combined odds ratio is compatible with that previously reported for C. pneumoniae IgG titres and coronary heart disease (1.15, 0.97-1.36). CONCLUSION: Neither C. pneumoniae IgA titres nor IgG titres are strongly predictive of coronary heart disease in the general population.

Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis.

BACKGROUND: Previous studies have suggested that circulating concentrations of soluble adhesion molecules are useful predictors of risk of coronary heart disease (CHD). Larger studies are needed, however, to test this hypothesis. METHODS: We measured serum concentrations of four soluble cell adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], E-selectin, and P-selectin) in the stored baseline serum samples of 643 men with coronary heart disease and 1278 controls nested in a prospective sutdy of 5661 men who were monitored for 16 years. We also did a meta-analysis of previous relevant studies to place our findings in context. RESULTS: Concentrations of soluble adhesion molecules were significantly associated with one another, with other markers of inflammation, and with some classic coronary risk factors. For ICAM-1, the odds ratio for CHD was 1.68 (95% CI 1.32-2.14) in a comparison of men in the top third with those in the bottom third of baseline measurements after adjustments for age and town. This decreased to 1.11 (0.75-1.64) after adjustment for some classic coronary risk factors and indicators of socioeconomic status. For the three other cell adhesion molecules, the odds ratios for CHD, first adjusted for age and town only, and then additionally adjusted for other risk factors, were: VCAM-1: 1.26 (0.99-1.61) and 0.96 (0.66-1.40); E-selectin: 1.27 (1.00-1.61) and 1.13 (0.78-1.62); and P-selectin: 1.23 (0.96-1.56) and 1.20 (0.81-1.76). INTERPRETATION: The measurement of these adhesion molecules is unlikely to add much predictive information to that provided by more established risk factors.

A prospective study of Helicobacter pylori seropositivity and the risk for future myocardial infarction among socioeconomically similar U.S. men.

BACKGROUND: The role of Helicobacter pylori as a determinant of cardiovascular disease is controversial. OBJECTIVE: To determine whether previous exposure to H. pylori is associated with an increased risk for myocardial infarction. DESIGN: Prospective case-control study. SETTING: Physicians' Health Study. PARTICIPANTS: Initially healthy U.S. men. MEASUREMENTS: Titers of IgG antibody against H. pylori and several inflammatory markers were measured in baseline blood samples obtained from 445 men who subsequently had a myocardial infarction (case-patients) and 445 men matched for age and smoking status who remained free of vascular disease (controls) during a mean follow-up of 8.9 years. RESULTS: Baseline seropositivity was similar among case-patients and controls (43.4% vs. 44.3%; rate ratio, 0.96 [95% CI, 0.7 to 1.3]). Minimal evidence of association was found between magnitude of seropositivity and subsequent risk and between seropositivity and levels of the inflammatory biomarkers. CONCLUSION: In a socioeconomically homogeneous population, we found limited evidence of association between H. pylori exposure and risk for future myocardial infarction.

Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis.

BACKGROUND: It is unknown whether modest increases of fibrin D-dimer, a circulating marker of fibrin turnover, are relevant to coronary heart disease (CHD) in the general population. METHODS AND RESULTS: We measured serum concentrations of D-dimer antigen in the stored baseline blood samples of 630 CHD cases and 1269 controls "nested" in a prospective cohort of 5661 men who were monitored for 16 years, and we conducted a meta-analysis of previous relevant studies to place our findings in context. In a comparison of men in the top third compared with those in the bottom third of baseline fibrin D-dimer values (tertile cutoffs, >94 versus <49 ng/mL), the odds ratio for CHD was 1.67 (95% CI, 1.31 to 2.13; P<0.0001) after adjustments for age and town. The odds ratio increased slightly after further adjustment for smoking, other classic risk factors, and indicators of socioeconomic status (1.79; 95% CI, 1.36 to 2.36). Strong correlations were observed of fibrin D-dimer values with circulating concentrations of C-reactive protein and serum amyloid A protein but not with smoking, blood lipids, blood pressure, and other risk factors. CONCLUSION: Although there may be an association between circulating D-dimer values and CHD, further studies are needed to determine the extent to which this is causal.

Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies.

BACKGROUND: -Studies of the association between the plasma concentration of lipoprotein(a) [Lp(a)] and coronary heart disease (CHD) have reported apparently conflicting findings. We report a meta-analysis of the prospective studies with at least 1 year of follow-up published before 2000. METHODS AND RESULTS: The following information was abstracted for each study: geographical location of study, size, type of cohort (population-based or selected because of previous disease), mean age, follow-up duration, blood storage temperature and duration, assay methods, degree of adjustment for potential confounders, and relationship of baseline Lp(a) measurement with subsequent CHD risk. There were 5436 deaths from CHD or nonfatal myocardial infarctions during a weighted mean follow-up of 10 years in the 27 eligible studies. Comparison of individuals in the top third of baseline plasma Lp(a) measurements with those in the bottom third in each study yielded a combined risk ratio of 1.6 (95% CI 1.4 to 1.8, 2P:<0.00001), with similar findings when the analyses were restricted to the 18 studies of general populations (combined risk ratio 1.7, 95% CI 1.4 to 1.9; 2P:<0. 00001). Despite differences among studies in blood storage techniques and assay methods, there was no significant heterogeneity among the results from the 18 population-based studies or among those from the 9 studies of patients with previous disease. Lp(a) was only weakly correlated with classical vascular risk factors, and adjustment for those that had been recorded made little difference to the reported risk ratios. CONCLUSIONS: These prospective studies demonstrate a clear association between Lp(a) and CHD, but further studies are needed to determine the extent to which this is causal.

Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses.

OBJECTIVE: To assess associations between baseline values of four different circulating markers of inflammation and future risk of coronary heart disease, potential triggers of systemic inflammation (such as persistent infection), and other markers of inflammation. DESIGN: Nested case-control comparisons in a prospective, population based cohort. SETTING: General practices in 18 towns in Britain. PARTICIPANTS: 506 men who died from coronary heart disease or had a non-fatal myocardial infarction and 1025 men who remained free of such disease until 1996 selected from 5661 men aged 40-59 years who provided blood samples in 1978-1980. MAIN OUTCOME MEASURES: Plasma concentrations of C reactive protein, serum amyloid A protein, and serum albumin and leucocyte count. Information on fatal and non-fatal coronary heart disease was obtained from medical records and death certificates. RESULTS: Compared with men in the bottom third of baseline measurements of C reactive protein, men in the top third had an odds ratio for coronary heart disease of 2.13 (95% confidence interval 1.38 to 3.28) after age, town, smoking, vascular risk factors, and indicators of socioeconomic status were adjusted for. Similar adjusted odds ratios were 1.65 (1.07 to 2.55) for serum amyloid A protein; 1.12 (0.71 to 1.77) for leucocyte count; and 0.67 (0.43 to 1.04) for albumin. No strong associations were observed of these factors with Helicobacter pylori seropositivity, Chlamydia pneumoniae IgG titres, or plasma total homocysteine concentrations. Baseline values of the acute phase reactants were significantly associated with one another (P<0.0001), although the association between low serum albumin concentration and leucocyte count was weaker (P=0.08). CONCLUSION: In the context of results from other relevant studies these findings suggest that some inflammatory processes, unrelated to the chronic infections studied here, are likely to be involved in coronary heart disease.