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.

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.

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.

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.

Prospective study of potentially virulent strains of Helicobacter pylori and coronary heart disease in middle-aged men.

BACKGROUND: Studies are needed to test claims that potentially virulent strains of Helicobacter pylori are more strongly related to coronary heart disease (CHD) than are other strains. METHODS AND RESULTS: We measured serum IgG antibodies to mixed H pylori antigens and separately to the virulence-associated H pylori antigen CagA (cytotoxin-associated gene product A) in 505 CHD cases and in 1025 age-matched controls "nested" in a prospective study of 7735 British men (mean duration of follow-up in controls, 16 years). Of the 505 cases, 401 (79%) were seropositive for H pylori antibodies compared with 740 (72%) of the 1025 controls, yielding an odds ratio for CHD of 1.55 (95% CI 1.19 to 2.03), which fell to 1.30 (95% CI 0.88 to 1. 90) after adjustments were made for standard vascular risk factors and indicators of socioeconomic status. Of the CHD cases, 240 (48%) were seropositive for IgG antibodies to CagA compared with 450 (44%) of the controls. When CagA-seropositive individuals were compared with H pylori-seronegative individuals, the odds ratio for CHD was 1. 42 (95% CI 1.06 to 1.91), which fell to 1.10 (95% CI 0.71 to 1.71) after adjustments. In an analysis restricted to the 1141 (75%) H pylori-seropositive participants, the odds ratio for CHD was 1.0 (95% CI 0.78 to 1.29) in CagA-seropositive men. No strong associations were observed between H pylori seropositivity and blood lipids, blood pressure, markers of systemic inflammation, or plasma homocysteine. CONCLUSIONS: H pylori infection is not strongly related to the incidence of CHD in late middle-aged men, and CagA-positive strains appear to be no more strongly related to the disease than other strains. However, further studies are required to confirm or refute the existence of any moderate associations, particularly at younger ages.

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.

Systematic review of the epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated dyspepsia.

BACKGROUND: Previous studies have yielded conflicting results and substantial uncertainty about any independent association of Helicobacter pylori infection with dyspepsia, and about any benefits of antibiotic treatments for nonulcer or uninvestigated dyspepsia. OBJECTIVES: To perform a systematic review of the literature to determine whether chronic infection with H pylori is relevant to nonulcer or uninvestigated dyspepsia. METHODS: Observational studies of associations between H pylori and dyspepsia published before April 1999 and randomized trials of the effects of H pylori eradication on dyspepsia published before January 2000 were identified by computer-assisted literature searches of relevant journals, reference lists, and discussions with authors. Relevant data were abstracted from the published reports by 2 investigators according to a fixed protocol. RESULTS: Thirty relevant observational studies were identified involving approximately 3392 patients with nonulcer dyspepsia, and 11 separate observational studies were identified, involving 6426 patients with uninvestigated dyspepsia. Reports of strong associations in small observational studies without appropriate adjustment for potential confounding factors were not generally confirmed by larger and better-designed studies. No studies have been reported, however, that can reliably confirm or exclude the existence of any weak associations. Twenty-two randomized trials of treatments against H pylori were found involving a total of 2340 patients with nonulcer dyspepsia, almost all with positive H pylori test results. Only a few of these trials involved effective antibacterial regimens with prolonged follow-up, and even these studies were too small to assess the possibility of moderate benefits. CONCLUSION: The available evidence indicates that there is no strong association between H pylori and dyspepsia, but there is insufficient evidence to confirm or refute the existence of a modest association.

Helicobacter pylori infection and gastric cancer: systematic review of the epidemiological studies.

BACKGROUND: The published epidemiological studies of chronic Helicobacter pylori infection and gastric cancer yield conflicting results, so there is uncertainty as to whether any material association exists and, if so, how strong it is. AIM: To review these studies quantitatively. METHODS: A systematic review of sero-epidemiological studies published before 1998 of H. pylori and gastric cancer, as identified by computer-assisted literature searches of relevant journals, reference lists and discussions with authors. All relevant studies identified were included, subdivided by study design. The following was abstracted from published reports: adjusted odds ratio (or, in prospective studies, the risk ratio) and confidence interval, study design, type of controls, mean age, mean duration of follow-up, assay methods, location of study, and degree of adjustment for confounders. RESULTS: The 34 retrospective studies included in total 3300 gastric cancers, but their controls were of uncertain validity. The 10 'nested' case-control comparisons in prospective studies included in total only 800 gastric cancers, and combined analysis of them yielded a risk ratio of 2.5 (95% CI: 1.9-3.4; 2P < 0.00001) for gastric cancer in people seropositive for H. pylori antibodies. CONCLUSIONS: The prospective studies suggest that gastric cancer is 2 or 3 times as common in those chronically infected by H. pylori, but to help investigate causality, further observational studies are still needed, as are large-scale randomized trials of whether antibacterial regimens reduce the eventual incidence of gastric cancer.

Chronic infection with Helicobacter pylori, Chlamydia pneumoniae, or cytomegalovirus: population based study of coronary heart disease.

OBJECTIVE: To study possible associations between coronary heart disease and serological evidence of persistent infection with Helicobacter pylori, Chlamydia pneumoniae, or cytomegalovirus. DESIGN: Population based, case-control study, nested within a randomised trial. SETTING: Five general practices in Bedfordshire, UK. INDIVIDUALS: 288 patients with incident or prevalent coronary heart disease and 704 age and sex matched controls. RESULTS: High concentrations of serum IgG antibodies to H pylori were present in 54% of cases v 46% of controls, with corresponding results for C pneumoniae seropositivity (33% v 33%), and cytomegalovirus seropositivity (40% v 31%). After adjustments for age, sex, smoking, indicators of socioeconomic status, and standard risk factors, the odds ratios (95% confidence intervals) for coronary heart disease of seropositivity to these agents were: 1.28 (0.93 to 1.75) for H pylori, 0.95 (0.66 to 1.36) for C pneumoniae, and 1.40 (0.96 to 2. 05) for cytomegalovirus. CONCLUSIONS: There is no good evidence of strong associations between coronary heart disease and serological markers of persistent infection with H pylori, C pneumoniae, or cytomegalovirus. To determine the existence of moderate associations between these agents and disease, however, larger scale studies will be needed that can keep residual confounders to a minimum.

Helicobacter pylori infection and early onset myocardial infarction: case-control and sibling pairs study.

OBJECTIVES: To examine the association between coronary heart disease and chronic Helicobacter pylori infection. DESIGN: Case-control study of myocardial infarction at young ages and study of sibling pairs with one member affected and the other not. SETTING: United Kingdom. PARTICIPANTS: 1122 survivors of suspected acute myocardial infarction at ages 30-49 (mean age 44 years) and 1122 age and sex matched controls with no history of coronary heart disease; 510 age and sex matched pairs of siblings (mean age 59 years) in which one sibling had survived myocardial infarction and one had no history of coronary heart disease. MAIN OUTCOME MEASURES: Serological evidence of chronic infection with H pylori. RESULTS: 472 (42%) of the 1122 cases with early onset myocardial infarction were seropositive for H pylori antibodies compared with 272 (24%) of the 1122 age and sex matched controls, giving an odds ratio of 2.28 (99% confidence interval 1.80 to 2.90). This odds ratio fell to 1.87 (1.42 to 2.47; P<0.0001) after smoking and indicators of socioeconomic status were adjusted for and to 1.75 (1.29 to 2.36) after additional adjustment for blood lipid concentrations and obesity. Only 158 of the 510 pairs of siblings were discordant for H pylori status; among these, 91 cases and 67 controls were seropositive (odds ratio 1.33 (0.86 to 2.05)). No strong correlations were observed between H pylori seropositivity and measurements of other risk factors for coronary heart disease (plasma lipids, fibrinogen, C reactive protein, albumin, etc). CONCLUSION: In the context of results from other relevant studies, these two studies suggest a moderate association between coronary heart disease and H pylori seropositivity that cannot be fully accounted for by other risk factors. But even if this association is causal and largely reversible by eradication of chronic infection, very large randomised trials would be needed to show this.

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.

Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis.

OBJECTIVE: To examine the association between coronary heart disease and serum markers of chronic Chlamydia pneumoniae infection. DESIGN: "Nested" case-control analysis in a prospective cohort study and an updated meta-analysis of previous relevant studies. SETTING: General practices in 18 towns in Britain. PARTICIPANTS: Of the 5661 men aged 40-59 who provided blood samples during 1978-80, 496 men who died from coronary heart disease or had non-fatal myocardial infarction and 989 men who had not developed coronary heart disease by 1996 were included. MAIN OUTCOME MEASURES: IgG serum antibodies to C pneumoniae in baseline samples; details of fatal and non-fatal coronary heart disease from medical records and death certificates. RESULTS: 200 (40%) of the 496 men with coronary heart disease were in the top third of C pneumoniae titres compared with 329 (33%) of the 989 controls. The corresponding odds ratio for coronary heart disease was 1.66 (95% confidence interval 1.25 to 2.21), which fell to 1.22 (0.82 to 1.82) after adjustment for smoking and indicators of socioeconomic status. No strong associations were observed between C pneumoniae IgG titres and blood lipid concentrations, blood pressure, or plasma homocysteine concentration. In aggregate, the present study and 14 other prospective studies of C pneumoniae IgG titres included 3169 cases, yielding a combined odds ratio of 1. 15 (0.97 to 1.36), with no significant heterogeneity among the separate studies (chi(2)=10.5, df=14; P>0.1). CONCLUSION: This study, together with a meta-analysis of previous prospective studies, reliably excludes the existence of any strong association between C pneumoniae IgG titres and incident coronary heart disease. Further studies are required, however, to confirm or refute any modest association that may exist, particularly at younger ages.

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.