Background

Germline mutations of BRCA1/2 are associated with hereditary breast and ovarian cancer. Recent data suggests excess mortality in mutation carriers beyond that conferred by neoplasia, and recent in vivo and in vitro studies suggest a modulatory role for BRCA proteins in endothelial and cardiomyocyte function. We therefore tested the association of BRCA2 variants with clinical cardiovascular disease (CVD).

Methods

Using data from 1,170 individuals included in two multi-ethnic population-based studies (SHARE and SHARE-AP), the association between BRCA2 variants and CVD was evaluated. 15 SNPs in BRCA2 with minor allele frequencies (MAF) > 0.01 had been previously genotyped using the cardiovascular gene-centric 50 k SNP array. 115 individuals (9.8%) reported a CVD event, defined as myocardial infarction (MI), angina, silent MI, stroke, and angioplasty or coronary artery bypass surgery. Analyses were adjusted for age and sex. The SNPs rs11571836 and rs1799943 were subsequently genotyped using the MassARRAY platform in 1,045 cases of incident MI and 1,135 controls from the South Asian subset of an international case-control study of acute MI (INTERHEART), and rs11571836 was imputed in 4,686 cases and 4500 controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS).

Results

Two BRCA2 SNPs, rs11571836 and rs1799943, both located in untranslated regions, were associated with lower risk of CVD (OR 0.47 p = 0.01 and OR 0.56 p = 0.03 respectively) in the SHARE studies. Analysis by specific ethnicities demonstrated an association with CVD for both SNPs in Aboriginal People, and for rs11571836 only in South Asians. No association was observed in the European and Chinese subgroups. A non-significant trend towards an association between rs11571836 and lower risk of MI was observed in South Asians from INTERHEART [OR = 0.87 (95% CI: 0.75-1.01) p = 0.068], but was not evident in PROMIS [OR = 0.96 (95% CI: 0.90-1.03) p = 0.230]. Meta-analysis of both case-control studies resulted in a combined OR of 0.94 (95% CI: 0.89-1.004, p = 0.06).

Conclusions

Although there was an association between two SNPs in BRCA2 and CVD in a multi-ethnic population, these results were not replicated in two South Asian case-control studies of incident MI. Future studies exploring the association between BRCA variants and cardiovascular disorders are needed to clarify the role, if any, for BRCA variants in CVD pathogenesis.

Aims

A higher intake of fruits and vegetables has been associated with a lower risk of ischaemic heart disease (IHD), but there is some uncertainty about the interpretation of this association. The objective was to assess the relation between fruit and vegetable intake and risk of mortality from IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study.

Methods and results

After an average of 8.4 years of follow-up, there were 1636 deaths from IHD among 313 074 men and women without previous myocardial infarction or stroke from eight European countries. Participants consuming at least eight portions (80 g each) of fruits and vegetables a day had a 22% lower risk of fatal IHD [relative risk (RR) = 0.78, 95% confidence interval (CI): 0.65–0.95] compared with those consuming fewer than three portions a day. After calibration of fruit and vegetable intake to account for differences in dietary assessment between the participating centres, a one portion (80 g) increment in fruit and vegetable intake was associated with a 4% lower risk of fatal IHD (RR = 0.96, 95% CI: 0.92–1.00, P for trend = 0.033).

Conclusion

Results from this large observational study suggest that a higher intake of fruits and vegetables is associated with a reduced risk of IHD mortality. Whether this association is causal and, if so, the biological mechanism(s) by which fruits and vegetables operate to lower IHD risks remains unclear.

Robert Clarke and colleagues conduct a meta-analysis of unpublished datasets to examine the causal relationship between elevation of homocysteine levels in the blood and the risk of coronary heart disease. Their data suggest that an increase in homocysteine levels is not likely to result in an increase in risk of coronary heart disease.

Background

Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality.

Methods and Findings

Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09–1.28) in the 72 smaller ones (total 15,498 cases).

Conclusions

The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Coronary heart disease (CHD) is the leading cause of death among adults in developed countries. With age, fatty deposits (atherosclerotic plaques) coat the walls of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. The resultant restriction of the heart's blood supply causes shortness of breath, angina (chest pains that are usually relieved by rest), and sometimes fatal heart attacks. Many established risk factors for CHD, including smoking, physical inactivity, being overweight, and eating a fat-rich diet, can be modified by lifestyle changes. Another possible modifiable risk factor for CHD is a high blood level of the amino acid homocysteine. Methylene tetrahydofolate reductase, which is encoded by the MTHFR gene, uses folate to break down and remove homocysteine so fortification of cereals with folate can reduce population homocysteine blood levels. Pooled results from prospective observational studies that have looked for an association between homocysteine levels and later development of CHD suggest that the reduction in homocysteine levels that can be achieved by folate supplementation is associated with an 11% lower CHD risk.

Why Was This Study Done?

Prospective observational studies cannot prove that high homocysteine levels cause CHD because of confounding, the potential presence of other unknown shared characteristics that really cause CHD. However, an approach called “Mendelian randomization” can test whether high blood homocysteine causes CHD. A common genetic variant of the MTHFR gene—the C677T polymorphism—reduces MTHFR efficiency so TT homozygotes (individuals in whom both copies of the MTHFR gene have the nucleotide thymine at position 677; the human genome contains two copies of most genes) have 25% higher blood homocysteine levels than CC homozygotes. In meta-analyses (statistical pooling of the results of several studies) of published Mendelian randomized studies, TT homozygotes have a higher CHD risk than CC homozygotes. Because gene variants are inherited randomly, they are not subject to confounding, so this result suggests that high blood homocysteine causes CHD. But what if only Mendelian randomization studies that found an association have been published? Such publication bias would affect this aggregate result. Here, the researchers investigate the association of the MTHFR C677T polymorphism with CHD in unpublished datasets that have analyzed this polymorphism incidentally during other genetic studies.

What Did the Researchers Do and Find?

The researchers obtained 19 unpublished datasets that contained data on the MTHFR C677T polymorphism in thousands of people with and without CHD. Meta-analysis of these datasets indicates that the excess CHD risk in TT homozygotes compared to CC homozygotes was 2% (much lower than predicted from the prospective observational studies), a nonsignificant difference (that is, it could have occurred by chance). When the probable folate status of the study populations (based on when national folic acid fortification legislation came into effect) was taken into account, there was still no evidence that TT homozygotes had an excess CHD risk. By contrast, in an updated meta-analysis of 86 published studies of the association of the polymorphism with CHD, the excess CHD risk in TT homozygotes compared to CC homozygotes was 15%. Finally, in a meta-analysis of randomized trials on the use of vitamin B supplements for homocysteine reduction, folate supplementation had no significant effect on the 5-year incidence of CHD.

What Do These Findings Mean?

These analyses of unpublished datasets are consistent with lifelong moderate elevation of homocysteine levels having no significant effect on CHD risk. In other words, these findings indicate that circulating homocysteine levels within the normal range are not causally related to CHD risk. The meta-analysis of the randomized trials of folate supplementation also supports this conclusion. So why is there a discrepancy between these findings and those of meta-analyses of published Mendelian randomization studies? The discrepancy is too large to be dismissed as a chance finding, suggest the researchers, but could be the result of publication bias—some studies might have been prioritized for publication because of the positive nature of their results whereas the unpublished datasets used in this study would not have been affected by any failure to publish null results. Overall, these findings reveal a serious example of publication bias and argue against the use of folate supplements as a means of reducing CHD risk.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001177.

The American Heart Association provides information about CHD and tips on keeping the heart healthy; it also provides information on homocysteine, folic acid, and CHD, general information on supplements and heart health, and personal stories about CHD

The UK National Health Service Choices website provides information about CHD, including personal stories about CHD

Information is available from the British Heart Foundation on heart disease and keeping the heart healthy

The US National Heart Lung and Blood Institute also provides information on CHD (in English and Spanish)

MedlinePlus provides links to many other sources of information on CHD (in English and Spanish)

Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Context

Walking speed is a fundamental parameter of human motion and is increasingly considered as an important indicator of individuals' health status.

Objective

To evaluate the relationship of gait parameters, and demographic and physical characteristics in healthy men and women.

Design, Setting, and Participants

Recruitment of a subsample (n = 358) of male and female blood donors taking part in the Cambridge CardioResource study. Collection of demographic data, measurement of physical characteristics (height, weight and blood pressure) and assessment of 7-day, free-living activity parameters using accelerometry and a novel algorithm to measure walking speed. Participants were a median (interquartile range[IQR]) age of 49 (16) years; 45% women; and had a median (IQR) BMI of 26 (5.4).

Main Outcome Measure

Walking speed.

Results

In this study, the hypothesis that walking speed declines with age was generated using an initial ‘open’ dataset. This was subsequently validated in a separate ‘closed’ dataset that showed a decrease of walking speed of −0.0037 m/s per year. This is equivalent to a difference of 1.2 minutes, when walking a distance of 1 km aged 20 compared to 60 years. Associations between walking speed and other participant characteristics (i.e. gender, BMI and blood pressure) were non-significant. BMI was negatively correlated with the number of walking and running steps and longest non-stop distance.

Conclusion

This is the first study using accelerometry which shows an association between walking speed and age in free-living, healthy individuals. Absolute values of gait speed are comparable to published normal ranges in clinical settings. This study highlights the potential use of mobile accelerometry to assess gait parameters which may be indicative of future health outcomes in healthy individuals.

Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.

Objective To quantify associations of chronic kidney disease stages with major cardiovascular disease and non-vascular mortality in the general adult population.

Design Prospective population based cohort study.

Setting Reykjavik, Iceland.

Participants 16 958 people aged 33-81 years without manifest vascular disease and with available information on stage of chronic kidney disease (defined by both estimated glomerular filtration rate and urinary protein) at study entry.

Main outcome measures Hazard ratios for time to major coronary heart disease outcomes and mortality.

Results 1210 (7%) of participants had chronic kidney disease at entry. During a median follow-up of 24 years, 4010 coronary heart disease outcomes, 559 deaths from stroke, and 3875 deaths from non-vascular causes were recorded. Compared with the reference group (estimated glomerular filtration rate 75-89 ml/min/1.73 m2 and no proteinuria), people with lower renal function within the normal range of glomerular filtration rate did not have significantly higher risk of coronary heart disease. By contrast, in 1210 (7%) participants with chronic kidney disease at entry, hazard ratios for coronary heart disease, adjusted for several conventional cardiovascular risk factors, were 1.55 (95% confidence interval 1.02 to 2.35) for stage 1, 1.72 (1.30 to 2.24) for stage 2, 1.39 (1.22 to 1.58) for stage 3a, 1.90 (1.22 to 2.96) for stage 3b, and 4.29 (1.78 to 10.32) for stage 4. Information on chronic kidney disease increased discrimination and reclassification indices for coronary heart disease when added to conventional risk factors (P<0.01). The incremental gain provided by chronic kidney disease was lower than that provided by diabetes or smoking (C index increases of 0.0015, 0.0024, and 0.0124 respectively). Hazard ratios with chronic kidney disease were 0.97 (0.82 to 1.15) for cancer mortality and 1.26 (1.07 to 1.50) for other non-vascular mortality.

Conclusions In people without manifest vascular disease, even the earliest stages of chronic kidney disease are associated with excess risk of subsequent coronary heart disease. Assessment of chronic kidney disease in addition to conventional risk factors modestly improves prediction of risk for coronary heart disease in this population. Further studies are needed to investigate associations between chronic kidney disease and non-vascular mortality from causes other than cancer.

Background

Associations between circulating markers of dysglycaemia and coronary heart disease (CHD) risk in people without diabetes have not been reliably characterised. We report new data from a prospective study and a systematic review to help quantify these associations.

Methods and Findings

Fasting and post-load glucose levels were measured in 18,569 participants in the population-based Reykjavik study, yielding 4,664 incident CHD outcomes during 23.5 y of mean follow-up. In people with no known history of diabetes at the baseline survey, the hazard ratio (HR) for CHD, adjusted for several conventional risk factors, was 2.37 (95% CI 1.79–3.14) in individuals with fasting glucose ≥7.0 mmol/l compared to those <7 mmol/l. At fasting glucose values below 7 mmol/l, adjusted HRs were 0.95 (0.89–1.01) per 1 mmol/l higher fasting glucose and 1.03 (1.01–1.05) per 1 mmol/l higher post-load glucose. HRs for CHD risk were generally modest and nonsignificant across tenths of glucose values below 7 mmol/l. We did a meta-analysis of 26 additional relevant prospective studies identified in a systematic review of Western cohort studies that recorded fasting glucose, post-load glucose, or glycated haemoglobin (HbA1c) levels. In this combined analysis, in which participants with a self-reported history of diabetes and/or fasting blood glucose ≥7 mmol/l at baseline were excluded, relative risks for CHD, adjusted for several conventional risk factors, were: 1.06 (1.00–1.12) per 1 mmol/l higher fasting glucose (23 cohorts, 10,808 cases, 255,171 participants); 1.05 (1.03–1.07) per 1 mmol/l higher post-load glucose (15 cohorts, 12,652 cases, 102,382 participants); and 1.20 (1.10–1.31) per 1% higher HbA1c (9 cohorts, 1639 cases, 49,099 participants).

Conclusions

In the Reykjavik Study and a meta-analysis of other Western prospective studies, fasting and post-load glucose levels were modestly associated with CHD risk in people without diabetes. The meta-analysis suggested a somewhat stronger association between HbA1c levels and CHD risk.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Among people diagnosed with type 2 diabetes mellitus (the commonest type of diabetes worldwide), poor management or lack of appropriate treatment can lead to long-term complications resulting from persistently high sugar levels in the blood. The long-term complications of type 2 diabetes are generally divided into two main groups: microvascular problems (such as nerve damage, kidney disease, and eye disorders), and macrovascular disease (such as heart disease, strokes, and peripheral vascular disease). A major goal of diabetes treatment is to keep glucose control as normal as possible through diet, weight control, exercise, and pharmacological treatments. However, it is unclear whether the link between high blood sugar and macrovascular disease (principally heart disease and strokes) also holds for people who have slightly higher than normal blood sugar levels, but in whom this level does not reach the diabetic threshold. Some previous research studies have suggested that a continuous relationship exists between blood sugar level and the risk of heart disease across the spectrum, i.e., below the diabetic threshold as well as above it. If such a relationship were confirmed this might have important implications for the management of high blood sugar levels even among people who would not normally meet the usual definition for a diagnosis of diabetes (the “diabetic threshold”).

Why Was This Study Done?

Studies which examine the risk of serious, but relatively common, outcomes (such as a nonfatal heart attack or fatal heart disease), often suffer from insufficient statistical power: a large number of participants need to be recruited, and followed up over a long time, to find out whether certain factors measured at baseline (e.g., fasting glucose) are indeed associated with a particular outcome (e.g., heart attack) or not during follow up. Given the inconclusive nature of some previous studies in this area, the researchers who carried out this work wanted to gather evidence from a large prospective cohort, and a reappraisal of all existing evidence, in relation to the possible link between high blood sugar and risk of heart disease in people without diabetes.

What Did the Researchers Do and Find?

In this study, the researchers report results from a prospective population-based study (in which participants are followed forward in time) from Reykjavik, Iceland. In the study, men and women without history of heart disease aged between 31 and 57 in 1966 were first invited to join the cohort, and were followed forward in time using national registries that recorded deaths (and causes of death), and incidence of heart disease. A total of 8,888 male and 9,681 female participants were recruited. At baseline, laboratory measurements were taken to record blood sugar levels using two different methods: fasting blood glucose and post-load glucose. Among the group of participants, 4,664 people were recorded as having either a nonfatal heart attack or fatal heart disease, during approximately 23 years of follow-up. In addition, the researchers attempted to identify from the published medical literature previous prospective studies conducted in Western populations that had looked at the association between blood sugar levels and risk of coronary heart disease. They requested, and obtained, re-analyses of data conducted in accordance with a common protocol for most of the identified studies and then analysed these, together with the results of the Reykjavik cohort, to produce a summary estimate (meta-analysis) of the association between blood sugar levels and risk of coronary heart disease in people without diabetes.

In the Reykjavik cohort, the researchers confirmed an increased risk of coronary heart disease among individuals with blood sugar above the diabetic threshold, as compared to those below it. However, when they looked at blood sugar in people below the diabetic threshold, they found no evidence that higher levels were strongly linked with greater risk of coronary heart disease. This held for both methods of measuring blood sugar levels (fasting and post-load).

In the meta-analysis, the researchers obtained data for 27 different studies, comprising 303,961 participants and 16,982 cases of heart disease. In this meta-analysis, very small increases in risk of heart disease were found with higher levels of blood sugar, when measured using fasting blood glucose or post-load glucose. However, studies using glycated haemoglobin (a measure of average sugar levels over the past 1–3 months or so) found this measure to be associated with a somewhat higher risk of heart disease.

What Do these Findings Mean?

In this prospective cohort and wider meta-analysis, the researchers did not find evidence of a strong or continuous association between blood sugar levels and risk of heart disease amongst people without diabetes. The prospective study, and analysis of other cohorts, was large, but only looked at participants of European decent, so it is not clear whether the findings will also hold for non-European groups.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000278.

Information is available from the US National Diabetes Information Clearinghouse about diabetes, heart disease, and stroke

Centers for Disease Control provides information for the public and professionals about diabetes on their diabetes minisite

Medline Plus encyclopedia has an entry about coronary heart disease

Background Meta-analysis of individual participant time-to-event data from multiple prospective epidemiological studies enables detailed investigation of exposure–risk relationships, but involves a number of analytical challenges.

Methods This article describes statistical approaches adopted in the Emerging Risk Factors Collaboration, in which primary data from more than 1 million participants in more than 100 prospective studies have been collated to enable detailed analyses of various risk markers in relation to incident cardiovascular disease outcomes.

Results Analyses have been principally based on Cox proportional hazards regression models stratified by sex, undertaken in each study separately. Estimates of exposure–risk relationships, initially unadjusted and then adjusted for several confounders, have been combined over studies using meta-analysis. Methods for assessing the shape of exposure–risk associations and the proportional hazards assumption have been developed. Estimates of interactions have also been combined using meta-analysis, keeping separate within- and between-study information. Regression dilution bias caused by measurement error and within-person variation in exposures and confounders has been addressed through the analysis of repeat measurements to estimate corrected regression coefficients. These methods are exemplified by analysis of plasma fibrinogen and risk of coronary heart disease, and Stata code is made available.

Conclusion Increasing numbers of meta-analyses of individual participant data from observational data are being conducted to enhance the statistical power and detail of epidemiological studies. The statistical methods developed here can be used to address the needs of such analyses.

Background

High rates of repeat offending are common across nations that are socially and culturally different. Although psychiatric disorders are believed to be risk factors for violent reoffending, the available evidence is sparse and liable to bias.

Method

We conducted a historical cohort study in Sweden of a selected sample of 4828 offenders given community sentences who were assessed by a psychiatrist during 1988–2001, and followed up for an average of 5 years for first violent offence, death, or emigration, using information from national registers. Hazard ratios for violent offending were calculated by Cox regression models.

Results

Nearly a third of the sample (n = 1506 or 31.3%) offended violently during follow-up (mean duration: 4.8 years). After adjustment for socio-demographic and criminal history variables, substance use disorders (hazard ratio 1.97, 95% CI, 1.40–2.77) and personality disorders (hazard ratio 1.71, 1.20–2.44) were significantly associated with an increased risk of violent offending. No other diagnoses were related to recidivism risk. Adding information on diagnoses of substance use and personality disorders to data recorded on age, sex, and criminal history improved only minimally the prediction of violent offending.

Conclusion

Diagnoses of substance use and personality disorders are associated with the risk of subsequent violent offending in community offenders about as strongly as are its better documented demographic and criminal history risk factors. Despite this, assessment of such disorders in addition to demographic and criminal history factors enhances only minimally the prediction of violent offending in the community.

Background

The relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context.

Methods and Findings

Measurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28–0.53, over 4 y, and 0.35, 95% CI 0.23–0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29–1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45–3.15) with long-term average (“usual”) IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42–1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45–4.56] per 2 SD increase in usual [long-term average] IL-6 levels).

Conclusions

Long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6–mediated pathways to CHD.

John Danesh and colleagues show that long-term IL-6 levels are associated with coronary heart disease risk, thus highlighting the potential relevance of IL-6−mediated pathways to coronary heart disease.

Editors' Summary

Background.

Coronary heart disease (CHD), the leading cause of death among adults in developed countries, kills one person in the US every minute. With age, “atherosclerotic plaques”—deposits of fats, calcium, and various cellular waste products—coat the walls of arteries, causing them to narrow and harden, interrupting blood flow through the body. When this occurs in the coronary arteries, which nourish the heart muscle, the end result is CHD. If a plaque breaks off the artery wall, it can get trapped in the arteries and completely stop the blood flow, causing death of the heart muscle. The technical term for this is “myocardial infarction” (MI), although it is more commonly known as a heart attack. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), being overweight, and being physically inactive all increase the risk of developing CHD, as do some inherited factors. Treatments for CHD include lifestyle changes (for example, losing weight and exercising regularly) and medications that lower blood pressure and blood cholesterol. In the worst cases, the narrowed artery can be widened using a device called a stent or surgically bypassed.

Why Was This Study Done?

Atherosclerosis might, at least partly, be an inflammatory condition. Inflammation—an immune response to injury characterized by swelling and redness—involves the production of proteins called “cytokines,” which attract cells of the immune system to the site of injury. In atherosclerosis, damage to the artery walls seems to trigger inflammation, which helps the atherosclerotic plaques grow. Because of the potential involvement of inflammation in atherosclerosis, increased levels of circulating cytokines might be associated with an increased risk of CHD. If they are, cytokines might provide a new therapeutic target for the treatment of CHD. In this study, the researchers have asked whether prolonged moderate increases in the cytokine interleukin-6 (IL-6) in the bloodstream are associated with CHD risk. IL-6, which is produced very early in inflammation, survives only briefly in the human body and its levels fluctuate within individuals. Consequently, its relevance to CHD has been unclear in previous studies.

What Did the Researchers Do and Find?

Between 1967 and 1991, nearly 25,000 healthy, mainly middle-aged people were enrolled into two studies—the Reykjavik Study and the British Regional Heart Study—and followed for about 20 years, during which time 2,138 people had a first-ever nonfatal heart attack or died of CHD. The researchers measured baseline IL-6 blood levels in these participants and in 4,267 similar participants who had not had a CHD event. They also measured IL-6 levels in 558 healthy participants several years into the study to determine a “regression dilution ratio” for IL-6. This ratio gives an idea of the year-to-year consistency of IL-6 levels. When the researchers used this ratio to estimate the impact of prolonged increases in IL-6 levels on CHD, they found that increased long-term IL-6 levels more than doubled the risk for CHD in their study populations. The researchers then combined these new results with those of 15 previous relevant studies. This combined analysis indicated very similar findings to those in the new data.

What Do These Findings Mean?

These findings indicate prolonged moderate increases in IL-6 levels are associated with risk of CHD as strongly as several major established risk factors, including blood pressure and blood cholesterol levels, but whether there is a cause-and-effect relationship remains unknown. More studies are needed to find out whether this result is generalisable to other populations, but the broad agreement between the Icelandic and British studies suggests that they should be. This study renews interest in IL-6–mediated inflammatory pathways and CHD.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050078.

Read a related PLoS Medicine Perspective article

The MedlinePlus encyclopedia has pages on coronary heart disease and atherosclerosis (in English and Spanish)

Information is available from the US National Heart Lung and Blood Institute on coronary heart disease and atherosclerosis

Information for patients and caregivers is provided by the American Heart Association on all aspects of heart disease, including inflammation and heart disease

Information is available from the British Heart Foundation on heart disease and on keeping the heart healthy

Further details are available about the Reykjavik Study and the British Regional Heart Study

Wikipedia has pages on inflammation and on interleukin-6 (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Background

End-stage chronic kidney disease is associated with striking excesses of cardiovascular mortality, but it is uncertain to what extent renal function is related to risk of subsequent coronary heart disease (CHD) in apparently healthy adults. This study aims to quantify the association of markers of renal function with CHD risk in essentially general populations.

Methods and Findings

Estimated glomerular filtration rate (eGFR) was calculated using standard prediction equations based on serum creatinine measurements made in 2,007 patients diagnosed with nonfatal myocardial infarction or coronary death during follow-up and in 3,869 people without CHD in the Reykjavik population-based cohort of 18,569 individuals. There were small and nonsignificant odds ratios (ORs) for CHD risk over most of the range in eGFR, except in the lowest category of the lowest fifth (corresponding to values of <60 ml/min/1.73m2), in which the OR was 1.33 (95% confidence interval 1.01–1.75) after adjustment for several established cardiovascular risk factors. Findings from the Reykjavik study were reinforced by a meta-analysis of six previous reports (identified in electronic and other databases) involving a total of 4,720 incident CHD cases (including Reykjavik), which yielded a combined risk ratio of 1.41 (95% confidence interval 1.19–1.68) in individuals with baseline eGFR less than 60 ml/min/1.73m2 compared with those with higher values.

Conclusions

Although there are no strong associations between lower-than-average eGFR and CHD risk in apparently healthy adults over most of the range in renal function, there may be a moderate increase in CHD risk associated with very low eGFR (i.e., renal dysfunction) in the general population. These findings could have implications for the further understanding of CHD and targeting cardioprotective interventions.

John Danesh and colleagues conclude there may be a moderate increase in risk of coronary heart disease associated with very low estimated glomerular filtration rate.

Editors' Summary

Background.

Coronary heart disease (CHD), the leading cause of death in most Western countries, is a “cardiovascular” disease—literally a disorder affecting the heart and/or blood vessels. In CHD, the blood vessels that supply the heart become increasingly narrow. Eventually, the flow of blood to the heart slows or stops, causing chest pains (angina), breathlessness, and heart attacks. Many factors increase the risk of developing CHD and other cardiovascular diseases, including high blood pressure, high blood levels of cholesterol (a type of fat), or being overweight. Individuals can reduce their chances of developing cardiovascular disease by taking drugs to reduce their blood pressure or cholesterol levels or by making lifestyle changes (so-called cardioprotective interventions). Another important risk factor for cardiovascular disease is end-stage chronic kidney disease (CKD), a condition in which the kidneys stop working. (In healthy people, the kidneys remove waste products and excess fluid from the body.) People with end-stage CKD (which is treated by dialysis) have about a five times higher risk of dying from cardiovascular disease compared with healthy people.

Why Was This Study Done?

End-stage CKD is preceded by a gradual loss of kidney function. There is a clear association between non-dialysis–dependent CKD and the incidence of cardiovascular events (such as heart attacks) in people who already have signs of cardiovascular disease. But are people with slightly dysfunctional kidneys (often because of increasing age) but without any obvious cardiovascular disease at greater risk of developing cardiovascular diseases than people with fully functional kidneys? If the answer is yes, it might be possible to reduce CHD deaths by minimizing the exposure of people with CKD to other risk factors for cardiovascular disease. In this study, the researchers have taken two approaches to answer this question. In a population-based study, they have examined whether there is any association in healthy adults between kidney function measured at the start of the study and incident CHD (the first occurrence of CHD) over subsequent years. In addition, they have systematically searched the published literature for similar studies and combined the results of these studies using statistical methods, a so-called “meta-analysis.”

What Did the Researchers Do and Find?

Between 1967 and 1991, nearly 19,000 middle-aged men and women without a history of heart attacks living in Reykjavik, Iceland, enrolled in a prospective study of cardiovascular disease. Baseline blood samples were taken at enrollment and the participants' health monitored for 20 years on average. The researchers identified 2,007 participants who suffered a nonfatal heart attack or died of CHD during follow-up and 3,869 who remained disease free. They then calculated the estimated glomerular filtration rate (eGFR; a measure of kidney function) for each participant from baseline creatinine measurements (creatinine is a muscle waste product). There was no association between lower-than-average eGFRs and the risk of developing CHD over most of the range of eGFR values. However, people whose eGFR was below approximately 60 units had about a 40% higher risk of developing CHD after allowing for established cardiovascular risk factors than individuals with higher eGFRs. This finding was confirmed by the meta-analysis of six previous studies, which included a further 2,700 incident CHD cases.

What Do These Findings Mean?

These findings indicate that people with an eGFR below about 60 units (the cut-off used to define CKD) may have an increased risk of developing CHD. They also indicate a nonliner association between kidney function and CHD risk. That is, any association with CHD became evident only when the eGFR dropped below about 60 units. These findings need confirming in different ethnic groups and by using more accurate methods to measure eGFRs. Nevertheless, they suggest that improving kidney function across the board is unlikely to have much effect on the overall incidence of CHD. Instead, they suggest that targeting cardioprotective interventions at the one in ten adults in Western countries whose eGFR is below 60 units might be a good way to reduce the burden of CHD.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040270.

MedlinePlus encyclopedia pages on coronary heart disease, chronic kidney failure, and end-stage kidney disease (in English and Spanish).

Information for patients and carers from the American Heart Association on all aspects of heart disease, including prevention of CHD

Information from the British Heart Foundation on heart disease and on keeping the heart healthy

Information on chronic kidney disease from the US National Kidney Foundation, and the US National Kidney and Urologic Diseases Information Clearing House (in English and Spanish)

Information on chronic kidney disease from the UK National Kidney Foundation

Background

Glutathione S-transferases (GSTs) are known to abolish or reduce the activities of intracellular enzymes that help detoxify environmental carcinogens, such as those found in tobacco smoke. It has been suggested that polymorphisms in the GST genes are risk factors for lung cancer, but a large number of studies have reported apparently conflicting results.

Methods and Findings

Literature-based meta-analysis was supplemented by tabular data from investigators of all relevant studies of five GST polymorphisms ( GSTM1 null, GSTT1 null, I105V, and A114V polymorphisms in the GSTP1 genes, and GSTM3 intron 6 polymorphism) available before August, 2005, with investigation of potential sources of heterogeneity. Included in the present meta-analysis were 130 studies, involving a total of 23,452 lung cancer cases and 30,397 controls. In a combined analysis, the relative risks for lung cancer of the GSTM1 null and GSTT1 null polymorphisms were 1.18 (95% confidence interval [CI]: 1.14–1.23) and 1.09 (95% CI: 1.02–1.16), respectively, but in the larger studies they were only 1.04 (95% CI: 0.95–1.14) and 0.99 (95% CI: 0.86–1.11), respectively. In addition to size of study, ethnic background was a significant source of heterogeneity among studies of the GSTM1 null genotype, with possibly weaker associations in studies of individuals of European continental ancestry. Combined analyses of studies of the 105V, 114V, and GSTM3*B variants showed no significant overall associations with lung cancer, yielding per-allele relative risks of 1.04 (95% CI: 0.99–1.09), 1.15 (95% CI: 0.95–1.39), and 1.05 (95% CI: 0.89–1.23), respectively.

Conclusions

The risk of lung cancer is not strongly associated with the I105V and A114V polymorphisms in the GSTP1 gene or with GSTM3 intron 6 polymorphism. Given the non-significant associations in the larger studies, the relevance of the weakly positive overall associations with the GSTM1 null and the GSTT1 null polymorphisms is uncertain. As lung cancer has important environmental causes, understanding any genetic contribution to it in general populations will require the conduct of particularly large and comprehensive studies.

Large meta-analysis finds little evidence for a link between gene variants encoding inactive or less active variants of detoxifying enzymes and lung cancer risk.

Objective

To assess the association between genotype at the insertion or deletion polymorphism of the angiotensin converting enzyme gene and risk of coronary restenosis after percutaneous coronary intervention.

Design

Meta-analysis of studies before July 2001 that reported on these genotypes and risk of coronary restenosis after a percutaneous coronary intervention, with or without coronary stenting.

Results

16 studies, involving 4631 patients undergoing a percutaneous coronary intervention, yielded 1683 patients with restenosis after a mean weighted follow up of 5.5 months. The combined odds ratio for restenosis in people with the DD genotype was 1.23 (99% confidence interval 1.03 to 1.46). When studies were grouped by size, however, the combined odds ratios for restenosis in people with the DD genotype were 1.94 (1.39 to 2.71) for studies with less than 100 cases, 1.33 (0.92 to 1.93) for studies with 100-200 cases, and 0.92 (0.72 to 1.18) for studies with more than 200 cases (trend P=0.02). Similarly, when studies were grouped by genotyping procedures, significantly larger odds ratios were found in the studies that did not conceal disease status from laboratory staff and in the studies that did not use a second polymerase chain reaction amplification to reduce genetic mistyping.

Conclusion

Compared with other studies, larger and more rigorous studies show a weaker association between the angiotensin converting enzyme gene DD genotype and restenosis. Publication bias or detection biases can produce artefactual associations at least as large as those that might be expected for common polymorphisms in complex diseases, suggesting the need for larger and more rigorous genetic epidemiological investigations than are now customary.

What is already known on this topicRestenosis after a percutaneous coronary intervention is one of the principal limitations of the techniqueGenotype at the angiotensin converting enzyme insertion or deletion polymorphism is proposed to be important in restenosisWhat this study addsWeaker associations between the angiotensin converting enzyme DD genotype and restenosis were found in larger and more rigorous studies than in other studiesPublication bias or detection biases, or both, can produce artefactual associations at least as large as those that might be expected for common polymorphisms in complex diseases

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.

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 (χ2=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.

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.

Key messagesMost previous studies of associations between chronic H pylori infection and coronary heart disease have been too small or prone to biasThis case-control study found myocardial infarction was twice as common in people infected with H pylori as in those not infectedAmong sibling pairs, myocardial infarction was about a third more common in seropositive people than those who were seronegativeThese results support a weak association between H pylori infection and coronary heart disease

Objective: To find out if chronic infection with Helicobacter pylori is correlated with risk factors for coronary heart disease.

Design: Meta-analysis of 18 epidemiological studies, involving a total of 10 000 patients, that measured serum antibody titres to H pylori and risk factors for coronary heart disease. Any study published in any language before 1998 was eligible for inclusion.

Results: Only small absolute differences in body mass index, blood pressure, or haematological risk factors were found between subjects who were seropositive and those who were seronegative. In those who were seropositive body mass index was slightly higher (0.37, SE 0.09) and concentrations of high density lipoprotein cholesterol were slightly lower (0.032 mmol/l, 0.008). None of the other differences were highly significant.

Conclusion: Previous claims of substantial correlations between H pylori seropositivity and certain vascular risk factors were largely or wholly due to chance or the preferential publication of positive results, or both.

Key messages Epidemiological studies suggest that there is a weakly positive association between coronary heart disease and chronic infection with Helicobacter pylori A number of reports have also claimed that there are strong correlations between infection with H pylori and an increase in vascular risk factors, such as plasma fibrinogen concentrations Meta-analysis of 18 studies that involved 10 000 people found no strong correlations between H pylori seropositivity and vascular risk factors; previous findings of the existence of such correlations in small studies were largely or wholly due to chance or to the preferential publication of positive results

Background

It has been suggested throughout the past fifty years that serum uric acid concentrations can help predict the future risk of coronary heart disease (CHD), but the epidemiological evidence is uncertain.

Methods and Findings

We report a “nested” case-control comparison within a prospective study in Reykjavik, Iceland, using baseline values of serum uric acid in 2,456 incident CHD cases and in 3,962 age- and sex-matched controls, plus paired serum uric acid measurements taken at baseline and, on average, 12 y later in 379 participants. In addition, we conducted a meta-analysis of 15 other prospective studies in eight countries conducted in essentially general populations. Compared with individuals in the bottom third of baseline measurements of serum uric acid in the Reykjavik study, those in the top third had an age- and sex-adjusted odds ratio for CHD of 1.39 (95% confidence interval [CI], 1.23–1.58) which fell to 1.12 (CI, 0.97–1.30) after adjustment for smoking and other established risk factors. Overall, in a combined analysis of 9,458 cases and 155,084 controls in all 16 relevant prospective studies, the odds ratio was 1.13 (CI, 1.07–1.20), but it was only 1.02 (CI, 0.91–1.14) in the eight studies with more complete adjustment for possible confounders.

Conclusions

Measurement of serum uric acid levels is unlikely to enhance usefully the prediction of CHD, and this factor is unlikely to be a major determinant of the disease in general populations.

The largest ever prospective analysis and meta-analysis of uric acid in coronary heart disease finds no evidence that uric acid is useful in predicting coronary heart disease