Lack of association between serological evidence of past Coxiella burnetii infection and incident ischaemic heart disease: nested case-control study

BACKGROUND: Coxiella burnetii causes the common worldwide zoonotic infection, Q fever. It has been previously suggested that patients who had recovered from acute Q fever (whether symptomatic or otherwise) may be at increased risk of ischaemic heart disease. We undertook this study to determine if past infection with Coxiella burnetii, the aetiological agent of Q fever, is a risk factor for the subsequent development of ischaemic heart disease. METHODS: A nested case-control study within the Prospective Epidemiological Study of Myocardial Infarction (PRIME). The PRIME study is a cohort study of 10,593 middle-aged men undertaken in France and Northern Ireland in the 1990s. A total of 335 incident cases of ischaemic heart disease (IHD) were identified and each case was matched to 2 IHD free controls. Q fever seropositivity was determined using a commercial IgG ELISA method. RESULTS: Seroprevalence of Q fever in the controls from Northern Ireland and France were 7.8% and 9.0% respectively. No association was seen between seropositivity and age, smoking, lipid levels, or inflammatory markers. The unadjusted odds ratio (95% CI) for Q fever seropositivity in cases compared to controls was 0.95 (0.59, 1.57). The relationship was substantially unaltered following adjustment for cardiovascular risk factors and potential confounders. CONCLUSION: Serological evidence of past infection with C. burnetii was not found to be associated with an increased risk of IHD

Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohort

Association of apolipoprotein E gene polymorphisms with blood lipids and their interaction with dietary factors

Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. METHODS: The population studied for this investigation included 660 individuals from the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ) in PRECISE and a validated semi-quantitative FFQ in the CaPS. Interaction analyses were performed by including the interaction term in the linear regression model adjusted for age, body mass index, sex and country. RESULTS: There was no association between dietary factors and blood lipids after Bonferroni correction and adjustment for confounding factors in either cohort. In the PRECISE study, after correction for multiple testing, there was a statistically significant association of the APOE haplotype (rs7412 and rs429358; E2, E3, and E4) and APOE tagSNP rs445925 with total cholesterol (P = 4 × 10- 4 and P = 0.003, respectively). Carriers of the E2 allele had lower total cholesterol concentration (5.54 ± 0.97 mmol/L) than those with the E3 (5.98 ± 1.05 mmol/L) (P = 0.001) and E4 (6.09 ± 1.06 mmol/L) (P = 2 × 10- 4) alleles. The association of APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 with total cholesterol (P = 2 × 10- 6 and P = 3 × 10- 4, respectively) was further replicated in the CaPS. Additionally, significant association was found between APOE haplotype and APOE SNP rs445925 with low density lipoprotein cholesterol in CaPS (P = 4 × 10- 4 and P = 0.001, respectively). After Bonferroni correction, none of the cohorts showed a statistically significant SNP-diet interaction on lipid outcomes. CONCLUSION: In summary, our findings from the two cohorts confirm that genetic variations at the APOE locus influence plasma total cholesterol concentrations, however, the gene-diet interactions on lipids require further investigation in larger cohorts

Replication of the association of chromosomal region 9p21.3 with generalized aggressive periodontitis (gAgP) using an independent case-control cohort

Background: The human chromosomal region 9p21.3 has been shown to be strongly associated with Coronary Heart Disease (CHD) in several Genome-wide Association Studies (GWAS). Recently, this region has also been shown to be associated with Aggressive Periodontitis (AgP), strengthening the hypothesis that the established epidemiological association between periodontitis and CHD is caused by a shared genetic background, in addition to common environmental and behavioural risk factors. However, the size of the analyzed cohorts in this primary analysis was small compared to other association studies on complex diseases. Using our own AgP cohort, we attempted to confirm the described associations for the chromosomal region 9p21.3. Methods: We analyzed our cohort consisting of patients suffering from the most severe form of AgP, generalized AgP (gAgP) (n = 130) and appropriate periodontally healthy control individuals (n = 339) by genotyping four tagging SNPs (rs2891168, rs1333042, rs1333048 and rs496892), located in the chromosomal region 9p21.3, that have been associated with AgP. Results: The results confirmed significant associations between three of the four SNPs and gAgP. The combination of our results with those from the study which described this association for the first time in a meta-analysis of the four tagging SNPs produced clearly lower p-values compared with the results of each individual study. According to these results, the most plausible genetic model for the association of all four tested SNPs with gAgP seems to be the multiplicative one. Conclusion: We positively replicated the finding of an association between the chromosomal region 9p21.3 and gAgP. This result strengthens support for the hypothesis that shared susceptibility genes within this chromosomal locus might be involved in the pathogenesis of both CHD and gAgP

Models for Prediction of Factor VIII Half-Life in Severe Haemophiliacs: Distinct Approaches for Blood Group O and Non-O Patients

BACKGROUND: Von Willebrand factor (VWF) is critical for the in vivo survival of factor VIII (FVIII). Since FVIII half-life correlates with VWF-antigen pre-infusion levels, we hypothesized that VWF levels are useful to predict FVIII half-life. METHODOLOGY: Standardized half-life studies and analysis of pre-infusion VWF and VWF-propeptide levels were performed in a cohort of 38 patients with severe haemophilia A (FVIII <1 IU/ml), aged 15-44 years. Nineteen patients had blood-group O. Using multivariate linear regression-analysis (MVLR-analysis), the association of VWF-antigen, VWF-propeptide, age and body-weight with FVIII half-life was evaluated. PRINCIPAL FINDINGS: FVIII half-life was shorter in blood-group O-patients compared to non-O-patients (11.5+/-2.6 h versus 14.3+/-3.0 h; p = 0.004). VWF-antigen levels correlated with FVIII half-life considerably better in patients with blood-group non-O than O (Pearson-rank = 0.70 and 0.47, respectively). Separate prediction models evolved from MVLR-analysis for blood-group O and non-O patients, based on VWF-antigen and VWF/propeptide ratio. Predicted half-lives deviated less than 3 h of observed half-life in 34/38 patients (89%) or less than 20% in 31/38 patients (82%). CONCLUSION: Our approach may identify patients with shorter FVIII half-lives, and adapt treatment protocols when half-life studies are unavailable. In addition, our data indicate that survival of FVIII is determined by survival of endogenous VWF rather than VWF levels per se

Elevated white cell count in acute coronary syndromes: relationship to variants in inflammatory and thrombotic genes

BACKGROUND: Elevated white blood cell counts (WBC) in acute coronary syndromes (ACS) increase the risk of recurrent events, but it is not known if this is exacerbated by pro-inflammatory factors. We sought to identify whether pro-inflammatory genetic variants contributed to alterations in WBC and C-reactive protein (CRP) in an ACS population. METHODS: WBC and genotype of interleukin 6 (IL-6 G-174C) and of interleukin-1 receptor antagonist (IL1RN intronic repeat polymorphism) were investigated in 732 Caucasian patients with ACS in the OPUS-TIMI-16 trial. Samples for measurement of WBC and inflammatory factors were taken at baseline, i.e. Within 72 hours of an acute myocardial infarction or an unstable angina event. RESULTS: An increased white blood cell count (WBC) was associated with an increased C-reactive protein (r = 0.23, p < 0.001) and there was also a positive correlation between levels of β-fibrinogen and C-reactive protein (r = 0.42, p < 0.0001). IL1RN and IL6 genotypes had no significant impact upon WBC. The difference in median WBC between the two homozygote IL6 genotypes was 0.21/mm(3 )(95% CI = -0.41, 0.77), and -0.03/mm(3 )(95% CI = -0.55, 0.86) for IL1RN. Moreover, the composite endpoint was not significantly affected by an interaction between WBC and the IL1 (p = 0.61) or IL6 (p = 0.48) genotype. CONCLUSIONS: Cytokine pro-inflammatory genetic variants do not influence the increased inflammatory profile of ACS patients

Markers of Dysglycaemia and Risk of Coronary Heart Disease in People without Diabetes: Reykjavik Prospective Study and Systematic Review

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 > or = 7.0 mmol/l compared to those or = 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 HbA(1c) (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 HbA(1c) levels and CHD risk

Clinically diagnosed childhood asthma and follow-up of symptoms in a Swedish case control study

BACKGROUND: Childhood asthma has risen dramatically not only in the western societies and now forms a major and still increasing public health problem. The aims of this study were to follow up at the age of ten the patterns of asthma symptoms and associations among children with a clinically diagnosed asthma in a sizeable urban-rural community and to in compare them with demographic controls using a standardised questionnaire. METHODS: In a defined region in Sweden with a population of about 150 000 inhabitants, all children (n = 2 104) born in 1990 were recorded. At the age of seven all primary care and hospital records of the 1 752 children still living in the community were examined, and a group of children (n = 191) was defined with a well-documented and medically confirmed asthma diagnosis. At the age of ten, 86 % of these cases (n = 158) and controls (n = 171) completed an ISAAC questionnaire concerning asthma history, symptoms and related conditions. RESULTS: Different types of asthma symptoms were highly and significantly over-represented in the cases. Reported asthma heredity was significantly higher among the cases. No significant difference in reported allergic rhinitis or eczema as a child was found between cases and controls. No significant difference concerning social factors or environmental exposure was found between case and controls. Among the control group 4.7 % of the parents reported that their child actually had asthma. These are likely to be new asthma cases between the age of seven and ten and give an estimated asthma prevalence rate at the age of ten of 15.1 % in the studied cohort. CONCLUSION: A combination of medical verified asthma diagnosis through medical records and the use of self-reported symptom through the ISAAC questionnaire seem to be valid and reliable measures to follow-up childhood asthma in the local community. The asthma prevalence at the age of ten in the studied birth cohort is considerably higher than previous reports for Sweden. Both the high prevalence figure and allowing the three-year lag phase for further settling of events in the community point at the complementary roles of both hospital and primary care in the comprehensive coverage and control of childhood asthma in the community

IL6 and CRP haplotypes are associated with COPD risk and systemic inflammation: a case-control study

<p>Abstract</p> <p>Background</p> <p>Elevated circulating levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen (FG) have been repeatedly associated with many adverse outcomes in patients with chronic obstructive pulmonary disease (COPD). To date, it remains unclear whether and to what extent systemic inflammation is primary or secondary in the pathogenesis of COPD.</p> <p>The aim of this study was to examine the association between haplotypes of <it>CRP</it>, <it>IL6 </it>and <it>FGB </it>genes, systemic inflammation, COPD risk and COPD-related phenotypes (respiratory impairment, exercise capacity and body composition).</p> <p>Methods</p> <p>Eighteen SNPs in three genes, representing optimal haplotype-tagging sets, were genotyped in 355 COPD patients and 195 healthy smokers. Plasma levels of CRP, IL-6 and FG were measured in the total study group. Differences in haplotype distributions were tested using the global and haplotype-specific statistics.</p> <p>Results</p> <p>Raised plasma levels of CRP, IL-6 and fibrinogen were demonstrated in COPD patients. However, COPD population was very heterogeneous: about 40% of patients had no evidence of systemic inflammation (CRP < 3 mg/uL or no inflammatory markers in their top quartile). Global test for haplotype effect indicated association of <it>CRP </it>gene and CRP plasma levels (P = 0.0004) and <it>IL6 </it>gene and COPD (P = 0.003). Subsequent analysis has shown that <it>IL6 </it>haplotype H2, associated with an increased COPD risk (p = 0.004, OR = 4.82; 1.64 to 4.18), was also associated with very low CRP levels (p = 0.0005). None of the genes were associated with COPD-related phenotypes.</p> <p>Conclusion</p> <p>Our findings suggest that common genetic variation in <it>CRP </it>and <it>IL6 </it>genes may contribute to heterogeneity of COPD population associated with systemic inflammation.</p