Abstract Background Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD). Methods and results We ...searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test. In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification ( P -value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification. Conclusions In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.
The objective of this study was to evaluate 1) whether non single nucleotide polymorphisms-coding (non-cSNP) in the apolipoprotein E gene (APOE) identified by resequencing studies contribute to ...statistically explaining dyslipidemia if variations in the two cSNPs in exon 4 that define the 2, 3, and 4 alleles are ignored, and 2) whether the contribution of these additional SNPs persists when variations in the cSNPs are considered. We used an ecological, multiple-population, data-mining strategy to identify single-SNP and two-SNP genotypes that distinguish between high and low levels of plasma lipids in three training samples, European-Americans from Rochester, MN, African-Americans from Jackson, MS, and Europeans from North Karelia, Finland. We found that a pair of SNPs located in the 5' region define genotypes A560T832/A560T832, A560T832/A560G832, and A560T832/T560T832, which distinguish between high and low levels of HDL-cholesterol (HDL-C), triglycerides (TG), and/or total cholesterol (T-C). The A560T832/- genotypes predicted high TG and high T-C in both genders in a large independent test sample from Copenhagen, Denmark. Prediction of high T-C in the Danish females was dependent on genotypes defined by the cSNPs. Our study suggests that both regulatory and structural variations should be considered when evaluating the utility of APOE for predicting dyslipidemia in the population at large.
Summary
The objective of this study was to evaluate whether an increased hazard of developing ischemic heart disease (IHD) is associated with any of the three genotypes A560T832/A560T832, ...A560T832/A560G832 and A560T832/T560T832, defined by variations in two non‐coding SNPs in the 5′ promoter region of the apolipoprotein E (APOE) gene. These genotypes were selected because they distinguished between high and low levels of HDL‐C, TG and/or T‐C in our earlier study of multiple samples defined by gender and population. We found a significant increase (p<0.05) in the hazard of IHD in females with the A560T832/T560T832 genotype that remained significant after fitting the effects of dyslipidemia, other established risk factors, and the structural isoform variations of the ApoE molecule. We discuss why this statistically significant genetic predictor may not be an appropriate screening test for IHD in the Danish population at large.
The synergism of infection with conventional cardiovascular risk factors in atherosclerosis is much debated. We hypothesized that coronary arterial injury correlates with infection recurrence and ...pathogen burden and is further aggravated by hypercholesterolemia. Forty-two Göttingen minipigs were assigned to repeated intratracheal inoculation of PBS, Chlamydia pneumoniae (Cpn), or both Cpn and influenza virus at 8, 11, and 14 wk of age. Animals were fed either standard or 2% cholesterol diet (chol-diet). At 19 wk of age coronary vasomotor responses to acetylcholine (ACh) and adenosine were assessed in vivo and blood and tissue samples were collected. Nonparametric tests were used to compare the groups. In cholesterol-fed animals, total cholesterol/HDL was significantly increased in infected animals compared with noninfected animals 3.13 (2.17-3.38) vs. 2.03 (1.53-2.41), respectively; P = 0.01. C-reactive protein (CRP) rose in infected animals 10.60 (4.96-18.00) vs. 2.47 (1.44-3.01) μg/ml in noninfected; P < 0.01 without significant difference between the mono- and coinfected groups. Among coinfected animals, both CRP and haptoglobin were lower in those fed chol-diet than in those fed standard diet (P < 0.05). The vasoconstricting response to ACh was most prominent in coinfected animals {769.3 (594-1,129) cm; P = 0.03 vs. noninfected 342 (309-455) cm and P = 0.07 vs. monoinfected 415 (252.5-971.8) cm}. Among monoinfected animals, similar to CRP, a trend for less vasoconstriction was observed in those fed chol-diet (P = 0.08). Coinfection of piglets appears to be associated with more pronounced coronary muscarinic vasomotor dysfunction. In monoinfected animals, use of chol-diet seems to dampen both coronary dysfunction and systemic inflammation induced by infection.
Highlights ► Examined association of genetic variants with ankle brachial index (ABI). ► Studies were ethnically diverse, African-American and European ancestry. ► Variants in TCF7L2 and SYTL3 ...associated with ABI in European ancestry participants. ► However, the associations failed replication in further studies. ► New and more powerful approaches to PAD gene discovery are sorely needed.
Motivation
Discrimination statistics describe the ability of a survival model to assign higher risks to individuals who experience earlier events: examples are Harrell's C‐index and Royston and ...Sauerbrei's D, which we call the D‐index. Prognostic covariates whose distributions are controlled by the study design (e.g. age and sex) influence discrimination and can make it difficult to compare model discrimination between studies. Although covariate adjustment is a standard procedure for quantifying disease‐risk factor associations, there are no covariate adjustment methods for discrimination statistics in censored survival data.
Objective
To develop extensions of the C‐index and D‐index that describe the prognostic ability of a model adjusted for one or more covariate(s).
Method
We define a covariate‐adjusted C‐index and D‐index for censored survival data, propose several estimators, and investigate their performance in simulation studies and in data from a large individual participant data meta‐analysis, the Emerging Risk Factors Collaboration.
Results
The proposed methods perform well in simulations. In the Emerging Risk Factors Collaboration data, the age‐adjusted C‐index and D‐index were substantially smaller than unadjusted values. The study‐specific standard deviation of baseline age was strongly associated with the unadjusted C‐index and D‐index but not significantly associated with the age‐adjusted indices.
Conclusions
The proposed estimators improve meta‐analysis comparisons, are easy to implement and give a more meaningful clinical interpretation.
Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all ...of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering > 90% of cases, are KCNQ1, KCNH2 and SCN5A.
We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2.
Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 "unrelated" families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of < 1:1000.
The genetic etiology of LQTS in Denmark is similar to that found in other populations. A large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
