Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions

BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0x10(-3) (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P= 1.3x10(-16)) in comparison with 5% in ever-smokers (P= 2.5x10(-4)), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value= 8.7x10(-5)). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.Peer reviewe

Lipid network for control-group with parameter values ε = 0.4 and minimum modular size = 3.

<p>Significant lipids from the test for differential connectivity of a single lipid are circulated. Modules consisting of lipids belonging to the same lipid class are highlighted with a rectangle as well.</p

Test for differential modular structure in the case and control networks for MI LURIC data.

<p>For comparison, the same statistics and p-values are given for complete case (CC) data with subgroup of lipids from which 90% of the values were detected.</p

The 13 imputed lipids having significantly different mean concentrations between case and control groups by the marginal analysis implemented by using Rubin’s rules.

<p>The 13 imputed lipids having significantly different mean concentrations between case and control groups by the marginal analysis implemented by using Rubin’s rules.</p

The 10 most differentially connected lipids for MI LURIC data based on the test for differential connectivity of individual lipids between case and control groups.

<p>The 10 most differentially connected lipids for MI LURIC data based on the test for differential connectivity of individual lipids between case and control groups.</p

The three fully observed lipids having significantly different mean concentrations between case and control groups by the marginal analysis.

<p>The three fully observed lipids having significantly different mean concentrations between case and control groups by the marginal analysis.</p

Propeptide big-endothelin, N-terminal-pro brain natriuretic peptide and mortality. The Ludwigshafen risk and cardiovascular health (LURIC) study

<p><b>Context:</b> The endothelin system (Big-ET-1) is a key regulator in cardiovascular (CV) disease and congestive heart failure (CHF).</p> <p><b>Objectives:</b> We have examined the incremental value of Big-ET-1 in predicting total and CV mortality next to the well-established CV risk marker N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP).</p> <p><b>Methods:</b> Big-ET-1 and NT-proBNP were determined in 2829 participants referred for coronary angiography (follow-up 9.9 years).</p> <p><b>Results:</b> Big-ET-1 is an independent predictor of total, CV mortality and death due to CHF.</p> <p><b>Discussion:</b> The conjunct use of Big-ET-1 and NT-proBNP improves the risk stratification of patients with intermediate to high risk of CV death and CHF.</p> <p><b>Conclusions:</b> Big-ET-1improves risk stratification in patients referred for coronary angiography.</p

Telomere length and mortality in the Ludwigshafen Risk and Cardiovascular Health study

<div><p>Introduction</p><p>Short telomeres have been associated with adverse lifestyle factors, cardiovascular risk factors and age-related diseases, including cardiovascular disease (CVD), myocardial infarction, atherosclerosis, hypertension, diabetes, and also with mortality. However, previous studies report conflicting results.</p><p>Objectives</p><p>The aim of the present study has been to investigate the involvement of telomere length in all-cause and CVD mortality in subjects hospitalized for diagnostic coronary angiography of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.</p><p>Methods</p><p>Relative telomere length (RTL) was measured with a Q-PCR based method in 3,316 participants of the LURIC study. Age-corrected RTL was calculated as the ratio between RTL and age. Median follow-up was 9.9 years. Cox regression and Kaplan-Maier analyses were performed to evaluate the role of RTL for all-cause and cardiovascular mortality.</p><p>Results</p><p>RTL correlated negatively with age (r = -0.09; p<0.001). In surviving patients the correlation between age and RTL was statistically significant (r = -0.088; p<0.001), but not in patients who died during follow-up (r = -0.043; p = 0.20). Patients in quartiles 2–4 of RTL had a lower hazard ratio for all-cause mortality (HR:0.822; 95%CI 0.712–0.915; p = 0.008) and CVD-mortality (HR:0.836; 95%CI 0.722–0.969; p = 0.017) when compared to those in the 1^st quartile. Adjustment for major cardiovascular risk factors did not change this result, however additional adjustment for age attenuated this effect. Patients in the 4^th quartile of age-corrected RTL compared to those in the 1^st quartile had a lower hazard ratio for all-cause mortality, even with adjustment for major cardiovascular risk factors.</p><p>Conclusions</p><p>The present study supports the hypothesis that short telomere length increases the risk of all-cause and CVD mortality. Age appears to be an important co-variate that explains a substantial fraction of this effect. It remains unclear whether short telomeres contribute directly to the increase in mortality or if they are simply a surrogate marker for other adverse processes of aging.</p></div

Associations between RTL and age.

<p>A) Correlation between RTL (log-transformed) and age. B) RTL according to age strata.</p

Kaplan-Meier plots.

<p>Cumulative survival according to RTL quartiles (A), RTL quartile 1 versus all others quartiles (B).</p