Large Scale Association Analysis Identifies Three Susceptibility Loci for Coronary Artery Disease

Genome wide association studies (GWAS) and their replications that have associated DNA variants with myocardial infarction (MI) and/or coronary artery disease (CAD) are predominantly based on populations of European or Eastern Asian descent. Replication of the most significantly associated polymorphisms in multiple populations with distinctive genetic backgrounds and lifestyles is crucial to the understanding of the pathophysiology of a multifactorial disease like CAD. We have used our Lebanese cohort to perform a replication study of nine previously identified CAD/MI susceptibility loci (LTA, CDKN2A-CDKN2B, CELSR2-PSRC1-SORT1, CXCL12, MTHFD1L, WDR12, PCSK9, SH2B3, and SLC22A3), and 88 genes in related phenotypes. The study was conducted on 2,002 patients with detailed demographic, clinical characteristics, and cardiac catheterization results. One marker, rs6922269, in MTHFD1L was significantly protective against MI (OR = 0.68, p = 0.0035), while the variant rs4977574 in CDKN2A-CDKN2B was significantly associated with MI (OR = 1.33, p = 0.0086). Associations were detected after adjustment for family history of CAD, gender, hypertension, hyperlipidemia, diabetes, and smoking. The parallel study of 88 previously published genes in related phenotypes encompassed 20,225 markers, three quarters of which with imputed genotypes The study was based on our genome-wide genotype data set, with imputation across the whole genome to HapMap II release 22 using HapMap CEU population as a reference. Analysis was conducted on both the genotyped and imputed variants in the 88 regions covering selected genes. This approach replicated HNRNPA3P1-CXCL12 association with CAD and identified new significant associations of CDKAL1, ST6GAL1, and PTPRD with CAD. Our study provides evidence for the importance of the multifactorial aspect of CAD/MI and describes genes predisposing to their etiology

Magnesium isotope evidence that accretional vapour loss shapes planetary compositions

It has long been recognized that Earth and other differentiated planetary bodies are chemically fractionated compared to primitive, chondritic meteorites and, by inference, the primordial disk from which they formed. However, it is not known whether the notable volatile depletions of planetary bodies are a consequence of accretion1 or inherited from prior nebular fractionation2. The isotopic compositions of the main constituents of planetary bodies can contribute to this debate3, 4, 5, 6. Here we develop an analytical approach that corrects a major cause of measurement inaccuracy inherent in conventional methods, and show that all differentiated bodies have isotopically heavier magnesium compositions than chondritic meteorites. We argue that possible magnesium isotope fractionation during condensation of the solar nebula, core formation and silicate differentiation cannot explain these observations. However, isotopic fractionation between liquid and vapour, followed by vapour escape during accretionary growth of planetesimals, generates appropriate residual compositions. Our modelling implies that the isotopic compositions of magnesium, silicon and iron, and the relative abundances of the major elements of Earth and other planetary bodies, are a natural consequence of substantial (about 40 per cent by mass) vapour loss from growing planetesimals by this mechanism

Genetic and environmental influences on total plasma homocysteine and its role in coronary artery disease risk.

BACKGROUND: Elevated levels of total plasma homocysteine are a risk factor for atherosclerotic disease. AIMS: The rationale behind this study is to explore the correlation between degree and site of coronary lesion and hyperhomocysteinemia in Lebanese CAD patients and assess environmental and genetic factors for elevated levels of total plasma homocysteine. METHODS: A total of 2644 patients were analyzed for traditional CAD risk factors. Logistic regression was performed to determine the association of hyperhomocysteinemia with degree and site of coronary lesions controlling for risk factors. Environmental and genetic factors for hyperhomocysteinemia were analyzed by logistic regression using a candidate gene approach. RESULTS: Traditional risk factors were correlated with stenosis. Hyperhomocysteinemia associated with increased risk of overall stenosis, and risk of mild and severe occlusion in major arteries. Hyperhomocysteinemia and hypertension were highly correlated suggesting that hyperhomocysteinemia acts as a hypertensive agent leading to CAD. Diuretics and genetic polymorphisms in MTHFR and SLCO1B1 were associated with hyperhomocysteinemia. CONCLUSIONS: Hyperhomocysteinemia is a medical indicator of specific vessel stenosis in the Lebanese population. Hypertension is a major link between hyperhomocysteinemia and CAD occurrence. Genetic polymorphisms and diuretics' intake explain partly elevated homocysteine levels. This study has important implications in CAD risk prediction

Thermochemical interpretation of 1-D seismic data for the lower mantle : The significance of nondiabatic thermal gradients and compositional heterogeneity

International audienceEquation-of-state (EOS) modeling, whereby the seismic properties of a specified thermochemical structure are constructed from mineral physics constraints, and compared with global seismic data, provides a potentially powerful tool for distinguishing between plausible mantle structures. However, previous such studies at lower mantle depths have been hampered by insufficient evaluation of mineral physics uncertainties, overestimation of seismic uncertainties, or biases in the type of seismic and/or mineral physics data used. This has led to a wide, often conflicting, variety of models being proposed for the average lower mantle structure. In this study, we perform a thorough reassessment of mineral physics and seismic data uncertainties. Uncertainties in both the type of EOS, and mineral elastic parameters, used are taken into account. From this analysis, it is evident that the seismic variability due to these uncertainties is predominantly controlled by only a small subset of the mineral parameters. Furthermore, although adiabatic pyrolite cannot be ruled out completely, it is problematic to explain seismic velocities and gradients at all depth intervals with such a structure, especially in the interval 1660­2000 km. We therefore consider a range of alternative thermal and chemical structures, and map out the sensitivity of average seismic velocities and gradients to deviations in temperature and composition. Compositional sensitivity is tested both in terms of plausible end-member compositions (e.g., MORB, chondrite), and via changes in each of the five major mantle oxides, SiO2, MgO, FeO, CaO, and Al2O3. Fe enrichment reduces both P and S velocities significantly, while Si enrichment (and Mg depletion) increases P and S velocities, with a larger increase in P than in S. Using purely thermal deviations from adiabatic pyrolite, it remains difficult to explain simultaneously all seismic observations. A superadiabatic temperature gradient does improve the seismic fit in the lowermost mantle, but should be accompanied by concurrent bulk chemistry changes. Our results suggest that the most plausible way to alter bulk chemistry in the lowermost mantle, simultaneously fitting density, bulk velocity and shear velocity constraints, is an increasing contribution of a hot, basalt-enriched component with depth

Properties of lower-mantle Al-(Mg,Fe)SiO3 perovskite

The properties of the main lower-mantle phase appear to be more complex than expected. The common procedure of using the properties of the simplified MgSiO3 (and [Mg,Fe]SiO3) composition for direct analogy to the Al-bearing (Mg,Fe)SiO3 lower-mantle perovskite can lead to significant misinterpretations. The presence of Al and Fe affects the equation of state, the defect population, the ability of this phase to insert minor and trace elements, and the transport properties, etc. Some difficulties remain for the quantitative determination of these effects because of two main reasons: many experimental techniques are ineffective because silicate perovskite is metastable at ambient conditions, and the crystal chemistry of Al-(Mg,Fe)SiO3 perovskite is complex and can evolve with pressure, temperature, and chemical composition. This paper reviews the recent progress made in the determination of its properties and presents additional new results from our group. The original data concern the pressure- volume-temperature (P-V-T) equation of state of Al-(Mg,Fe)SiO3 perovskite, the change of oxidation state (dismutation) of Fe2+ into a mixture of Fe3+ and Fe0, which drives the lower-mantle oxygen fugacity to the Fe/(Mg,Fe)O buffer, and the stability of the (Mg,Fe)SiO3 perovskite to the highest pressure and temperature conditions