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

Scott MS JPaleo data file

Excel file of species and measurements of morphological parameter

Reconstructing Palaeozoic and Mesozoic tectonic evolution of Novaya Zemlya: combing geochronology and thermochronology

Detrital zircon U–Pb LA-ICP-MS data of samples from Novaya Zemlya

Additional file 3: of Clinical and surgical risk factors in the development of proliferative vitreoretinopathy following retinal detachment surgery: a systematic review protocol

Sample search strategy for MEDLINE. (61 kb

Additional file 2: of Clinical and surgical risk factors in the development of proliferative vitreoretinopathy following retinal detachment surgery: a systematic review protocol

Inclusion/exclusion criteria. (69 kb

Historic catch rates comparison and total catch of Patagonian toothfish.

<p>Gray bars show total catch of toothfish, blue line shows catch rates without mammals at the longline set, and red line shows catch rates when orcas were observed at the longline set.</p

Difference in catch rates under various depredation scenarios.

<p>Mean difference (Tukey’s honest statistical difference) in catch rates of the three main mammal scenarios to the no-mammal scenario around South Georgia. P—present, F—feeding. Originally 21 scenarios were calculated (orcas, sperm whales, fur seals: present/ absent, feeding/not feeding, and combinations of these) and the three most damaging scenarios to catch rates were chosen to be graphically represented. No-mammal-scenario average catch rates: Shag rocks = 300±0.06 g, North West = 233±0.05 g, North East = 276±0.07 g, South West = 253±0.05 g, and South East = 272±0.08 g of toothfish/hook. Stars denote difference between mammal scenarios.</p

Mammal movements over the winter season.

<p>Observations per unit effort (animals/longline/box) of orcas, fur seals and sperm whales around South Georgia throughout the winter season.</p

Additional file 1: Supplemental Information. of A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans

Figure S1. In-silico predictions of the impact of premature termination codon p.Q121X suggests that the variant would trigger nonsensemediated decay. Table S1. ANGPTL8 p.Q121X and type 2 diabetes status by study. (PDF 145 kb

Novel Microtubule-Targeting 7‑Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities

Docking studies of tubulin-targeting C2-substituted 7-deazahypoxanthine analogues of marine alkaloid rigidins led to the design and synthesis of compounds containing linear C2-substituents. The C2-alkynyl analogue was found to have double- to single-digit nanomolar antiproliferative IC₅₀ values and showed statistically significant tumor size reduction in a colon cancer mouse model at nontoxic concentrations. These results provide impetus and further guidance for the development of these rigidin analogues as anticancer agents