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

Patient factors associated with MMAS

†<p>-P<0.05</p

Characteristics of hypertension and anti-hypertensive treatment

†<p>-P<0.05</p><p>HTN–Hypertension, BP–Blood pressure.</p

Factors that, in the patient’s views, encouraged or discouraged the patient’s drug taking behavior

†<p>-P<0.05</p

Awareness about hypertension and anti-hypertensive treatment

†<p>-P<0.05</p><p>HTN–Hypertension, BP–Blood pressure.</p

Demographic and clinical characteristics of the study population

†<p>-P<0.05</p><p>HTN–Hypertension, PKR–Pakistani Rupee, AKU–Aga Khan University Hospital, NICVD–National Institute of Cardiovascular Diseases, AKU-ADS-Aga Khan University-Anxiety and Depression Scale, Hx. –History</p

Il futuro del personalismo fra etica e politica

Il personalismo rappresenta nella storia del pensiero politico una posizione che intende superare sia l'individualismo sia il collettivismo. Caratteristica fondamentale delle diverse concezioni del personalismo è la sua disposizione a difendere la sfera dell'uomo dalle invadenze di poteri assoluti e dispotici, che nel mondo contemporaneo assumono il volto del totalitarismo .Con la fine delle ideologie e la caduta delle utopie, il personalismo ha anche la funzione di criticare la tendenza delle società liberaldemocratiche e consumiste verso nuove forme di anomie e di controllo sociale della persona con la potenza dei nuovi media.Personality represents in the history of political thought a position that goes beyond both individualism and collectivism. The fundamental feature of the different conceptions of personalism is its disposition to defend the sphere of man from the invasions of absolute and despotic powers that in the contemporary world assume the face of totalitarianism. With the end of ideologies and the fall of utopias, personalism has It is also the function of criticizing the tendency of liberaldemocratic and consumer societies towards new forms of anomie and social control of the person with the power of the new media

Relevance in population surveys of study place and time to (i) the mean general population serum folate level, and (ii) the excess plasma homocysteine level in the TT versus CC <i>MTHFR</i> C677T genotype.

a<p>Mean folate levels average all who were surveyed; SE denotes the standard error due only to within-survey variation. Between-survey variation in folate levels is illustrated in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001177#pmed-1001177-g001" target="_blank">Figure 1</a>.</p>b<p>From inverse-variance-weighted averages of within-study differences in log homocysteine; <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001177#pmed.1001177.s001" target="_blank">Figure S1</a>, Table S2 in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001177#pmed.1001177.s006" target="_blank">Text S1</a>.</p>c<p>Mainly of Japanese, Chinese, or Korean populations; none of South Asians.</p

Homozygote CHD OR (TT versus CC <i>MTHFR</i> C677T genotype) in 19 unpublished datasets, yielding 24 parts that are classified by genotyping panel size.

<p>For these datasets, being unpublished introduces a negligible bias (less than 0.3% for each OR and about 0.1% for the overall OR: eAppendix 1). Black squares indicate OR (with areas inversely proportional to the variance of log OR), and horizontal lines indicate 99% CIs. The subtotals and their 99% CIs are indicated by black diamonds. The overall OR and its 95% CI is indicated by a white diamond. The weight (defined as the inverse of the variance of the maximum likelihood estimate of the log OR) and the product of the weight times OR indicates how much each study has contributed to the subtotals and totals. Because the weights and products are approximately additive, they can be used to estimate the effects of ignoring particular studies, or of grouping studies in different ways.</p

Homozygote CHD OR (TT versus CC <i>MTHFR</i> C677T genotype) in each probable folate status category, from meta-analyses of 86 published studies, 14 large (i.e., variance of log OR less than 0.05) and 72 smaller studies.

<p>Black squares indicate OR (with areas inversely proportional to the variance of log OR in each subdivision), and horizontal lines indicate 99% CIs. The overall OR and its 95% CI are indicated by a black diamond. Average homocysteine difference (in the non-CHD general population) for all areas and periods is weighted in proportion to the numbers of TT CHD cases in all 86 studies.</p