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

MOESM1 of Changes in waist circumference and risk of all-cause and CVD mortality: results from the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) cohort study

Additional file 1. Supplementary information. Baseline characteristics of EPIC-Norfolk men and women who attended 1HE, and those who attended both 1HE and 2HE, before and after exclusion criteria were applied. Cox multivariable-adjusted HRs after 16 years of follow-up for CVD mortality in 5469 men

Odds ratios for CHD in men and women, EPIC-Norfolk 1993–2009 by quartile of plasma PFA mol%, age and sex adjusted, and multivariate adjusted and as a continuous variable, per approximate standard deviation increase.

<p><i>p</i>-Value derived from Wald statistic. PFAs grouped according to quartiles of mo% total FAs.</p>a<p>BMI, smoking, alcohol intake, physical activity, plasma vitamin C, social class, education, diabetes, systolic blood pressure.</p>b<p>BMI, smoking, alcohol intake, physical activity, plasma vitamin C, social class, education, diabetes, systolic blood pressure, and cholesterol.</p

Additional file 1: of Prospective association of the Mediterranean diet with cardiovascular disease incidence and mortality and its population impact in a non-Mediterranean population: the EPIC-Norfolk study

Text S1. Scoring method of the four Mediterranean diet scores. Table S1. Mediterranean dietary pattern scores, components and corresponding food frequency questionnaire items used in EPIC-Norfolk. Table S2. Pyramid based Mediterranean diet score (PyrMDS) scoring criteria. Table S3. Characteristics of dietary consumption of components of the Mediterranean diet at baseline and follow-up among 23,902 adults in EPIC-Norfolk. Table S4. Prospective association between fifths of the degree of adherence to the Mediterranean diet and incident cardiovascular diseases in EPIC-Norfolk (n = 23,902, 7606 cases/269,935 person-years). Table S5. Associations of adherence to the Mediterranean diet with incident CVD when two measures of the adherence were evaluated simultaneously for comparison: EPIC-Norfolk Study. Table S6. Cardiovascular disease incidence or mortality and all-cause mortality, the number of cases and proportion preventable by increasing adherence to the Mediterranean diet to the top third of the Mediterranean dietary score based on the dietary pyramid: the EPIC-Norfolk cohort. Table S7. Prospective association between adherence to the Mediterranean diet and incident cardiovascular diseases in EPIC-Norfolk: sensitivity analysis to examine robustness of the findings across different analytical approaches. Figure S1. Prospective association between adherence to the Mediterranean diet and incidence of cardiovascular diseases in EPIC-Norfolk: sensitivity analysis to examine influence of each component of the Mediterranean diet. (DOCX 215 kb

Survival Function According to Number of Health Behaviours in Men and Women Aged 45–79 Years without Known Cardiovascular Disease or Cancer, Adjusted for Age, Sex, Body Mass Index and Social Class, EPIC-Norfolk 1993–2006

<p>Survival Function According to Number of Health Behaviours in Men and Women Aged 45–79 Years without Known Cardiovascular Disease or Cancer, Adjusted for Age, Sex, Body Mass Index and Social Class, EPIC-Norfolk 1993–2006</p

MOESM2 of Changes in behaviors after diagnosis of type 2 diabetes and 10-year incidence of cardiovascular disease and mortality

Additional file 2. Hazard ratios for the association of health behavior changes from baseline to 1 year and 10-year CVD and mortality incidence, adjusting for weight change from baseline to 1 year (N = 725)

MOESM4 of Changes in behaviors after diagnosis of type 2 diabetes and 10-year incidence of cardiovascular disease and mortality

Additional file 4. Hazard ratios for the associations of a behaviour change scoring method giving equal weight to dietary changes, and CVD and all-cause mortality. ADDITION-Cambridge 2002–2014 (N = 565*)

MOESM3 of Changes in behaviors after diagnosis of type 2 diabetes and 10-year incidence of cardiovascular disease and mortality

Additional file 3. Hazard ratios for the associations of health behavior changes from baseline to 1 year and 10-year CVD and mortality incidence, adjusting for individual behavior changes (N = 565*)

Baseline characteristics of participants by quartile of plasma saturated PFA concentration.

*<p><i>p</i>-Value using analysis of covariance.</p

MOESM1 of Changes in behaviors after diagnosis of type 2 diabetes and 10-year incidence of cardiovascular disease and mortality

Additional file 1. Hazard ratios for the associations of health behavior changes from baseline to 1 year and 10-year incidence of CVD and mortality, with multiple imputation* to account for missing data (N = 852)