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

Maximum daily temperature (solid line) and mean daily relative humidity (dashed line) data recorded in a field cage over course of the experiment.

<p>The marked Periods indicate the duration of each experiment.</p

Delta trap: assembled (left) and opened (right) with grids marked A-F horizontally and 1-10 vertically, to hold 60 moths.

<p>The inner, white surface is coated with glue, which traps any insects that come into contact with it.</p

Reliability of DsRed2 fluorescent marker over time, during the four experimental periods.

<p>In each graph, the dashed line represents results from the trap kept in the laboratory at 26°C, and the solid lines represent traps kept in the field cage.</p

Mean reliability (traps combined) of DsRed2 fluorescent marker over time for Periods 1-4.

<p>Mean reliability (traps combined) of DsRed2 fluorescent marker over time for Periods 1-4.</p

Genotyping moths by PCR.

<p>(a) Schematic diagram showing genotyping PCR reactions for the OX1138B transgene insertion and its wild-type counterpart. The junction of the OX1138B insertion site in the wild-type sequence is indicated by the TTAA nucleotide sequence (<i>piggyBac</i> transposase recognition sequence which is duplicated on insertion of the <i>piggy</i>Bac transposon). Primers and binding sites for primers A, B and C are indicated. PCR reactions containing primers A and B will amplify a fragment of 580 bp from OX1138B genomic DNA and no fragment from wild-type genomic DNA. PCR reactions containing primers A and C will amplify a fragment of 336 bp from wild-type genomic DNA and no fragment from OX1138B-homozygous genomic DNA. A moth that is heterozygous for the OX1138B insertion – carrying both the OX1138B and wild-type loci – would yield the amplified fragments in both PCR reactions. In OX1138B-positive genomic DNA, primers A and C would theoretically yield an amplified fragment, but the distance is usually too great for the PCR to amplify. (b) Gel images showing PCR genotyping results of moths from an experimental field cage trap (samples 1–10), a known wild-type moth (sample 11) and a known OX1138B-homozygous moth (sample 12). PCR for the transgene insertion yields the 580 bp fragment OX1138B moths (samples 1–5, 7 and 9) and PCR for the wild-type (no transgene insertion) locus yields the 336 bp fragment in APHIS moths (samples 6, 8 and 10). In the latter PCRs, amplification of the whole sequence spanning the transgene insertion is achieved, as seen in the reaction for sample 12.</p

Photographs showing wild-type (left) and OX1138B (right) adult moths under bright field and DsRed2 excitation wavelength light, respectively.

<p>Photographs showing wild-type (left) and OX1138B (right) adult moths under bright field and DsRed2 excitation wavelength light, respectively.</p

A randomized controlled trial to investigate the effects of intra-dialytic cycling on left ventricular mass

Cardiovascular disease is the leading cause of death for patients receiving hemodialysis. Since exercise mitigates many risk factors which drive cardiovascular disease for these patients, we assessed effects of a program of intra-dialytic cycling on left ventricular mass and other prognostically relevant measures of cardiovascular disease as evaluated by cardiac MRI (the CYCLE-HD trial). This was a prospective, open-label, single-blinded cluster-randomized controlled trial powered to detect a 15g difference in left ventricular mass measured between patients undergoing a six-month program of intra-dialytic cycling (exercise group) and patients continuing usual care (control group). Pre-specified secondary outcomes included measures of myocardial fibrosis, aortic stiffness, physical functioning, quality of life and ventricular arrhythmias. Outcomes were analyzed as intention-to-treat according to a pre-specified statistical analysis plan. Initially, 130 individuals were recruited and completed baseline assessments (65 each group). Ultimately, 101 patients completed the trial protocol (50 control group and 51 exercise group). The six-month program of intra-dialytic cycling resulted in a significant reduction in left ventricular mass between groups (-11.1g; 95% confidence interval -15.79, -6.43), which remained significant on sensitivity analysis (missing data imputed) (-9.92g; 14.68, -5.16). There were significant reductions in both native T1 mapping and aortic pulse wave velocity between groups favoring the intervention. There was no increase in either ventricular ectopic beats or complex ventricular arrhythmias as a result of exercise with no significant effect on physical function or quality of life. Thus, a six-month program of intradialytic cycling reduces left ventricular mass and is safe, deliverable and well tolerated

A randomized controlled trial to investigate the effects of intra-dialytic cycling on left ventricular mass

Cardiovascular disease is the leading cause of death for patients receiving hemodialysis. Since exercise mitigates many risk factors which drive cardiovascular disease for these patients, we assessed effects of a program of intra-dialytic cycling on left ventricular mass and other prognostically relevant measures of cardiovascular disease as evaluated by cardiac MRI (the CYCLE-HD trial). This was a prospective, open-label, single-blinded cluster-randomized controlled trial powered to detect a 15g difference in left ventricular mass measured between patients undergoing a six-month program of intra-dialytic cycling (exercise group) and patients continuing usual care (control group). Pre-specified secondary outcomes included measures of myocardial fibrosis, aortic stiffness, physical functioning, quality of life and ventricular arrhythmias. Outcomes were analyzed as intention-to-treat according to a pre-specified statistical analysis plan. Initially, 130 individuals were recruited and completed baseline assessments (65 each group). Ultimately, 101 patients completed the trial protocol (50 control group and 51 exercise group). The six-month program of intra-dialytic cycling resulted in a significant reduction in left ventricular mass between groups (-11.1g; 95% confidence interval -15.79, -6.43), which remained significant on sensitivity analysis (missing data imputed) (-9.92g; 14.68, -5.16). There were significant reductions in both native T1 mapping and aortic pulse wave velocity between groups favoring the intervention. There was no increase in either ventricular ectopic beats or complex ventricular arrhythmias as a result of exercise with no significant effect on physical function or quality of life. Thus, a six-month program of intradialytic cycling reduces left ventricular mass and is safe, deliverable and well tolerated