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

Genomewide association analysis of coronary artery disease

Background - Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. Methods - We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Results - Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10–14 and P=3.40x10–6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). Conclusions - We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease

Elevated C-reactive protein in atherosclerosis--chicken or egg?

Elevated C-reactive protein in atherosclerosis--chicken or egg

Sorting out cholesterol and coronary artery disease

Sorting out cholesterol and coronary artery diseas

ST segment detail.

<p>Recordings show baseline ST depression in both recording channels (left tracing). During an automatically detected ischemic event at 20 h 26 min 59s an additional transient ST depression occurs in channel 1 (arrow, right tracing).</p

Typical left ventricular apical ballooning.

<p>Left ventriculography in right anterior oblique projection during diastole (1a) and systole (1b) demonstrating akinesia of the apical and midventricular segments. Selective coronary angiograms of the left (1c) and right coronary artery (1d) excluding obstructive coronary artery disease.</p

Automatic analysis of ST segment changes during Holter recording.

<p>The upper image depicts the deviation of the J +80 measurement point (80 ms after J point) within a 10 minute period (pt. no. 7). At 20 h 26 min 50 s an ischemic episode of 2 min 45s duration was detected. J +80 measurement point deviation >100 µV is marked in black. The lower image depicts the corresponding heart rate (HR).</p

Association analysis results in female gout case-control sample.

<p>Numbers of genotypes (11, 12, 22) according to alleles from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007729#pone-0007729-t003" target="_blank">Table 3</a>.</p>a<p>Model including medication with diuretics, lipid lowering and antihypertensive therapy, HDL-C, type 2 diabetes, smoking, and BMI.</p

SNP marker used in analysis.

a<p>on human genome build 18.</p>b<p>in total sample (<i>n</i> = 4,960).</p

Characteristics of gout case and control study sample.

<p>Values denote means±standard deviations unless indicated otherwise. n. s., not significant; CAD, coronary artery disease; MI, myocardial infarction; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; BMI, body mass index.</p>a<p>At inclusion to study.</p>b<p>Defined as LDL-C ≥160 mg/dL or intake of lipid lowering medication.</p>c<p>Defined as blood pressure ≥140/90 mmHg or ongoing antihypertensive therapy.</p>d<p>Defined as history of diabetes mellitus or intake of antidiabetic medication.</p>e<p>Former or current smoking habit.</p