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

Additional file 1: of Association of NOS3 gene polymorphisms with essential hypertension in Sudanese patients: a case control study

Questionnaire data. This excel file contains data collected by interviewed questionnaire from both patients and controls. Also the file contain BMI measurement, blood pressure measurements and lab investigation results. (XLSX 120 kb

Media 1: Ultrahigh-resolution, high-speed spectral domain optical coherence phase microscopy

Originally published in Optics Letters on 01 January 2014 (ol-39-1-45

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

Association analysis results in male 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

Association analysis results in female gout case-control sample.

<p>MAF: minor allele frequency; numbers of genotypes (11, 12, 22) according to alleles from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001948#pone-0001948-t003" target="_blank">Table 3</a>.</p><p>n. a.: not applicable due to low counts of minor allele for χ².</p

Schematic representation of a ∼1,214 kb region on human chromosome 4p16.1 (position 8,936,948 and 10,150,970; human genome build 18) used for association analyses.

<p>Position numbers are given on top. (A) Relative positions of SNPs analyzed in this study. GWA SNPs from WTCCC and Cardiogenics CAD/MI case-control study are shown above the four SNPs genotyped in this work (gt SNPs). From left to right: rs6855911, rs7442295, rs6449213, and rs12510549. (B) Graphic illustration of genes in this genomic region. Relative positions of RefSeq genes with gene names are presented. Exons are depicted as vertical blocks and orientation of genes is indicated by arrows on the horizonal lines representing introns. <i>GLUT9</i> gene is highlighted with bold letters. (C) Delineation of LD structure. Pairwise <i>r</i>²-values between markers from HapMap phase II release 22 for the CEPH (CEU) sample were calculated and presented. Red denotes perfect LD with <i>r</i>² = 1 and decreasing <i>r</i>²-values are shown in brighter color with white representing <i>r</i>² = 0.</p