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

Meta-Analysis of Prospective Observational Studies of Serum Uric Acid and CHD in Essentially General Populations, Subdivided by Sex

<p>Conventions are the same as in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0020076#pmed-0020076-g001" target="_blank">Figure 1</a>. Combined odds ratios and their CIs are indicated by unshaded diamonds for subtotals and shaded diamonds for grand totals. +, adjustment reported only for age and sex; ++, adjustment for these plus smoking; +++, adjustment for these plus some additional established risk factors; ++++, adjustment for these plus existing cardiovascular disease. Study abbreviations: ARIC, Atherosclerosis Risk in Communities; BIRNH, Belgium Interuniversity Research on Nutrition and Health; BRHS, British Regional Heart Study; CHA, Chicago Heart Association Detection Project in Industry; GRIPS, Göttingen Risk Incidence and Prevalence Study; IIHDS, Israeli Ischemic Heart Disease Study; MONICA, World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease; NHANES, National Health and Nutrition Examination Survey; NHEFS, NHANES I Epidemiologic Follow-Up Study; PROCAM, Prospective Cardiovascular Munster Study.</p

Prospective Studies of the Association of Serum Uric Acid and CHD, Grouped by Various Characteristics

<p>Conventions are the same as in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0020076#pmed-0020076-g001" target="_blank">Figure 1</a>. *, each sex-specific estimate was treated as a “study”; †, two studies (6 and 13) were drawn from general practice registers; §, risk factors adjusted for included: smoking, blood pressure, total cholesterol, triglycerides, alcohol consumption, obesity, use of cardiovascular medication, history of hypertension, and history of diabetes. PTA, phosphotungstic acid.</p

Associations between Serum Uric Acid and CHD in 2,456 cases and 3,962 Controls in the Reykjavik Study at Different Levels of Established Risk Factors

<p>Squares indicate odds ratios, with the size of the square proportional to the effective sample size.</p

Population numbers and CHD deaths in Iceland in 2010, and expected population numbers and CHD deaths in 2040 if 2010 rates persist.

<p>Population numbers and CHD deaths in Iceland in 2010, and expected population numbers and CHD deaths in 2040 if 2010 rates persist.</p

Data sources.

<p>CHD mortality in 2010 was not available.</p

Estimated deaths per 100.000 prevented or added in 2040.

<p>Estimated deaths by risk factor change, under three risk factor scenarios.</p

Future CHD mortality rate among 25–74 year old Icelanders in three different risk factor scenarios.

<p>Future CHD mortality rate among 25–74 year old Icelanders in three different risk factor scenarios.</p

Data on sample characteristics and risk factor values from the Reykjavik study (1981) and REFINE Reykjavik study (2006 and 2010).

<p>Data on sample characteristics and risk factor values from the Reykjavik study (1981) and REFINE Reykjavik study (2006 and 2010).</p

CHD deaths per 100,000 prevented or added as a result of risk factor changes, under three cardiovascular risk factor scenarios.

<p>May not sum to total due to rounding.</p