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

Forest plot of multivariate adjusted relative risk for CKD incidence associated with continuous values of serum uric acid (mg/dL).

<p>Forest plot of multivariate adjusted relative risk for CKD incidence associated with continuous values of serum uric acid (mg/dL).</p

The association between serum uric acid (mg/dL) and decline in estimated glomerular filtration rate (ml/min per 1.73 m²).

*<p>CI: confidence interval.</p>**<p>Adjusted for age, sex, and baseline eGFR.</p>†<p>Adjusted for age, sex, systolic blood pressure, body mass index, alcohol consumption, smoking, high density lipoprotein, diabetes mellitus, coronary heart disease, total cholesterol, and the use of diuretics, beta blockers, calcium channel blockers, ACE inhibitors, and baseline eGFR.</p

Baseline characteristics of the participants in different quartiles of uric acid levels.

*<p>To convert to SI unit multiply by 59.48.</p>**<p>P-value adjusted for age and sex for continuous measure of uric acid.</p>†<p>Standard Deviation.</p

The association between serum uric acid (mg/dL) and incidence of chronic kidney disease.

*<p>HR: hazard ratio.</p>**<p>CI: confidence interval.</p>†<p>Adjusted for age, sex, and baseline eGFR.</p>††<p>Adjusted for age, sex, systolic blood pressure, body mass index, alcohol consumption, smoking, high density lipoprotein, diabetes mellitus, coronary heart disease, total cholesterol, diuretics, beta blockers, calcium channel blockers, ACE inhibitors, and baseline eGFR.</p

Association of serum uric acid with kidney function in normotensive and hypertensive subjects (A) Annual decline in eGFR in relation to serum uric acid quartiles in hypertensive and normotensive participants.

<p>Analyses are adjusted for age, sex and baseline eGFR. Quartiles are compared with participants in the first quartile of serum uric acid (<4.5 mg/dL) (<b>B</b>) Risk of incident CKD in relation to quartiles of serum uric acid level in hypertensive and normotensive participants. Analyses are adjusted for sex, age and baseline eGFR. All odds ratios are compared with participants in the first quartile of serum uric acid (<4.5 mg/dL).</p

Flow diagram of studies through the different phases of the meta-analysis.

<p>Flow diagram of studies through the different phases of the meta-analysis.</p

Population for analysis.

<p>Population for analysis.</p

Adiposity and risk of decline in glomerular filtration rate: meta-analysis of individual participant data in a global consortium

OBJECTIVE:To evaluate the associations between adiposity measures (body mass index, waist circumference, and waist-to-height ratio) with decline in glomerular filtration rate (GFR) and with all cause mortality. DESIGN:Individual participant data meta-analysis. SETTING:Cohorts from 40 countries with data collected between 1970 and 2017. PARTICIPANTS:Adults in 39 general population cohorts (n=5 459 014), of which 21 (n=594 496) had data on waist circumference; six cohorts with high cardiovascular risk (n=84 417); and 18 cohorts with chronic kidney disease (n=91 607). MAIN OUTCOME MEASURES:GFR decline (estimated GFR decline ≥40%, initiation of kidney replacement therapy or estimated GFR <10 mL/min/1.73 m2) and all cause mortality. RESULTS:Over a mean follow-up of eight years, 246 607 (5.6%) individuals in the general population cohorts had GFR decline (18 118 (0.4%) end stage kidney disease events) and 782 329 (14.7%) died. Adjusting for age, sex, race, and current smoking, the hazard ratios for GFR decline comparing body mass indices 30, 35, and 40 with body mass index 25 were 1.18 (95% confidence interval 1.09 to 1.27), 1.69 (1.51 to 1.89), and 2.02 (1.80 to 2.27), respectively. Results were similar in all subgroups of estimated GFR. Associations weakened after adjustment for additional comorbidities, with respective hazard ratios of 1.03 (0.95 to 1.11), 1.28 (1.14 to 1.44), and 1.46 (1.28 to 1.67). The association between body mass index and death was J shaped, with the lowest risk at body mass index of 25. In the cohorts with high cardiovascular risk and chronic kidney disease (mean follow-up of six and four years, respectively), risk associations between higher body mass index and GFR decline were weaker than in the general population, and the association between body mass index and death was also J shaped, with the lowest risk between body mass index 25 and 30. In all cohort types, associations between higher waist circumference and higher waist-to-height ratio with GFR decline were similar to that of body mass index; however, increased risk of death was not associated with lower waist circumference or waist-to-height ratio, as was seen with body mass index. CONCLUSIONS:Elevated body mass index, waist circumference, and waist-to-height ratio are independent risk factors for GFR decline and death in individuals who have normal or reduced levels of estimated GFR