Dataset Information

Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease.

ABSTRACT:

Importance

The relationship between exposure to lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) with the risk of cardiovascular disease has not been reliably quantified.

Objective

To assess the association of lifetime exposure to the combination of both lower LDL-C and lower SBP with the lifetime risk of cardiovascular disease.

Design, setting, and participants

Among 438?952 participants enrolled in the UK Biobank between 2006 and 2010 and followed up through 2018, genetic LDL-C and SBP scores were used as instruments to divide participants into groups with lifetime exposure to lower LDL-C, lower SBP, or both. Differences in plasma LDL-C, SBP, and cardiovascular event rates between the groups were compared to estimate associations with lifetime risk of cardiovascular disease.

Exposures

Differences in plasma LDL-C and SBP compared with participants with both genetic scores below the median. Genetic risk scores higher than the median were associated with lower LDL-C and lower SBP.

Main outcomes and measures

Odds ratio (OR) for major coronary events, defined as coronary death, nonfatal myocardial infarction, or coronary revascularization.

Results

The mean age of the 438 952 participants was 65.2 years (range, 40.4-80.0 years), 54.1% were women, and 24?980 experienced a first major coronary event. Compared with the reference group, participants with LDL-C genetic scores higher than the median had 14.7-mg/dL lower LDL-C levels and an OR of 0.73 for major coronary events (95% CI, 0.70-0.75; P?Conclusions and relevanceLifelong genetic exposure to lower levels of low-density lipoprotein cholesterol and lower systolic blood pressure was associated with lower cardiovascular risk. However, these findings cannot be assumed to represent the magnitude of benefit achievable from treatment of these risk factors.

SUBMITTER: Ference BA

PROVIDER: S-EPMC6724415 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease.

Ference Brian A BA Bhatt Deepak L DL Catapano Alberico L AL Packard Chris J CJ Graham Ian I Kaptoge Stephen S Ference Thatcher B TB Guo Qi Q Laufs Ulrich U Ruff Christian T CT Cupido Arjen A Hovingh G Kees GK Danesh John J Holmes Michael V MV Smith George Davey GD Ray Kausik K KK Nicholls Stephen J SJ Sabatine Marc S MS

JAMA 20191001 14

<h4>Importance</h4>The relationship between exposure to lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) with the risk of cardiovascular disease has not been reliably quantified.<h4>Objective</h4>To assess the association of lifetime exposure to the combination of both lower LDL-C and lower SBP with the lifetime risk of cardiovascular disease.<h4>Design, setting, and participants</h4>Among 438 952 participants enrolled in the UK Biobank between 2006 and 2 ...[more]

PMID: 31475726

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Project description:BackgroundPrevious work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.MethodsComputationally predicted damaging or loss-of-function (REVEL>0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n=1,062,595).ResultsCarriers of 45 predicted damaging or loss-of-function CCR2 variants (n=787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n=585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (Odds Ratio [OR]: 0.66 95% Confidence Interval [CI]: 0.54-0.81, p=6.1×10-5) and coronary artery disease (OR: 0.74 95%CI: 0.63-0.87, p=2.9×10-4) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.ConclusionsCarriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

Dataset Information

Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease.

Importance

Objective

Design, setting, and participants

Exposures

Main outcomes and measures

Results

Publications

Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease.

Similar Datasets

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