Genome-wide association study of peripheral artery disease in the Million Veteran Program

Klarin, Derek; Lynch, Julie; Aragam, Krishna; Chaffin, Mark; Assimes, Themistocles L.; Huang, Jie; Lee, Kyung Min; Shao, Qing; Huffman, Jennifer E.; Natarajan, Pradeep; Arya, Shipra; Small, Aeron; Sun, Yan V.; Vujkovic, Marijana; Freiberg, Matthew S.; Wang, Lu; Chen, Jinbo; Saleheen, Danish; Lee, Jennifer S.; Miller, Donald R.; Reaven, Peter D.; Alba, Patrick R.; Patterson, Olga V.; DuVall, Scott L.; Boden, William E.; Beckman, Joshua A.; Gaziano, J. Michael; Concato, John; Rader, Daniel J.; Cho, Kelly; Chang, Kyong–Mi; Wilson, Peter W.F.; O’Donnell, Christopher J.; Kathiresan, Sekar; Program, VA Million Veteran; Tsao, Philip S.; Damrauer, Scott M.

doi:10.1038/s41591-019-0492-5

Cited by 198 publications

(233 citation statements)

References 55 publications

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“…Lipoprotein(a) is also likely a causal risk factor for peripheral vascular disease and aortic stenosis 10,35 , and, to a lesser extent, ischemic stroke 12,36 . Since there is considerable overlap of risk factors between these cardiovascular conditions and CAD 37 , we sought to assess if CAD GRSs also modulate the risk of these conditions among individuals with elevated lipoprotein(a).…”

Section: Effect Of Coronary Artery Disease Genomic Risk Score On Othementioning

confidence: 99%

Polygenic modulation of lipoprotein(a)-associated cardiovascular risk

Trinder¹,

Brunham

2020

Preprint

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Aims: Elevated levels of lipoprotein(a) are one of the strongest inherited risk factors for coronary artery disease (CAD). However, there is variability in cardiovascular risk among individuals with elevated lipoprotein(a). The sources of this variability are incompletely understood. We assessed the effects of a genomic risk score (GRS) for CAD on risk of myocardial infarction among individuals with elevated lipoprotein(a). Methods: We calculated CAD GRSs for 408,896 individuals of British white ancestry from the UK Biobank using 6.27 million common genetic variants. Lipoprotein(a) levels were measured in 310,020 individuals. The prevalence and risk of myocardial infarction versus CAD GRS percentiles were compared for individuals with and without elevated lipoprotein(a) defined as ≥120 or 168 nmol/L (≈50 or 70 mg/dL, respectively). Results: Individuals with elevated lipoprotein(a) displayed significantly greater CAD GRSs than individuals without elevated lipoprotein(a), which was largely dependent on the influence of genetic variants within or near the LPA gene. Continuous levels of CAD GRS percentile were significantly associated with risk of myocardial infarction for individuals with elevated lipoprotein(a). Notably, the risk of myocardial infarction for males with elevated lipoprotein(a) levels, but a CAD GRS percentile in the lower quintile (<20th percentile), was less than the overall risk of myocardial infarction for males with non-elevated lipoprotein(a) levels (hazard ratio [95% CI]: 0.79 [0.64-0.97], p=0.02). Similar results were observed for females. Conclusion: These data suggest that CAD genomic scores influence cardiovascular risk among individuals with elevated lipoprotein(a) and may aid in identifying candidates for preventive therapies.

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Section: Effect Of Coronary Artery Disease Genomic Risk Score On Othementioning

confidence: 99%

Polygenic modulation of lipoprotein(a)-associated cardiovascular risk

Trinder¹,

Brunham

2020

Preprint

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“…Recently, large genome-wide association studies of smoking, coronary artery disease, stroke, and peripheral artery disease have identified genetic loci associated with each of these conditions. [8][9][10][11] The Mendelian randomization (MR) framework leverages the natural randomization of genetic variation at conception (under certain assumptions) to mitigate the risk of confounding when estimating relationships between traits. Therefore, this approach may allow for more precise quantification of potential differences between exposure-outcome pairs.…”

Section: Introductionmentioning

confidence: 99%

Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases: A Mendelian Randomization Study

Levin

Klarin

Assimes

et al. 2020

Preprint

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Importance: Smoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood. Objective: To determine the effect of smoking on risk of coronary artery disease, peripheral artery disease, and large-artery stroke. Design: Mendelian randomization study using summary statistics from genome-wide associations of smoking (up to 462,690 individuals), coronary artery disease (up to 60,801 cases, 123,504 controls), peripheral artery disease (up to 24,009 cases, 150,983 controls), and large-artery stroke (up to 4,373 cases, 406,111 controls) Setting: Population-based study of primarily European-ancestry individuals Participants: Participants in genome-wide association studies of smoking, coronary artery disease, peripheral artery disease, and stroke. Exposures: Genetic liability to smoking defined by lifetime smoking index: an integrated measure of smoking status, age at initiation, age at cessation, number of cigarettes smoked per day, and declining effect of smoking on health outcomes). Main Outcome Measure: Risk of coronary artery disease, peripheral artery disease, and large-artery stroke. Results: Genetic liability to smoking was associated with increased risk of PAD (OR 2.13; 95% CI 1.78-2.56; P = 3.6 x 10-16), CAD (OR 1.48; 95% CI 1.25-1.75; P = 4.4 x 10-6), and stroke (OR 1.4; 95% CI 1.02-1.92; P = 0.036). Risk of PAD in smokers was greater than risk of large-artery stroke (pdifference = 0.025) or CAD (pdifference = 0.0041). The effect of smoking on ASCVD remained independent from the effects of smoking on traditional cardiovascular risk factors. Conclusions and Relevance: Genetic liability to smoking is a strong, causal risk factor for CAD, PAD, and stroke, although the effect of smoking is strongest for PAD. The effect of smoking is independent of traditional cardiovascular risk factors.

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“…Recent efforts have demonstrated that a Veterans Health Administration–based biobank provides the ability to aid genetic discovery for understudied vascular diseases with a higher prevalence among US veterans. 10 , 11 Leveraging the MVP resource, we sought to perform a genetic discovery analysis for AAA; explore the spectrum of phenotypic consequences associated with AAA risk variants; examine the genetic relationship between smoking and blood pressure and AAA; test the effects of AAA risk variants on aneurysms in other territories; and develop and evaluate a genome-wide polygenic risk score (PRS) for AAA to identify a subset of the population at higher risk for disease.…”

mentioning

confidence: 99%

Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program

Klarin¹,

Verma²,

Judy³

et al. 2020

Circulation

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Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P =1.6×10 −6 ), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P =0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratio PRS , 1.26 [95% CI, 1.18–1.36]; P PRS =2.7×10 −11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratio PRS+family history+smoking , 1.24 [95% CI, 1.14–1.35]; P PRS =1.27×10 −6 ). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

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Genome-wide association study of peripheral artery disease in the Million Veteran Program

Cited by 198 publications

References 55 publications

Polygenic modulation of lipoprotein(a)-associated cardiovascular risk

Polygenic modulation of lipoprotein(a)-associated cardiovascular risk

Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases: A Mendelian Randomization Study

Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program

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