Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height ...within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation.
In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio OR 1.34; 95% CI 1.29 to 1.40; p = 5 × 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations.
In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cardiovascular disease is the leading contributor to years lost due to disability or premature death among adults. Current efforts focus on risk prediction and risk factor mitigation' which have been ...recognized for the past half-century. However, despite advances, risk prediction remains imprecise with persistently high rates of incident cardiovascular disease. Genetic characterization has been proposed as an approach to enable earlier and potentially tailored prevention. Rare mendelian pathogenic variants predisposing to cardiometabolic conditions have long been known to contribute to disease risk in some families. However, twin and familial aggregation studies imply that diverse cardiovascular conditions are heritable in the general population. Significant technological and methodological advances since the Human Genome Project are facilitating population-based comprehensive genetic profiling at decreasing costs. Genome-wide association studies from such endeavors continue to elucidate causal mechanisms for cardiovascular diseases. Systematic cataloging for cardiovascular risk alleles also enabled the development of polygenic risk scores. Genetic profiling is becoming widespread in large-scale research, including in health care-associated biobanks, randomized controlled trials, and direct-to-consumer profiling in tens of millions of people. Thus, individuals and their physicians are increasingly presented with polygenic risk scores for cardiovascular conditions in clinical encounters. In this scientific statement, we review the contemporary science, clinical considerations, and future challenges for polygenic risk scores for cardiovascular diseases. We selected 5 cardiometabolic diseases (coronary artery disease, hypercholesterolemia, type 2 diabetes, atrial fibrillation, and venous thromboembolic disease) and response to drug therapy and offer provisional guidance to health care professionals, researchers, policymakers, and patients.
A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, ...it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR).
Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR odds ratio = 1.08, 95% confidence interval CI = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study.
We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of this study was to use Mendelian randomization (MR) to determine the causality of the association between smoking and 14 different cardiovascular diseases (CVDs).
Our primary genetic ...instrument comprised 361 single-nucleotide polymorphisms (SNPs) associated with smoking initiation (ever smoked regularly) at genome-wide significance. Data on the associations between the SNPs and 14 CVDs were obtained from the UK Biobank study (N = 367 643 individuals), CARDIoGRAMplusC4D consortium (N = 184 305 individuals), Atrial Fibrillation Consortium (2017 dataset; N = 154 432 individuals), and Million Veteran Program (MVP; N = 190 266 individuals). The main analyses were conducted using the random-effects inverse-variance weighted method and complemented with multivariable MR analyses and the weighted median and MR-Egger approaches. Genetic predisposition to smoking initiation was most strongly and consistently associated with higher odds of coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension. Genetic predisposition to smoking initiation was additionally associated with higher odds of deep vein thrombosis and pulmonary embolism in the UK Biobank but not with venous thromboembolism in the MVP. There was limited evidence of causal associations of smoking initiation with atrial fibrillation, aortic valve stenosis, thoracic aortic aneurysm, and intracerebral and subarachnoid haemorrhage.
This MR study supports a causal association between smoking and a broad range of CVDs, in particular, coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension.
The advent of endovascular repair for both thoracic aortic aneurysm and type B dissection has transformed the management of these disease processes. This study was undertaken to better define, ...compare, and contrast the national trends in hospital admissions, invasive treatments, and inpatient mortality of patients with thoracic aortic aneurysm and type B dissection in the National Inpatient Sample.
The cohort was derived from International Classification of Diseases, Ninth Revision diagnosis codes for thoracic aortic dissection and thoracic aortic or thoracoabdominal aortic aneurysm. Patients receiving type A dissection or ascending aortic repair during their index admission were excluded using International Classification of Diseases, Ninth Revision procedure codes. A total of 155,187 patients were available for analysis from 2000 to 2012.
Admissions for thoracic aortic aneurysm outnumbered the admissions for type B dissection (69.8% vs 30.2%; P < .001), and the number of admissions for aneurysm grew more rapidly during this time (132% vs 63%; P < .001). Thoracic endovascular aortic repair (TEVAR) for aneurysm experienced an increase in 2005, concordant with Food and Drug Administration approval of TEVAR for thoracic aortic aneurysm indication, then superseded open repair for thoracic aortic aneurysm from 2006 onward. Despite this, the rate of thoracic aortic aneurysm repair has remained relatively stable over time. TEVAR for dissection increased in 2006, superseded open repair in 2010, and continues to account for 50.5% of all dissection repairs. Overall, the number of type B dissection repairs has increased (P < .001), over and above the increase in number of admissions for type B dissection. Despite the increased trends of utilization of TEVAR for both aneurysm and type B dissection, the overall in-hospital mortality rate among patients admitted for either disease state has decreased steadily over time (P < .001).
Whereas admissions for thoracic aortic aneurysm disease have increased over time, the rate of aneurysm repair has been stable, although TEVAR has supplanted a proportion of open repairs. In contrast, whereas admissions for type B dissection have experienced a more modest increase, there has been a disproportionate increase in type B dissection repair, largely due to increased use of TEVAR. These results show embracing of endovascular technology for dissection through expansion of indication. Despite the increase in rate of repair for type B dissection, inpatient mortality rate was reduced in both aneurysm and dissection patients, influenced by appropriate selection of patients for intervention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aim
Predicting progression in diabetic kidney disease (DKD) is critical to improving outcomes. We sought to develop/validate a machine-learned, prognostic risk score (KidneyIntelX™) combining ...electronic health records (EHR) and biomarkers.
Methods
This is an observational cohort study of patients with prevalent DKD/banked plasma from two EHR-linked biobanks. A random forest model was trained, and performance (AUC, positive and negative predictive values PPV/NPV, and net reclassification index NRI) was compared with that of a clinical model and Kidney Disease: Improving Global Outcomes (KDIGO) categories for predicting a composite outcome of eGFR decline of ≥5 ml/min per year, ≥40% sustained decline, or kidney failure within 5 years.
Results
In 1146 patients, the median age was 63 years, 51% were female, the baseline eGFR was 54 ml min
−1
1.73 m
−2
, the urine albumin to creatinine ratio (uACR) was 6.9 mg/mmol, follow-up was 4.3 years and 21% had the composite endpoint. On cross-validation in derivation (
n
= 686), KidneyIntelX had an AUC of 0.77 (95% CI 0.74, 0.79). In validation (
n
= 460), the AUC was 0.77 (95% CI 0.76, 0.79). By comparison, the AUC for the clinical model was 0.62 (95% CI 0.61, 0.63) in derivation and 0.61 (95% CI 0.60, 0.63) in validation. Using derivation cut-offs, KidneyIntelX stratified 46%, 37% and 17% of the validation cohort into low-, intermediate- and high-risk groups for the composite kidney endpoint, respectively. The PPV for progressive decline in kidney function in the high-risk group was 61% for KidneyIntelX vs 40% for the highest risk strata by KDIGO categorisation (
p
< 0.001). Only 10% of those scored as low risk by KidneyIntelX experienced progression (i.e., NPV of 90%). The NRI
event
for the high-risk group was 41% (
p
< 0.05).
Conclusions
KidneyIntelX improved prediction of kidney outcomes over KDIGO and clinical models in individuals with early stages of DKD.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
BACKGROUND:The mechanism of adverse limb events associated with peripheral artery disease remains incompletely understood. We investigated whether microvascular disease is associated with amputation ...in a large cohort of veterans to determine whether microvascular disease diagnosed in any location increases the risk of amputation alone and in concert with peripheral artery disease.
METHODS:Participants in the Veterans Aging Cohort Study were recruited from April 1, 2003 through December 31, 2014. We excluded participants with known prior lower limb amputation. Using time-updated Cox proportional hazards regression, we analyzed the effect of prevalent microvascular disease (retinopathy, neuropathy, and nephropathy) and peripheral artery disease status on the risk of incident amputation events after adjusting for demographics and cardiovascular risk factors.
RESULTS:Among 125 674 veterans without evidence of prior amputation at baseline, the rate of incident amputation over a median of 9.3 years of follow-up was 1.16 per 1000 person-years, yielding a total of 1185 amputations. In time-updated multivariable-adjusted analyses, compared with those without peripheral artery disease or microvascular disease, microvascular disease alone was associated with a 3.7-fold (95% CI, 3.0–4.6) increased risk of amputation; peripheral artery disease alone conferred a 13.9-fold (95% CI, 11.3–17.1) elevated risk of amputation; and the combination of peripheral artery disease and microvascular disease was associated with a 22.7-fold (95% CI, 18.3–28.1) increased risk of amputation.
CONCLUSIONS:Independent of traditional risk factors, the presence of microvascular disease increases the risk of amputation alone and synergistically increases risk in patients with peripheral artery disease. Further research is needed to understand the mechanisms by which this occurs.
Peripheral artery disease-atherosclerosis of the abdominal aorta and lower extremity vascular bed-is a complex disease with both environmental and genetic determinants. Unmitigated disease is ...associated with major functional decline and can lead to chronic limb-threatening ischemia, amputation, and increased mortality. Over the last 10 years, major advances have been made in identifying the genetic basis of this common, complex disease. In this review, we provide an overview of the primary types of genetic analyses performed for peripheral artery disease, including heritability and linkage studies, and more recently biobank-based genome-wide association studies. Looking forward, we highlight areas of future study including efforts to identify causal peripheral artery disease genes, rare variant and structural variant analyses using whole-exome and whole-genome sequencing data, and the need to include individuals of diverse genetic ancestries.
Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative ...contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk.
Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies.
ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86;
=0.003) and CAD (marginal inclusion probability, 0.92;
=0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB 95% CI, 0.84-0.91;
=9×10
) and CAD (odds ratio,0.66 95% CI, 0.63-0.69;
=4×10
), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 95% CI, 2.29-4.60;
<1×10
). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91;
=2.3×10
), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95;
=0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 95% CI, 1.03-1.04;
=1.0×10
).
ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.
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