Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses

Malik, Rainer; Georgakis, Marios K.; Vujkovic, Marijana; Damrauer, Scott M.; Elliott, Paul; Karhunen, Ville; Giontella, Alice; Fava, Cristiano; Hellwege, Jacklyn N.; Shuey, Megan M.; Edwards, Todd L.; Rogne, Tormod; Åsvold, Bjørn Olav; Brumpton, Ben; Burgess, Stephen; Dichgans, Martin; Gill, Dipender

doi:10.1161/hypertensionaha.120.16534

Cited by 74 publications

(63 citation statements)

References 46 publications

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“…To further assess the shape of the association, we performed a non-linear Mendelian randomization with the fractional polynomial method 94,95 in HUNT, using the same GRS as genetic instrument for the iron traits. The method has been described in detail elsewhere [95][96][97][98] .…”

Section: Mendelian Randomization Of Iron Status On All-cause Mortalitymentioning

confidence: 99%

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Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT

Moksnes

Hansen

Graham

et al. 2021

Preprint

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Iron is essential for many biological processes, but iron levels must be tightly regulated to avoid harmful effects of both iron deficiency and overload. Here, we perform genome-wide association studies on four iron related biomarkers (serum iron, serum ferritin, transferrin saturation, total iron binding capacity) in the Trøndelag Health Study (HUNT), the Michigan Genomics Initiative (MGI) and the SardiNIA study, followed by their meta-analysis with publicly available summary statistics, analyzing up to 257 953 individuals. We identify 127 genetic loci associated with iron traits. Among 19 novel protein-altering variants, we observe a rare missense variant (rs367731784) in HUNT, which suggests a role for DNAJC13 in transferrin recycling. We further validate the latest genetic risk scores for each biomarker in HUNT (6% variance in serum iron explained) and present linear and non-linear Mendelian randomization analyses of the traits on all-cause mortality. We find evidence of a harmful effect of increased serum iron and transferrin saturation in linear analyses that estimate population-averaged effects. However, there was weak evidence of a protective effect of increasing serum iron at the very low end of its distribution. Our findings contribute to our understanding of the genes affecting iron status and its consequences on human health.

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Section: Mendelian Randomization Of Iron Status On All-cause Mortalitymentioning

confidence: 99%

“…The copyright holder for this this version posted September 23, 2021. ; https://doi.org/10.1101/2021.09.20.21262960 doi: medRxiv preprint 21 genetic instrument for the iron traits. The method has been described in detail elsewhere [95][96][97][98] .…”

Section: Mendelian Randomization Of Iron Status On All-cause Mortalitymentioning

confidence: 99%

Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT

Moksnes

Hansen

Graham

et al. 2021

Preprint

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“…In 2021, two studies using linear and nonlinear MR techniques further explored the association between diastolic BP and CVD events. 42 , 43 The first of these studies was performed on five large population cohorts to more definitively establish the causal direction and shape of the relationship between diastolic BP and CVD, particularly MI. 42 The second MR analysis was performed using MR methods within the comprehensive UK Biobank resource to study genetically proxied systolic and diastolic BP with incident CVD.…”

Section: Mendelian Randomization As a Strategy To Evaluate Causalitymentioning

confidence: 99%

The Diastolic Blood Pressure J-Curve in Hypertension Management: Links and Risk for Cardiovascular Disease

Gaffney¹,

Jacobsen²,

Pallippattu³

et al. 2021

IBPC

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Purpose of Review The treatment of hypertension has changed dramatically over the last century, with recent trials informing clinical guidelines that recommend aiming for lower blood pressure (BP) targets than ever before. However, a “J”- or “U-shaped curve” in the association between diastolic BP and cardiovascular events has been observed in epidemiological studies, suggesting that both high diastolic BPs and diastolic BPs below a certain nadir are associated with higher risk of cardiovascular disease (CVD) events. Despite the potential for confounding and reverse causation, this association may caution against overly intensive BP lowering in some hypertensive adults who also have a low baseline diastolic BP. Recent Findings Recent post-hoc analyses of the landmark Systolic Blood Pressure Intervention Trial (SPRINT) appear to contradict these J-curve concerns, finding that the benefit of more intensive BP treatment did not differ based on baseline blood pressure. Similarly, sensitivity analyses of The Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) randomized controlled trial found that patients experienced similar benefits from an intensive BP goal, regardless of whether their diastolic BP was above or below 60 mm Hg. Finally, several Mendelian randomization analyses, which are less susceptible to confounding and reverse causation, demonstrated a clear linear relationship between diastolic BP and cardiovascular events. These studies indicate that a potential reduction in CVD risk is possible, irrespective of baseline diastolic BP values. Summary Sufficient recent evidence indicates that low diastolic BP is not causal of worse cardiovascular outcomes but rather represents confounding or reverse causation. Therefore, while low diastolic BP can be considered a marker of CVD risk, this risk is not expected to increase with further BP lowering when necessary to control concomitant elevations of systolic BP. Indeed, BP reduction in this setting appears beneficial.

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“…This variable is defined similarly to the residual collider, except the collider variable is the risk factor itself. This method has been used previously to estimate the causal effect of blood pressure on coronary heart disease risk within strata of blood pressure, resulting in a curve that represents the shape of the causal relationship between the risk factor and the outcome [22]. This paper extends on that method, showing that the same idea can be used to provide causal estimates stratified on a separate variable even if that variable is a collider.…”

Section: Discussionmentioning

confidence: 92%

Avoiding bias in Mendelian randomization when stratifying on a collider

Coscia

Benítez

Pérez

et al. 2021

Preprint

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Background: Mendelian randomization (MR) uses genetic variants as instrumental variables to investigate the causal effect of a risk factor on an outcome. A collider is a variable influenced by two or more other variables. Naive calculation of MR estimates in strata of the population defined by a variable affected by the risk factor can result in collider bias. Methods: We propose an approach that allows MR estimation in strata of the population while avoiding collider bias. This approach constructs a new variable, the residual collider, as the residual from regression of the collider on the genetic instrument, and then calculates causal estimates in strata defined by quantiles of the residual collider. Estimates stratified on the residual collider will typically have an equivalent interpretation to estimates stratified on the collider, but they are not subject to collider bias. We apply the approach in several simulation scenarios considering different characteristics of the collider variable and strengths of the instrument. We then apply the proposed approach to investigate the causal effect of smoking on bladder cancer in strata of the population defined by bodyweight. Results: The new approach generated unbiased estimates in all the simulation settings. In the applied example, we observed a trend in the stratum-specific MR estimates at different bodyweight levels that suggested stronger effects of smoking on bladder cancer among individuals with lower bodyweight. Conclusions: The proposed approach can be used to perform MR studying heterogeneity among subgroups of the population while avoiding collider bias.

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Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses

Cited by 74 publications

References 46 publications

Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT

Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT

The Diastolic Blood Pressure J-Curve in Hypertension Management: Links and Risk for Cardiovascular Disease

Avoiding bias in Mendelian randomization when stratifying on a collider

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